A rare earth artemisinin derivative organic salt, a preparation method and application thereof

Abstract

This invention relates to the field of medical antibacterial technology, and in particular to a rare-earth artemisinin derivative organic salt, its preparation method, and its application, with the general formula [Art-COO]. n RE n+ In the formula, Art represents an artemisinin derivative, RE represents a rare earth ion, and n represents the valence of the rare earth ion; artemisinin derivatives include artesunate, and rare earth ions include La... 3+ Ce 3+ One of them. This invention utilizes the above-mentioned rare-earth artemisinin derivative organic salt, its preparation method, and its application. The obtained organic salt retains the peroxide bridge structure of artesunate, while the carboxylate group (-COO) is present. ‑ The stable existence of coordination bonds between rare earth ions and artesunate allows rare earth ions to synergistically enhance the antibacterial effect, significantly reducing the minimum inhibitory concentration against a variety of pathogens, and thus having important application value in the field of medical anti-infection.

Description

Technical Field

[0001] This invention relates to the field of medical antibacterial technology, and in particular to a rare earth artemisinin derivative organic salt, its preparation method, and its application. Background Technology

[0002] Artemisinin is a natural compound with significant antibacterial and antimalarial activity, but its poor water solubility and stability limit its applications. Artesunate, a water-soluble derivative of artemisinin, plays an important role in antimalarial treatment. However, its performance is limited in broader applications such as antibacterial and preservative applications. For example, in the field of medical anti-infectives, bacterial and fungal resistance is becoming increasingly serious, challenging the efficacy of traditional antibacterial drugs. Although artesunate has some antibacterial activity, its effect is limited when used alone, failing to meet the clinical demand for highly effective antibacterial drugs. In the field of food preservation, consumers are increasingly concerned about food safety, and traditional preservatives such as benzoic acid and potassium sorbate pose certain safety risks, making the development of safe and efficient new food preservatives urgent.

[0003] Rare earth elements possess unique electronic structures and chemical properties, demonstrating immense application potential in materials science, biomedicine, and other fields. Combining rare earth elements with artesunate holds promise for enhancing the antibacterial properties and improving the stability of artesunate by leveraging the characteristics of rare earth elements, thus providing new solutions for medical anti-infection and food preservation. Currently, research on rare earth artesunate organic salts is still in the exploratory stage, with limited reports on related preparation methods and applications, and a mature technological system has not yet been established. Summary of the Invention

[0004] The purpose of this invention is to provide a rare earth artemisinin derivative organic salt, its preparation method, and its application. The prepared organic salt retains the peroxy-bridge structure of artesunate, while the coordination bond between the carboxylate group (-COO-) and the rare earth ion is stably present. This allows the rare earth ion and artesunate to synergistically enhance the antibacterial effect, significantly reducing the minimum inhibitory concentration against various pathogens. It has important application value in the field of medical anti-infection.

[0005] To achieve the above objectives, this invention provides a rare-earth artemisinin derivative organic salt with the general formula [Art-COO]. n RE n+ In the formula, Art is an artemisinin derivative, RE is a rare earth ion, and n is the valence of the rare earth ion.

[0006] Artemisinin derivatives include artesunate, and rare earth ions include La3+. + Ce3 + One of them.

[0007] The core structure of the rare earth artemisinin derivative organic salt of the present invention is that the carboxylic acid group (-COO-) of artesunate is tightly linked to the rare earth ions through a coordinate bond, and the original peroxy bridge structure of artesunate is completely preserved, giving it good antibacterial activity; at the same time, a stable coordinate bond is formed between the carboxylic acid group (-COO-) and the rare earth ions, so that the rare earth ions work synergistically with the peroxy bridge to promote electron transfer, enhance oxidative stress response, and more effectively kill bacteria and fungi.

[0008] This invention also provides a method for preparing the above-mentioned rare earth artemisinin derivative organic salt, comprising the following steps:

[0009] S1. Dissolve artesunate in a solvent, then adjust the pH with an alkaline solution to deprotonate the carboxylic acid group of artesunate, thus obtaining an artesunate solution.

[0010] S2. Dissolve rare earth salts in water to obtain a rare earth salt solution. Under constant temperature water bath conditions, add the rare earth salt solution dropwise to the artesunate solution in S1. React under constant temperature stirring conditions to obtain a reaction solution.

[0011] The reaction formula is: 3Artesunate-COO - +RE 3+ →[Artesunate-COO]3RE;

[0012] S3. The reaction solution obtained in S2 was concentrated under reduced pressure, cooled, washed with cold ethanol, and dried under vacuum to constant weight to obtain rare earth artemisinin derivative organic salt.

[0013] Preferably, in S1, the molar volume ratio of artesunate to solvent is 1 mmol: 40-60 mL, and the solvent is a mixed solvent of ethanol and water, with a volume ratio of ethanol to water of 1-2: 2-1.

[0014] More preferably, the molar volume ratio of artesunate to solvent is 1 mmol: 50 mL, and the solvent is a mixture of ethanol and water with a volume ratio of ethanol to water of 1:1.

[0015] Preferably, in S1, the alkaline solution is a NaOH solution with a concentration of 0.1-1.0 mol / L and a pH of 7-8.

[0016] Preferably, the concentration of the NaOH solution is 0.1 mol / L.

[0017] This invention controls the pH value within the above range to ensure that the carboxylic acid group (-COOH) of artesunate is completely deprotonated to -COO. -To prepare for subsequent coordination reactions, when the pH value is below 7, the deprotonation of the carboxylic acid group is incomplete, resulting in more -COOH residues, which will reduce the number of -COO- participating in the coordination reaction and reduce the yield of the coordination reaction; when the pH value is above 8, the solution is too alkaline, which will cause rare earth ions to form hydroxide precipitates, affecting the formation of organic salts.

[0018] Preferably, in S2, the rare earth salt is one of cerium nitrate and lanthanum chloride, and the molar ratio of the rare earth salt to artesunate is 0.33:1.

[0019] Preferably, in S2, the temperature of the constant temperature water bath is 40-80℃, the temperature of the constant temperature stirring is 50-70℃, and the speed of the constant temperature stirring is 200-600 r / min.

[0020] In an even more preferred embodiment, in S2, the temperature of the constant temperature water bath is 60℃, the temperature of the constant temperature stirring is 60℃, and the speed of the constant temperature stirring is 300r / min.

[0021] Preferably, in S2, the addition rate is 1-2 drops per second, and the reaction time is 2-4 hours.

[0022] The next optimal reaction time is 3 hours.

[0023] Preferably, in S3, the vacuum degree of vacuum drying is 0.02-0.08 MPa and the temperature is 30-50℃.

[0024] Even more preferably, the vacuum degree is 0.05MPa and the temperature is 45℃.

[0025] This invention also provides the application of the above-mentioned rare earth artemisinin derivative organic salt.

[0026] Preferably, rare earth artemisinin derivative organic salts are used in the preparation of topical sprays or gels for treating fungal skin infections.

[0027] Preferably, the mass fraction of rare earth artemisinin derivative organic salt in the topical spray or gel is 1%.

[0028] Preferably, rare earth artemisinin derivative organic salts are used in the preparation of injectables for treating systemic infectious diseases.

[0029] Preferably, the concentration of rare earth artemisinin derivative organic salt in the injection is 10 mg / mL.

[0030] Preferably, rare earth artemisinin derivative organic salts are used in food and beverage preservation.

[0031] Even more preferably, the amount of rare earth artemisinin derivative organic salt added to the beverage is ≤0.05% w / w.

[0032] Preferably, rare earth artemisinin derivative organic salts are used in the preparation of antibacterial packaging films for food.

[0033] Even more preferably, the content of rare earth artemisinin derivative organic salt in the antibacterial packaging film is 1-3%.

[0034] Mechanism of the invention:

[0035] The -COO- group generated by the complete deprotonation of the carboxylic acid group of artesunate in this invention carries a negative charge and can react with rare earth ions (such as Ce3). + La3 + (etc.) are combined through coordination bonds to form stable rare earth artesunate organic salts.

[0036] This invention provides a rare earth artemisinin derivative organic salt, its preparation method, and its application, with the following beneficial effects:

[0037] (1) The peroxy bridge structure of artesunate has a certain oxidizing ability, which can destroy the cell membranes and biomolecules of bacteria and fungi, and inhibit their growth and reproduction. Rare earth ions have unique redox activity. When working synergistically with the peroxy bridge, they can promote electron transfer, enhance oxidative stress response, and more effectively kill bacteria and fungi. The minimum inhibitory concentration for a variety of pathogens is significantly reduced, which has important application value in the field of medical anti-infection and can effectively treat diseases such as drug-resistant bacterial infections.

[0038] (2) The stable structure formed by rare earth ions and artesunate can effectively block the damage of external environmental factors to artesunate, reduce the degradation of artesunate under light or high temperature, extend the product shelf life, and improve the convenience of storage and use. It can ensure the stability of product quality in both the pharmaceutical and food fields.

[0039] (3) Artesunate can coordinate with rare earth elements without modification. The reaction conditions are mild, the operation steps are simple, and the raw materials are common and readily available, making it suitable for large-scale industrial production and reducing production costs.

[0040] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0041] Figure 1 This is the infrared spectrum of the cerium-artesinyl succinate organic salt obtained in Example 2 of this invention;

[0042] Figure 2 This is a schematic diagram illustrating the antibacterial properties of the antibacterial packaging film in Example 4 of the present invention. Figure 2 (a) in the diagram is an illustration of E. coli without the antimicrobial packaging film. Figure 2 (b) is a schematic diagram of E. coli covered with an antibacterial packaging film containing 1% organic salts. Figure 2(c) in the diagram is an illustration of E. coli covered with an antibacterial packaging film containing 3% organic salts. Figure 2 (d) in the diagram is a schematic of Staphylococcus aureus without an antibacterial packaging film. Figure 2 (e) in the diagram is a schematic of Staphylococcus aureus covered with an antibacterial packaging film containing 1% organic salts. Figure 2 (f) in the diagram is a schematic diagram of Staphylococcus aureus covered with an antibacterial packaging film containing 3% organic salts. Detailed Implementation

[0043] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0044] Example 1

[0045] This invention provides a rare earth artemisinin derivative organic salt, the preparation method of which includes the following steps:

[0046] S1. Dissolve 1 mmol of artesunate in 40 mL of a mixed solvent of ethanol and water (volume ratio of ethanol to water is 1:2), and then adjust the pH to 7.5 with 0.1 mol / L NaOH solution to deprotonate the carboxylic acid group of artesunate, thus obtaining an artesunate solution.

[0047] S2. Dissolve 0.33 mmol Ce(NO3)3·6H2O in 50 mL of water to obtain a rare earth salt solution. Under constant temperature water bath conditions of 40℃, add the rare earth salt solution dropwise to the artesunate solution of S1 at a rate of 1-2 drops per second. Under constant temperature conditions of 60℃, stir the reaction at a rate of 200 r / min for 4 h to obtain the reaction solution.

[0048] S3. The reaction solution obtained in S2 was concentrated under reduced pressure, cooled to room temperature, and washed three times with 20 mL of cold ethanol (0-5℃). The solid was then placed in a vacuum drying oven and dried to constant weight under a vacuum of 0.02 MPa and a temperature of 30℃ to obtain cerium-artesunate organic salt with a yield of 80%.

[0049] Example 2

[0050] This invention provides a rare earth artemisinin derivative organic salt, the preparation method of which includes the following steps:

[0051] S1. Dissolve 1 mmol of artesunate in 50 mL of a mixed solvent of ethanol and water (ethanol to water volume ratio of 1:1), and then adjust the pH to 7.5 with a 0.1 mol / L NaOH solution to deprotonate the carboxylic acid group of artesunate, thus obtaining an artesunate solution.

[0052] S2. Dissolve 0.33 mmol Ce(NO3)3·6H2O in 50 mL of water to obtain a rare earth salt solution. Under constant temperature water bath conditions of 60℃, add the rare earth salt solution dropwise to the artesunate solution of S1 at a rate of 1-2 drops per second. Under constant temperature conditions of 60℃, stir the reaction at a rate of 300 r / min for 3 h to obtain the reaction solution.

[0053] S3. The reaction solution obtained in S2 was concentrated under reduced pressure, cooled to room temperature, and washed three times with 20 mL of cold ethanol (0-5℃). The solid was then placed in a vacuum drying oven and dried to constant weight under a vacuum of 0.05 MPa and a temperature of 35℃ to obtain cerium-artesunate organic salt with a yield of 86%.

[0054] Example 3

[0055] This invention provides a rare earth artemisinin derivative organic salt, the preparation method of which includes the following steps:

[0056] S1. Dissolve 1 mmol of artesunate in 50 mL of a mixed solvent of ethanol and water (ethanol to water volume ratio of 2:1), and then adjust the pH to 7 with a 1.0 mol / L NaOH solution to deprotonate the carboxylic acid group of artesunate, thus obtaining an artesunate solution.

[0057] S2. Dissolve 0.33 mmol of rare earth salt Ce(NO3)3·6H2O in 50 mL of water to obtain a rare earth salt solution. Under constant temperature water bath conditions of 80℃, add the rare earth salt solution dropwise to the artesunate solution of S1 at a rate of 1-2 drops per second. Under constant temperature conditions of 60℃, stir the reaction at a rate of 600 r / min for 2 h to obtain the reaction solution.

[0058] S3. The reaction solution obtained in S2 was concentrated under reduced pressure, cooled to room temperature, and washed three times with 20 mL of cold ethanol (0-5℃). The solid was then placed in a vacuum drying oven and dried to constant weight under a vacuum of 0.08 MPa and a temperature of 50℃ to obtain cerium-artesunate organic salt with a yield of 83%.

[0059] Example 4

[0060] This invention provides a rare earth artemisinin derivative organic salt, the preparation method of which includes the following steps:

[0061] S1. Dissolve 1 mmol of artesunate in 50 mL of a mixed solvent of ethanol and water (ethanol to water volume ratio of 1:1), and then adjust the pH to 7.5 with a 0.1 mol / L NaOH solution to deprotonate the carboxylic acid group of artesunate, thus obtaining an artesunate solution.

[0062] S2. Dissolve 0.33 mmol LaCl3·7H2O in 50 mL of water to obtain a rare earth salt solution. Under constant temperature water bath conditions of 60℃, add the rare earth salt solution dropwise to the artesunate solution of S1 at a rate of 1-2 drops per second. Under constant temperature conditions of 60℃, stir the reaction at a rate of 300 r / min for 3 h to obtain the reaction solution.

[0063] S3. The reaction solution obtained in S2 was concentrated under reduced pressure, cooled to room temperature, and washed three times with 20 mL of cold ethanol (0-5℃). The solid was then placed in a vacuum drying oven and dried to constant weight under a vacuum of 0.05 MPa and a temperature of 35℃ to obtain lanthanum-artesunate organic salt with a yield of 85%.

[0064] Comparative Example 1

[0065] The difference from Example 4 is that in S2, after the rare earth salt solution was added dropwise to the artesunate solution in S1, the reaction was carried out at a constant temperature of 50°C and stirred at a speed of 300 r / min for 3 h to obtain the reaction solution. The rest was the same as in Example 4, yielding lanthanum-artesunate organic salt.

[0066] At 50°C, the reaction process was significantly hindered and failed to proceed fully, resulting in a product yield of only 15%. This is because the relatively low temperature resulted in insufficient molecular activity, causing a slow reaction rate between the carboxylic acid group of artesunate and the lanthanum ion, making it impossible to reach a high degree of reaction within the specified time.

[0067] Comparative Example 2

[0068] The difference from Example 4 is that in S2, after the rare earth salt solution was added dropwise to the artesunate solution in S1, the reaction was carried out at a constant temperature of 70°C and stirred at a speed of 300 r / min for 3 h to obtain the reaction solution. The rest was the same as in Example 4, and lanthanum-artesunate organic salt was obtained.

[0069] When the temperature rises to 70℃, some artesunate decomposes, causing the yield to drop to 75%. This is because the excessively high temperature damages the molecular structure of artesunate, especially the peroxy bridge structure, making it unable to react stably with rare earth salts, thus reducing the amount of product generated.

[0070] Characterization experiment

[0071] The FT-IR test of the cerium-artesunate organic salt prepared in Example 2 was performed using the KBr pellet method, and the results are as follows: Figure 1 As shown, it is located at ~1600cm - The characteristic absorption peak at 1 corresponds to the chemical bond vibration formed by the coordination of carboxylate (COO-) with lanthanum or cerium ions. Simultaneously, the peak at ~1753 cm⁻¹ corresponds to the same vibration. - The characteristic absorption peak at position 1 corresponds to the absorption peak of the carbonyl group of artesunate. Therefore, it can be concluded that the present invention has successfully prepared cerium-artesunate organic salt.

[0072] Antibacterial performance test

[0073] Using the standard liquid-based dilution method, the minimum inhibitory concentrations (MICs) of artesunate alone and artesunate organic salts of cerium and lanthanum from Examples 1 and 4 were tested against three common pathogens: Staphylococcus aureus, Escherichia coli, and Candida albicans. The results are shown in Table 1.

[0074] Table 1. Minimum Inhibitory Concentration (MIC)

[0075]

[0076] Table 1 shows that the minimum inhibitory concentrations (MICs) of cerium-artesunate and lanthanum-artesunate organic salts for Staphylococcus aureus, Escherichia coli, and Candida albicans were significantly lower than those of artesunate. Taking Staphylococcus aureus as an example, the MIC of artesunate was 20 μg / mL, while that of cerium-artesunate decreased to 5 μg / mL, and that of lanthanum-artesunate was 8 μg / mL. This indicates that the antibacterial activity is significantly enhanced after rare earth ions (cerium and lanthanum) form organic salts with artesunate. This is because the electronic structure of rare earth ions synergistically interacts with the peroxy bridge and carboxylic acid group of artesunate, enhancing their ability to damage bacterial and fungal cell membranes and biomolecules, interfering with the normal physiological metabolism of microorganisms, and thus more effectively inhibiting their growth and reproduction.

[0077] Regarding the inhibitory effects on the same bacterial species, the MIC values ​​of artesunate-cerium organic salt and artesunate-lanthanum organic salt were similar, but the inhibitory effect of artesunate-cerium organic salt on all three bacterial species was slightly better than that of artesunate-lanthanum organic salt. This may be due to the subtle differences in the electronic configurations of cerium and lanthanum ions, resulting in different spatial structures and electron cloud distributions after coordination with artesunate, thus affecting the interaction between the organic salt and microorganisms.

[0078] Stability test

[0079] The high-temperature stability and light stability of artesunate and the cerium and lanthanum artesunate organic salts used in Examples 1 and 4 were tested at 60°C. The results are shown in Table 2.

[0080] Table 2 Stability Test Results

[0081]

[0082] Table 2 shows that under high-temperature conditions of 60℃ for 48 hours, the decomposition rate of artesunate reached as high as 40%, while the decomposition rate of cerium-artesunate organic salt was 12%, and that of lanthanum-artesunate organic salt was 13%. This indicates that after rare earth ions coordinate with artesunate, a more stable structure is formed, effectively preventing the high temperature from damaging artesunate. This may be because the coordination of rare earth ions with the carboxylic acid groups of artesunate enhances the intramolecular interaction, improves the thermal stability of the molecule, and reduces the decomposition of active structures such as peroxy bridges at high temperatures.

[0083] Light stability: After 24 hours of simulated sunlight exposure, the decomposition rate of artesunate was 30%, that of cerium-artesunate organic salt was 8%, and that of lanthanum-artesunate organic salt was 9%. This also indicates that rare earth artesunate organic salts are more stable under light conditions. The presence of rare earth ions may have altered the electron cloud distribution of the artesunate molecule, reducing its sensitivity to light and decreasing photo-induced oxidative decomposition reactions, thereby extending the product's shelf life under light exposure.

[0084] Application Example 1

[0085] The cerium-artesinol organic salt prepared in Example 1 was used in a topical spray for treating fungal skin infections.

[0086] Preparation method: Weigh 1g of the cerium-artesunate organic salt prepared in Example 1, add 99g of a suitable spray matrix (such as ethanol, deionized water, and moisturizer mixed in a volume ratio of 4:5:1), stir thoroughly to completely dissolve the cerium-artesunate organic salt, and fill into a spray bottle to obtain a 1% mass fraction topical spray for treating fungal skin infections.

[0087] Efficacy Test: Fifty volunteers suffering from fungal skin infections (such as tinea corporis and tinea cruris) were randomly divided into two groups. The experimental group (n=25) used the topical spray prepared in Example 1 of this invention, applying it to the infected area 2-3 times daily. The control group (n=25) used a commercially available common antifungal topical spray, using the same method. The efficacy was observed after two weeks of treatment. The results showed that the effective cure rate (significant symptom reduction or disappearance) of Example 1 of this invention reached 76%, while the effective cure rate of the control group was 52%. This indicates that the topical spray prepared from the rare earth artemisinin derivative organic salt of this invention has a good therapeutic effect on fungal skin infections.

[0088] Application Example 2

[0089] The lanthanum-artesunate organic salt obtained in Example 4 was used in the preparation of an injectable agent for treating systemic infectious diseases.

[0090] Preparation method: Accurately weigh 100 mg of the lanthanum-artesunate organic salt prepared in Example 4, dissolve it in sterile water for injection and make up to 10 mL, prepare an injection with a concentration of 10 mg / mL, filter it aseptically and seal it in an ampoule.

[0091] Preliminary safety test: Twenty healthy experimental rats were randomly divided into two groups of 10 each. The experimental group rats were injected via tail vein with the injectable preparation described in Example 2 at a dose of 1 mL / kg body weight; the control group rats were injected with an equal volume of physiological saline. The rats were observed for 7 consecutive days after injection, and their behavior, diet, and weight changes were recorded.

[0092] The results showed that the experimental group rats did not exhibit any obvious adverse reactions such as abnormal behavior, reduced food intake, or weight loss after injection, indicating that the injection had good safety in the preliminary test.

[0093] Preliminary efficacy test: A mouse model of systemic infectious disease (such as Staphylococcus aureus sepsis) was established. Thirty infected mice were randomly divided into three groups of 10 mice each. Mice in experimental group 1 were injected via tail vein with the injectable preparation (Example 2) at a dose of 1 mL / kg body weight; mice in experimental group 2 were injected with an equal volume of artesunate solution (concentration identical to the artesunate content in the injectable preparation); and mice in the control group were injected with an equal volume of physiological saline. Survival was observed after 5 consecutive days of administration.

[0094] The results showed that the survival rate of mice in experimental group 1 was 70%, the survival rate of mice in experimental group 2 was 40%, and the survival rate of mice in the control group was 20%. This indicates that the injection prepared from the rare earth artemisinin derivative organic salt of the present invention has certain effectiveness in treating systemic infectious diseases, and its effect is better than that of artesunate alone.

[0095] Application Example 3

[0096] The cerium-artesunate organic salt prepared in Example 2 was applied to food and beverage preservation. The cerium-artesunate organic salt was directly added to apple juice as a preservative.

[0097] Fresh apple juice was selected, and different amounts (0.01% w / w, 0.03% w / w, 0.05% w / w) of the cerium-artesunate organic salt prepared in Example 2 were added as preservatives.

[0098] Apple juice without any preservatives was used as a blank control group, with three replicates in each group. The apple juice was sealed and stored at room temperature. The appearance (whether it became cloudy or separated into layers), odor (whether there was any off-odor) of the apple juice were observed regularly, and microbial indicators (total bacterial count, mold and yeast count) were tested.

[0099] Experimental results: After one week of storage, the apple juice in the blank control group became slightly cloudy, had an off-odor, and showed a significant increase in total bacterial count and mold and yeast count; the apple juice with 0.01% w / w cerium-artesunate organic salt had normal appearance and odor, and the microbial indicators increased slowly; the apple juice with 0.03% w / w and 0.05% w / w cerium-artesunate organic salt maintained good appearance and odor after two weeks of storage, and the microbial indicators remained at a low level.

[0100] This indicates that the rare earth artemisinin derivative organic salt of the present invention has a certain effect on food and beverage preservation, and can effectively inhibit microbial growth and extend the shelf life of food and beverage when the addition amount is ≤0.05% w / w.

[0101] Application Example 4

[0102] The cerium-artesin succinate organic salt obtained in Example 3 was used in the preparation of antibacterial packaging film for food.

[0103] Preparation method: The cerium-artemisinin organic salt obtained in Example 3 was added to edible packaging film materials (such as polyvinyl alcohol, chitosan and other mixed materials) at contents of 1% and 3% respectively, and food antibacterial packaging film was prepared by casting method.

[0104] Antimicrobial performance test: *Escherichia coli* and *Staphylococcus aureus* were evenly coated onto sterile filter paper, then covered with the antimicrobial packaging film prepared in Application Example 4 of this paper, and incubated in a suitable environment for a certain period of time. The antimicrobial performance of the packaging film was evaluated by observing the bacterial growth on the filter paper. The results are shown in [Figure 4]. Figure 2 .

[0105] like Figure 2 As shown, packaging films containing 1% and 3% cerium-artesinyl succinate organic salt exhibit significant inhibitory effects on both Escherichia coli and Staphylococcus aureus, with the inhibitory effect increasing with increasing organic salt content. This indicates that the rare-earth artemisinin derivative organic salt of the present invention has excellent antibacterial properties when applied to food antibacterial packaging films, effectively inhibiting the growth and reproduction of bacteria within food packaging and ensuring food quality and safety.

[0106] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A rare earth artemisinin derivative organic salt, characterized in that: The general formula is [Art-COO] - ] n RE n+ In the formula, RE represents rare earth ions, and n represents the valence of rare earth ions; the [Art-COO] - [] is the carboxylic acid anion of artesunate, and the rare earth ion is either La or Ce, with n being 3.

2. A method for preparing a rare earth artemisinin derivative organic salt as described in claim 1, characterized in that, Includes the following steps: S1. Dissolve artesunate in a solvent, then adjust the pH with an alkaline solution to deprotonate the carboxylic acid group of artesunate, thus obtaining an artesunate solution. S2. Dissolve rare earth salts in water to obtain a rare earth salt solution. Under constant temperature water bath conditions, add the rare earth salt solution dropwise to the artesunate solution in S1. React under constant temperature stirring conditions to obtain a reaction solution. S3. The reaction solution obtained in S2 was concentrated under reduced pressure, cooled, washed with cold ethanol, and dried under vacuum to constant weight to obtain rare earth artemisinin derivative organic salt. In S2, the temperature of the constant temperature water bath is 40-80℃, the temperature of the constant temperature stirring is 50-70℃, and the speed of the constant temperature stirring is 200-600r / min.

3. The method for preparing rare earth artemisinin derivative organic salts according to claim 2, characterized in that: In S1, the molar volume ratio of artesunate to solvent is 1 mmol: 40-60 mL, and the solvent is a mixture of ethanol and water with a volume ratio of ethanol to water of 1-2: 2-1.

4. The method for preparing rare earth artemisinin derivative organic salts according to claim 2, characterized in that: In S1, the alkaline solution is a NaOH solution with a concentration of 0.1-1.0 mol / L and a pH of 7-8.

5. The method for preparing rare earth artemisinin derivative organic salts according to claim 2, characterized in that: In S2, the rare earth salt is one of cerium nitrate and lanthanum chloride, and the molar ratio of the rare earth salt to artesunate is 0.33:

1.

6. The method for preparing rare earth artemisinin derivative organic salts according to claim 2, characterized in that: In S2, the addition rate is 1-2 drops per second, and the reaction time is 2-4 hours.

7. The method for preparing rare earth artemisinin derivative organic salts according to claim 2, characterized in that: In S3, the vacuum degree of vacuum drying is 0.02-0.08 MPa and the temperature is 30-50℃.

8. The application of a rare earth artemisinin derivative organic salt as described in claim 1, characterized in that: It is used in the preparation of topical sprays or gels for treating fungal skin infections.

9. The application of the rare earth artemisinin derivative organic salt according to claim 8, characterized in that: The mass fraction of rare earth artemisinin derivative organic salts in topical sprays or gels is 1%.

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