Pesticide composite drug-loading system and preparation and application thereof

Abstract

The present application provides a kind of pesticide composite drug delivery system and its preparation and application, the pesticide composite drug delivery system includes pesticide, MOF-NH2 and nano calcium carbonate, the pesticide is respectively loaded on MOF-NH2 and nano calcium carbonate, and the nano calcium carbonate of loading pesticide is covered outside the MOF-NH2 of loading pesticide.The pesticide composite drug delivery system of the present application overcomes the problem that the MOF-NH2 drug delivery system of loading pesticide in the prior art occurs easily in the process of application in acidic or high salinity environment Skeleton collapse, affect its drug loading performance and pesticide slow-release effect problem.The composite drug delivery system containing pesticide of the present application has good application and popularization prospect.

Description

Technical Field

[0001] This invention relates to the field of pesticide formulation technology, and in particular to a pesticide composite loading system and its preparation and application. Background Technology

[0002] With the continuous development of functional materials, slow-release technology, and processing techniques, controlled-release technology has become a hot topic in pesticide formulation research. Controlled-release technology can precisely regulate the spatiotemporal release behavior of pesticides according to the needs of pest control, achieving the control requirements of the entire crop growth period with a single root and soil application, thereby avoiding multiple application operations.

[0003] In recent years, metal-organic frameworks (MOFs) have been widely used in the field of pesticide carriers due to their unique structural and functional advantages. The applicant previously reported in CN114437365A a nanoparticle drug-loaded particle framework material, MOF-NH2, that can meet the loading requirements of different pesticides. However, further research revealed that this framework material still faces challenges such as limited stability in field applications. For example, it is prone to framework collapse in acidic or high-salinity environments, affecting its drug-loading performance.

[0004] Researching better pesticide delivery systems to improve pesticide application efficiency is an important research topic in this field. Summary of the Invention

[0005] To address the shortcomings of existing pesticide nanoparticle framework materials like MOF-NH2, which are prone to framework collapse in acidic environments, thus affecting their pesticide loading performance, this invention provides a composite pesticide loading system of MOF-NH2 and nano-calcium carbonate. To achieve the above objective, this invention involves covering the original pesticide-loaded MOF-NH2 system with a pesticide-loaded nano-calcium carbonate system.

[0006] Specifically, the present invention adopts the following technical solution:

[0007] A pesticide-containing composite drug-loaded system includes a pesticide, MOF-NH2, and nano-calcium carbonate, wherein the pesticide is loaded onto MOF-NH2 and nano-calcium carbonate respectively, and the pesticide-loaded nano-calcium carbonate covers the outside of the pesticide-loaded MOF-NH2.

[0008] The present invention also provides a method for preparing a composite drug delivery system of MOF-NH2 and nano-calcium carbonate.

[0009] Beneficial effects

[0010] 1. The MOF-NH2 and nano-calcium carbonate composite drug delivery system of the present invention overcomes the challenges faced by the MOF-NH2 drug delivery system in field applications, such as the limited stability, which is prone to skeleton collapse in acidic environments, affecting its drug delivery performance.

[0011] 2. The sustained-release effect of the MOF-NH2 and nano-calcium carbonate composite drug delivery system of the present invention is significantly better than that of the MOF-NH2 drug delivery system in the prior art. Attached Figure Description

[0012] Figure 1 Schematic diagram of the drug delivery system structure of fludioxonil@MOF-NH2@CA.

[0013] Figure 2 Scanning electron microscope images: (a, b) Fludioxonil@MOF-NH2@CA drug delivery system; (c) MOF-NH2 carrier material; (d) Fludioxonil@MOF-NH2.

[0014] Figure 3 Particle size distribution diagrams: (a) Nano-calcium carbonate drug delivery system; (b) MOF-NH2 carrier material; (c) Fludioxonil@MOF-NH2@CA drug delivery system.

[0015] Figure 4 TEM-EDS elemental distribution of fludioxonil@MOF-NH2@CA.

[0016] Figure 5 Preparation of fludioxonil@MOF-NH2@CA in different solvents: (a) methanol; (b) dichloromethane; (c) acetonitrile; (d) ethanol.

[0017] Figure 6 Preparation of fludioxonil@MOF-NH2@CA with different molar ratios of calcium chloride and sodium carbonate: (a) 1:1; (b) 1:2; (c) 1:3; (d) 2:1.

[0018] Figure 7 Fludioxonil@MOF-NH2@CA drug delivery systems prepared with different active ingredient concentrations: (a) 15 mg / mL; (b) 30 mg / mL; (c) 60 mg / mL.

[0019] Figure 8 Effects of different treatments (fludioxonil technical, MOF-NH2@CA, fludioxonil@MOF-NH2@CA) on wheat growth.

[0020] Figure 9The effects of different treatments (fludioxonil technical, MOF-NH2@CA, fludioxonil@MOF-NH2@CA) on wheat plant height, root length, fresh weight, and dry weight were compared using a two-way ANOVA test. The significance level was marked as: P ≥ 0.05 indicating no significant difference, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[0021] Figure 10 Thermogravimetric analysis (TGA) and differential thermogravimetric analysis (DTG) of fludioxonil technical, MOF-NH2, MOF-NH2@CA and fludioxonil@MOF-NH2@CA (a).

[0022] Figure 11 Release curves of fludioxonil technical, fludioxonil@MOF-NH2, and fludioxonil@MOF-NH2@CA.

[0023] Figure 12 Fludioxonil@MOF-NH2@PLGA drug delivery system: a, b, and c represent electron micrographs at different scales. Detailed Implementation

[0024] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings. To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.

[0025] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, methods, and means well-known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0026] In this invention, terms such as "external," "peripheral," and "upper" represent a relative spatial concept.

[0027] In this invention, "pesticide" refers to the active ingredient in a pesticide, such as fludioxonil, but is not limited thereto.

[0028] In this invention, fludioxonil@MOF-NH2@CA represents a composite drug delivery system containing fludioxonil, which includes fludioxonil, MOF-NH2 and nano-calcium carbonate. The fludioxonil is loaded onto MOF-NH2 and nano-calcium carbonate respectively, and the nano-calcium carbonate loaded with fludioxonil covers the outside of the MOF-NH2 loaded with fludioxonil.

[0029] In this invention, "MOF-NH2" represents an amino-modified metal-organic framework material.

[0030] In this invention, "CA" represents nano-calcium carbonate.

[0031] The content of this invention generally refers to the mass percentage.

[0032] The present invention first provides a composite drug delivery system containing fludioxonil, characterized in that it includes fludioxonil, MOF-NH2 and nano-calcium carbonate, wherein the fludioxonil is loaded on MOF-NH2 and nano-calcium carbonate respectively, and the nano-calcium carbonate loaded with fludioxonil covers the outside of the MOF-NH2 loaded with fludioxonil.

[0033] The MOF-NH2 carrier material of the present invention was prepared according to the method disclosed in CN114437365A.

[0034] This invention first provides a pesticide composite loading system, comprising a pesticide, MOF-NH2, and nano-calcium carbonate. The pesticide is loaded onto both MOF-NH2 and nano-calcium carbonate, with the pesticide-loaded nano-calcium carbonate covering the exterior of the MOF-NH2 loaded with fludioxonil. Preferably, the pesticide is fludioxonil.

[0035] The present invention also provides a method for preparing the pesticide-containing composite drug-loaded system described above, comprising the following steps:

[0036] Step 1) Preparation of MOF-NH2 support material;

[0037] Step 2) Preparation of pesticide-loaded MOF-NH2 loading system;

[0038] Step 3) Preparation of pesticide-containing composite drug delivery system.

[0039] Preferably, the preparation of the pesticide-loaded MOF-NH2 loading system in step two of the above preparation method includes the following steps: weighing the MOF-NH2 carrier material prepared in step one) and dissolving it with the pesticide technical in an organic solvent, stirring and reacting at room temperature, wherein the organic solvent is one of methanol, ethanol, dichloromethane and acetonitrile, preferably dichloromethane.

[0040] Preferably, the preparation of the pesticide-containing composite drug-loaded system in step three of the above preparation method includes the following steps:

[0041] 1) β-cyclodextrin was dispersed in water and ultrasonically dispersed to obtain solution A;

[0042] 2) The pesticide-loaded MOF-NH2 loading system was added to water and ultrasonically dispersed to obtain suspension B;

[0043] 3) Add suspension B dropwise to solution A, then add calcium chloride aqueous solution dropwise. Continue stirring after the addition is complete, then add organic solvent containing pesticide, and finally add sodium carbonate aqueous solution dropwise.

[0044] Preferably, in step three above, the organic solvent is one of methanol, ethanol, dichloromethane and acetonitrile, preferably dichloromethane, and the pesticide concentration in the organic solvent containing pesticide is 15-60 mg / mL, preferably 30 mg / mL.

[0045] Preferably, in step three above, the molar ratio of calcium chloride to sodium carbonate is 1:(0.5-3), more preferably 1:1.

[0046] Preferably, in step three above, the mass concentration of β-cyclodextrin in solution A is 1-20 mg / mL, more preferably 3-16 mg / mL, and even more preferably 10 mg / mL.

[0047] Preferably, the pesticide is fludioxonil.

[0048] The product obtained under the preferred conditions in the preparation method has superior performance.

[0049] The present invention will be further described below with reference to the embodiments and accompanying drawings. The raw materials in the embodiments can be obtained by purchasing them from the market.

[0050] Example 1: Preparation of fludioxonil@MOF-NH2@CA drug delivery system

[0051] Preparation of MOF-NH2: MOF-NH2 was prepared by a solvothermal method using 2-aminoterephthalic acid as the organic chain and ferric ions as the metal nodes. The specific method is as follows: 253.6 mg of 2-aminoterephthalic acid, 756.8 mg of ferric chloride hexahydrate, and 416.7 mg of polyvinylpyrrolidone were weighed and dispersed in a beaker containing 23 ml of N,N-dimethylformamide. 1 ml of acetic acid and 21 μl of triethylamine were added, and the mixture was ultrasonically mixed. The resulting solution was transferred to a round-bottom flask and reacted in an oil bath at 130°C for 72 h. After the reaction was complete, the mixture was naturally cooled to room temperature, centrifuged (10000 rpm) to collect the precipitate, and washed three times alternately with dichloromethane and ultrapure water. Finally, the precipitate was dried at 65°C.

[0052] Preparation of fludioxonil@MOF-NH2: Weigh 120 mg of MOF-NH2 and 120 mg of fludioxonil into a 10 mL centrifuge tube, add 4 mL of dichloromethane, seal the centrifuge tube, and stir at room temperature for 6 h. Centrifuge at 10000 rpm for 10 min, collect the precipitate, and dry it in an oven at 65°C to obtain the drug-loaded system fludioxonil@MOF-NH2, with a drug loading rate of 47.8%.

[0053] Preparation of fludioxonil@MOF-NH2@CA: 300 mg of β-cyclodextrin was dissolved in 30 ml of water and ultrasonically dispersed. 50 mg of the prepared fludioxonil@MOF-NH2 was dissolved in 10 ml of water, ultrasonically dispersed, and then added dropwise to the β-cyclodextrin aqueous solution. The mixture was stirred at 320 rpm for 30 min. 50 ml of 100 mmol / L calcium chloride aqueous solution was then added dropwise, and stirring was continued for 5 min. 120 mg of fludioxonil was dissolved in 4 ml of dichloromethane and added dropwise to the above mixture. Stirring was continued for 5 min. Finally, 50 ml of 100 mmol / L sodium carbonate aqueous solution was added dropwise, and stirring was continued for 10 min. After standing for 10 min, the solid product was collected by centrifugation at 5000 rpm for 5 min. The precipitate was washed three times with ultrapure water and finally dried under vacuum at 65 °C to obtain the fludioxonil@MOF-NH2@CA drug loading system with a drug loading rate of 16.5%. The schematic diagram of the drug delivery system structure, scanning electron microscope images, particle size distribution, and TEM-EDS elemental distribution are as follows: Figure 1-4 As shown.

[0054] Particle size distribution and electron microscopy images showed that the fludioxonil@MOF-NH2@CA drug-loading system consisted of microspheres composed of 81.82±13.07 nm wide nano-calcium carbonate particles and 470.57±53.02 nm wide spindle-shaped MOF-NH2 particles, with a relatively uniform particle size of 6.35 ± 1.07 μm on average. After loading fludioxonil onto MOF-NH2, the particle size and morphology did not change significantly, but the surface became rougher.

[0055] TEM-EDS elemental distribution analysis showed that N, F, and Fe elements were uniformly distributed in the fludioxonil@MOF-NH2@CA drug delivery system, with Fe having a relatively higher content in the outer layer, indicating that MOF-NH2 was mainly deposited on the outer layer of the microspheres. F and N elements were uniformly distributed in fludioxonil, with F being more concentrated at the MOF-NH2 deposition sites, further indicating that fludioxonil was not only uniformly distributed among the calcium carbonate nanoparticles but also successfully bound to MOF-NH2. Figure 4(f) It can be seen that the microspheres also have many tiny pores, which is conducive to the adsorption of guest molecules. In addition, FIB cross-section observation revealed that there is a void structure inside the drug-loaded system, which may be due to the migration of MOF-NH2 to the surface during the formation of this controlled-release system. MOF-NH2 may act as a nucleus or template in the early stage of deposition, promoting the rapid precipitation of nano-calcium carbonate. However, due to its large size and the influence of surface energy, it failed to be completely and stably embedded in the interior of the microspheres, but gradually migrated to the surface and was eventually wrapped by the outer layer of nano-calcium carbonate, further demonstrating its dynamic behavior and distribution characteristics during the growth of nano-calcium carbonate crystals.

[0056] Example 2: Effect of fludioxonil loading solvent on the preparation of fludioxonil@MOF-NH2@CA drug delivery system

[0057] In the preparation of the fludioxonil@MOF-NH2@CA drug-loaded system, the choice of loading solvent for the active ingredient fludioxonil has a significant impact on its encapsulation efficiency, drug loading rate, and morphology. Changing the solvent choice for fludioxonil in Example 1 yielded drug-loaded systems with different drug loading rates, encapsulation efficiencies, and morphologies, as shown in Table 1. Figure 5 As shown.

[0058] The results showed that different solvents significantly affected the loading efficiency of fludioxonil and the morphology of the drug-loaded system. Ethanol was used as the solvent, resulting in the highest drug loading and encapsulation efficiency. Figure 5 As can be seen from d, regular spheres cannot be formed under these conditions, indicating that when the solvent is ethanol, nano-calcium carbonate cannot effectively form and encapsulate MOF-NH2, and cannot form a structurally complete drug-loaded system. When the solvent is dichloromethane, the drug loading rate and encapsulation efficiency are 16.52% and 47.80%, respectively, both at a relatively high level. Figure 5 b shows that the drug-loaded system has a good morphology. Therefore, methanol, acetonitrile, ethanol, and dichloromethane can all meet the loading requirements when used as solvents, with dichloromethane showing the best performance.

[0059] Table 1. Effect of solvent on the drug delivery system of fludioxonil@MOF-NH2@CA

[0060]

[0061] Example 3: Effect of the molar ratio of calcium chloride to sodium carbonate on the fludioxonil@MOF-NH2@CA drug delivery system

[0062] In the preparation of the fludioxonil@MOF-NH2@CA drug-loaded system, the molar ratio of calcium chloride to sodium carbonate has a significant impact on its encapsulation efficiency, drug loading rate, and morphology. Changing the molar ratio of calcium chloride to sodium carbonate in Example 1 yielded drug-loaded systems with different drug loading rates, encapsulation efficiencies, and morphologies, as shown in Table 2. Figure 6 As shown.

[0063] The results showed that the highest drug loading rate and encapsulation efficiency were achieved when the molar ratio of calcium chloride to sodium carbonate was 1:2, but only a small amount of MOF-NH2 drug loading system remained on the surface (see [link to relevant documentation]). Figure 6 (b) indicates that under these conditions, the amount of MOF-NH2 encapsulated by nano-calcium carbonate is relatively small, while a large amount of fludioxonil is directly encapsulated by nano-calcium carbonate. When the volume ratio of calcium chloride to sodium carbonate is 1:1, the drug loading rate and encapsulation efficiency are 16.52% and 47.80%, respectively, both at a high level, and the morphology is well characterized (see [link to product description]). Figure 6 a). Therefore, a molar ratio of calcium chloride to sodium carbonate of 1:(0.5-3) can meet the load requirements, while a molar ratio of 1:1 is optimal.

[0064] Table 2. Effect of the molar ratio of calcium chloride and sodium carbonate on the fludioxonil@MOF-NH2@CA drug delivery system

[0065]

[0066] Example 4: Effect of β-cyclodextrin concentration on the drug delivery system of fludioxonil@MOF-NH2@CA

[0067] In the preparation of the fludioxonil@MOF-NH2@CA drug loading system, the mass concentration of β-cyclodextrin has a significant impact on its encapsulation efficiency and drug loading rate. By changing the mass concentration of β-cyclodextrin in Example 1, drug loading systems with different drug loading and encapsulation efficiencies were obtained, as shown in Table 3.

[0068] The results showed that when the mass of β-cyclodextrin was 10 mg / mL, the drug loading rate and encapsulation efficiency were 16.52% and 47.80%, respectively. Therefore, the drug loading requirement could be met when the mass concentration of β-cyclodextrin was 3-16 mg / mL, with 10 mg / mL showing the best effect.

[0069] Table 3. Effect of β-cyclodextrin concentration on the drug delivery system of fludioxonil@MOF-NH2@CA

[0070]

[0071] Example 5: Effect of the mass concentration of the active ingredient fludioxonil on the fludioxonil@MOF-NH2@CA drug delivery system

[0072] In the preparation of the fludioxonil@MOF-NH2@CA drug-loaded system, the mass concentration of the active ingredient fludioxonil has a significant impact on its encapsulation efficiency, drug loading rate, and morphology. During the preparation of the fludioxonil@MOF-NH2@CA drug-loaded system, changing the mass concentration of fludioxonil in Example 1 resulted in drug-loaded systems with different drug loading rates, encapsulation rates, and morphologies, as shown in Table 4. Figure 7 As shown.

[0073] The results showed that when the fludioxonil concentration was 15 mg / mL, the drug loading rate was low, due to insufficient fludioxonil input. When the fludioxonil concentration was 60 mg / mL, the active ingredient fludioxonil could not be completely dissolved in the solvent dichloromethane. Although the drug loading rate and encapsulation efficiency were high, the morphology was irregular. This was because a large amount of fludioxonil could be directly loaded by nano-calcium carbonate, but could not simultaneously load the fludioxonil technical and the MOF-NH2 drug-loading system, leading to some morphological differences. When the fludioxonil concentration was 15 mg / mL, the drug loading rate, encapsulation efficiency, and morphology were suitable, which was beneficial for the preparation of this drug-loading system. Therefore, in the preparation of the fludioxonil@MOF-NH2@CA drug-loading system, the loading effect could be achieved when the concentration of the active ingredient fludioxonil was 15-60 mg / mL, and the effect was optimal at a concentration of 30 mg / mL.

[0074] Table 4. Effect of fludioxonil mass concentration on the fludioxonil@MOF-NH2@CA drug delivery system

[0075]

[0076] Example 6: Effects of the fludioxonil@MOF-NH2@CA drug delivery system on crop growth

[0077] Based on the recommended dosage of fludioxonil, wheat seeds were treated with fludioxonil technical and the fludioxonil@MOF-NH2@CA loading system from Example 1 at concentrations of 25 mg / L and 50 mg / L, respectively. Simultaneously, following the method in Example 1, an empty MOF-NH2@CA loading material was prepared without adding the active ingredient of fludioxonil, and wheat seeds were also treated with the MOF-NH2@CA dosage in the fludioxonil@MOF-NH2@CA loading system. After culturing the wheat seeds in an incubator for 30 days, the plant height, root length, fresh weight, and dry weight of the wheat were measured. The results are as follows: Figure 8 , 9 As shown in the figure. The results indicate that, compared to the control (CK), fludioxonil technical grade had a significant inhibitory effect on wheat growth; the MOF-NH2@CA carrier, rich in iron and calcium nutrients, could promote the growth of wheat seedlings; the wheat growth status after treatment with the fludioxonil@MOF-NH2@CA loading system was better than that of the technical grade group. The technical grade may be due to the slow release of fludioxonil by the MOF-NH2@CA carrier, which allows wheat to gradually adapt to the microenvironment, enhances the plant's stress resistance, and thus further alleviates the negative impact of fludioxonil on wheat growth.

[0078] Comparative Example 1

[0079] This study investigated the thermal stability of fludioxonil technical, MOF-NH2 carrier material, MOF-NH2@CA composite carrier, and fludioxonil@MOF-NH2@CA drug loading system using thermogravimetric analysis (TGA). Figure 10 The results showed that the differential thermogravimetric (DTG) curves of MOF-NH2 exhibited local minimums at 64℃, 202℃, 270℃, 441℃, and 608℃, indicating that the decomposition process of MOF-NH2 involves multiple stages of mass loss. MOF-NH2@CA showed relatively small mass loss (approximately 3.02%) between 55-583℃, while the mass loss reached 41.67% in the 591-712℃ range. The lowest peak of the DTG curve occurred at 683℃ (-5.9798 % / min), indicating that the composite support material MOF-NH2@CA effectively improved the overall thermal stability of MOF-NH2.

[0080] Furthermore, the TGA curve of fludioxonil technical grade showed a mass decrease starting at 170℃, with a cumulative mass loss of approximately 94.7% at 279℃; the DTG curve reached its lowest point at 253℃ (-19.278 % / min), indicating that the main thermal decomposition of fludioxonil occurred around this temperature. In contrast, the TGA curve of fludioxonil@MOF-NH2@CA showed a mass decrease at 165℃, with a cumulative mass loss of approximately 29.4% at 240℃; the DTG curve reached its lowest peak at 220℃ (-6.5048 % / min), indicating that the thermal decomposition temperature of fludioxonil in fludioxonil@MOF-NH2@CA was slightly lower. This is because the higher dispersibility of fludioxonil after loading leads to easier contact with the heat source, resulting in earlier thermal decomposition.

[0081] Therefore, the MOF-NH2@CA composite carrier material exhibits better thermal stability than MOF-NH2 and improves the dispersibility of fludioxonil active ingredient in the drug delivery system.

[0082] Comparative Example 2: Release Effect

[0083] Prepare a release medium solution with an ethanol:PBS aqueous solution volume ratio of 40:60 and a pH of 5.0. Weigh 25 mg of fludioxonil technical grade active ingredient, as well as the fludioxonil@MOF-NH2 and fludioxonil@MOF-NH2@CA drug loading systems from Example 1, and place them separately into 200 mL of release medium solution. Release the drug by shaking at 120 rpm at 25 ± 1 °C in a constant-temperature shaking reactor. Take 0.7 mL samples at regular intervals, filter through a 0.22 μm aqueous filter membrane, and determine the fludioxonil content using high-performance liquid chromatography (HPLC). After each sampling, add 0.7 mL of release medium solution, and calculate the cumulative release rate using the following formula.

[0084]

[0085] In the formula:

[0086] Q: Cumulative release percentage (%)

[0087] Ct: Concentration of the active ingredient in the release medium (mg / mL) measured at the release time point;

[0088] The cumulative concentration of all previous sampling points;

[0089] W: Total mass of the coated active ingredients (mg);

[0090] V0: Total volume of the release medium (mL);

[0091] V: Volume of each sample taken (mL).

[0092] Figure 11 The cumulative release rate of the active ingredient, fludioxonil. Under acidic conditions, fludioxonil technical grade dissolves rapidly, while the dissolution rate of the fludioxonil@MOF-NH2 loading system is even higher than that of the technical grade (almost completely dissolved within 100 hours). This is because the MOF-NH2 framework structure is disrupted under acidic conditions, leading to the rapid release of the active ingredient, fludioxonil. Furthermore, because fludioxonil is dispersed within the porous structure of the MOF-NH2 carrier material, its dispersion performance is better than that of the technical grade, resulting in a faster release rate. The fludioxonil@MOF-NH2@CA loading system, however, increases its stability under acidic conditions. The release of the active ingredient, fludioxonil, is slower, with 68% released at 100 hours and over 90% released after 400 hours. Its release rate is significantly lower than that of the fludioxonil@MOF-NH2 loading system and the technical grade fludioxonil. Therefore, the MOF-NH2@CA composite loading system exhibits better controlled-release performance than the MOF-NH2 monolayer coating loading system.

[0093] Comparative Example 3: Comparison of MOF-NH2 Coating Materials

[0094] This invention employs inorganic nano-calcium carbonate (CaCO3) to coat fludioxonil@MOF-NH2, obtaining a fludioxonil@MOF-NH2@CA drug-loaded system, thereby improving the stability of the MOF-NH2 drug-loaded system. Besides inorganic nano-calcium carbonate (CaCO3), other commonly used materials in the field can also be used to coat fludioxonil@MOF-NH2, such as the polymeric organic material polylactic-co-glycolic acid copolymer (PLGA), which is also expected to yield stable composite drug-loaded systems. The applicant compared the coating effects of inorganic nano-calcium carbonate (CaCO3) and organic polymeric material PLGA on the fludioxonil@MOF-NH2 drug-loaded system. The PLGA coating method is as follows:

[0095] In Example 1, after preparing MOF-NH2 and fludioxonil@MOF-NH2, 25 mL of a 20 mg / mL PLGA solution was prepared. Under stirring, 4 mL of a dichloromethane suspension containing 120 mg of fludioxonil@MOF-NH2 was added dropwise to the PLGA solution to form an initial mixture. Under continuous stirring, 16 mL of a 2% PVA solution was added dropwise to the above system, and the mixture was stirred for 5 min. Subsequently, the mixture was emulsified using a cell disruptor with a disruption power of 65 W and a total working time of 2 min, using a 3 s working time followed by a 7 s interval. After disruption, 32 mL of a 1% PVA solution was added to the system, and the mixture was stirred at 1400 r / min for 10 min, followed by standing for 20 min to stabilize the emulsion system. The dichloromethane solvent in the system was evaporated by rotary evaporation to complete the PLGA curing process. After the reaction was complete, the product was washed three times with deionized water and centrifuged at 10,000 r / min for 8 min. The precipitate was collected and freeze-dried for 3 h to obtain the fludioxonil@MOF-NH2@PLGA drug delivery system, with the structure shown below. Figure 12 As shown.

[0096] The results showed that, compared with Example 1 ( Figure 2 a) In contrast, the fludioxonil@MOF-NH2@PLGA drug-loaded system obtained by PLGA coating lacks regular structural features, and the PLGA coating layer is not obvious. The surface of the metal-organic framework material MOF-NH2 typically contains exposed metal sites (Fe³⁺) or polar functional groups, exhibiting strong polarity and high surface energy. In contrast, the PLGA molecular chain is mainly composed of nonpolar carbon chains with only a small number of carboxyl / hydroxyl groups at the ends, resulting in strong overall hydrophobicity. The lack of effective interactions (such as hydrogen bonding or electrostatic attraction) between the polar MOF-NH2 and the hydrophobic PLGA makes it difficult for PLGA to spread on the MOF-NH2 surface and achieve effective coating. Therefore, this invention uses inorganic nano-calcium carbonate (CaCO3) to coat fludioxonil@MOF-NH2 to obtain the fludioxonil@MOF-NH2@CA drug-loaded system. This method has a relatively simple process and good operability and application prospects.

[0097] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a pesticide composite delivery system, characterized in that, The mixture includes a pesticide, MOF-NH2, and nano-calcium carbonate. The pesticide is loaded onto both MOF-NH2 and nano-calcium carbonate, with the pesticide-loaded nano-calcium carbonate covering the outside of the pesticide-loaded MOF-NH2. The pesticide is fludioxonil. The process includes the following steps: Step 1) Preparation of MOF-NH2 support material; Step 2) Preparation of pesticide-loaded MOF-NH2 loading system; Step 3) Preparation of pesticide-containing composite drug delivery system; Step three) involves the preparation of the pesticide-containing composite drug-carrying system, which includes the following steps: 1) β-cyclodextrin was dispersed in water and ultrasonically dispersed to obtain solution A; 2) The pesticide-loaded MOF-NH2 loading system was added to water and ultrasonically dispersed to obtain suspension B; 3) Add suspension B dropwise to solution A, then add calcium chloride aqueous solution dropwise. After the addition is complete, continue stirring, then add an organic solvent containing fludioxonil, and finally add sodium carbonate aqueous solution dropwise. The organic solvent is one of methanol, ethanol, dichloromethane, and acetonitrile. The mass concentration of fludioxonil in the organic solvent containing fludioxonil is 15-60 mg / mL. The molar ratio of calcium chloride to sodium carbonate is 1:(0.5-3). The mass concentration of β-cyclodextrin in solution A is 1-20 mg / mL.

2. The preparation method according to claim 1, characterized in that, Step 2) The preparation of the pesticide-loaded MOF-NH2 loading system includes the following steps: Weigh the MOF-NH2 carrier material prepared in Step 1) and the pesticide technical material, dissolve them in an organic solvent, and stir the reaction at room temperature. The organic solvent is one of methanol, ethanol, dichloromethane and acetonitrile.

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