Fipronil-containing microcapsule suspending agent and preparation method thereof

Abstract

The invention relates to the technical field of pesticide slow release, in particular to a fipronil-containing microcapsule suspending agent and a preparation method thereof. The preparation method of the fipronil-containing microcapsule suspending agent comprises the following steps: (1) preparing a copolymer fipronil dispersion liquid; (2) preparing a chitosan copolymer fipronil suspension; (3) preparing fipronil microcapsules; and (4) adding the emulsifying dispersant into the fipronil microcapsule, complementing to 100% by weight with water, and stirring to obtain the fipronil microcapsule suspending agent. The fipronil microcapsule suspending agent prepared by the invention moderately releases about 45-50% of fipronil in an initial stage and rapidly establishes an effective insecticidal concentration, and slowly releases the residual fipronil through a compact wall material in a later stage, the accumulative release rate reaches 92-95%, the action time of the fipronil is effectively improved, the stability of the pesticide effect is improved, and the fipronil microcapsule suspending agent has a good application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pesticide slow release, and particularly relates to a microcapsule suspension agent containing fipronil and a preparation method thereof. BACKGROUND

[0002] Agrochemicals continue to play a key role in modern agriculture, improving crop yield and quality through pest control. The application of chemical pesticides in agricultural management has successfully reduced the loss rate of global agricultural products by more than 30%. Due to natural factors such as rainwater erosion, the low efficiency (<25%) of chemical pesticides on target organisms has weakened the effect of pest control. More than a million tons of pesticides are misused annually to achieve the expected insecticidal effect, resulting in huge costs, environmental and ecological burdens, and even potential harm to human health. For example, fipronil has good control effect on pests, but it is easily oxidized and decomposed in the light, has a short validity period, and has a small solubility in water, which affects the stability of its efficacy.

[0003] Therefore, improving the stability and efficacy of fipronil is an urgent problem to be solved. SUMMARY

[0004] The purpose of the present application is to provide a microcapsule suspension agent containing fipronil and a preparation method thereof, which solves the above technical problems in the prior art.

[0005] In order to achieve the above purpose, the present application adopts the following technical solutions: The present application provides a preparation method of a microcapsule suspension agent containing fipronil, comprising the following steps: Step (1) adding fipronil to a block copolymer solution, stirring and treating, then adding dropwise to water under stirring and continuing to stir to obtain a copolymer fipronil dispersion; In the above process, the block copolymer has a hydrophilic and hydrophobic block structure, the hydrophobic segment wraps the fipronil, and the hydrophilic segment makes the copolymer fipronil stably dispersed in the aqueous solution.

[0006] Step (2) adjusting the pH of the copolymer fipronil dispersion with acetic acid, then adding a chitosan solution under stirring, stirring at room temperature in the dark, centrifuging, discarding the supernatant and redispersing in water to obtain a 1wt% chitosan copolymer fipronil suspension; In the above process, the chitosan is protonated under acidic conditions and carries a positive charge, and the copolymer fipronil carries a negative charge (such as carboxyl) on the surface, and a dense chitosan layer is formed on the particle surface through electrostatic interaction.

[0007] Step (3) adding the oil-modified diatomite into the sodium alginate aqueous solution, under stirring, drop the chitosan copolymer fipronil suspension, after magnetic stirring, a mixed solution is obtained, the mixed solution is droped into a calcium chloride solution with the same volume as the mixed solution under stirring, continue stirring, impurity removal, fipronil microcapsules are obtained; In the above process, the sodium alginate and the chitosan layer are electrostatically combined, and the Ca 2+ Crosslinking and curing, and the nanosheet structure of the oil-modified diatomite is embedded in the wall material.

[0008] Step (4) adding the emulsifying dispersant into the fipronil microcapsules, and then adding water to 100% by weight, stirring, fipronil microcapsule suspending agent is obtained.

[0009] Preferably, in the step (1), the amount ratio of the block copolymer, fipronil and water is 20-40 mL:10-20 mg:400-800 mL; the concentration of the block copolymer solution is 1 mg / mL; the stirring treatment time is 10-20 min; the dropwise adding speed is 1 mL / min; and the continuous stirring time is 2-4 h.

[0010] Preferably, in the step (2), the amount ratio of the copolymer fipronil dispersion and the chitosan solution is 200-400 mL:200-400 mL; the acetic acid concentration is 0.1 mol / L; the pH value is adjusted to 4.5; the light-shielded stirring time is 40-50 min; and the centrifugal conditions are: the centrifugal speed is 7000-9000 rpm, and the centrifugal time is 15-20 min.

[0011] Preferably, in the step (3), the amount ratio of the oil-modified diatomite, the sodium alginate aqueous solution and the chitosan copolymer fipronil suspension is 50-100 mg:500-1000 mL:100-200 mL; the mass fraction of the sodium alginate aqueous solution is 0.3 wt%; the stirring speed when droping the chitosan copolymer fipronil suspension is 500-700 rpm, and the dropwise adding speed is 1 mL / min; the magnetic stirring time is 25-35 min; the re-dropping conditions are: the stirring speed is 300-400 rpm, and the dropwise adding speed is 2 mL / min; the calcium chloride solution concentration is 0.15 mol / L; the continuous stirring conditions are: the continuous stirring speed is 200-300 rpm, and the continuous stirring time is 1-2 h; and the impurity removal method is: passing through a 100-mesh sieve, and then washing with water for 3-5 times.

[0012] Preferably, in the step (4), the emulsifying dispersant accounts for 5-8% of the total weight of the final product; the stirring treatment conditions are: stirring treatment speed of 600-800 rpm, stirring treatment time of 55-65 min; the emulsifying dispersing aid is a compound of polyvinyl alcohol, sodium carboxymethyl cellulose, Tween 80, xanthan gum with a mass ratio of 2-3:1.0-1.5:0.5-1.0:0.3-0.5.

[0013] Preferably, in the step (1), the preparation method of the block copolymer solution comprises the following steps: S1: Dissolve tetraethylene glycol and triethylamine in dichloromethane, bubble nitrogen, then drop methyl acryloyl chloride solution, then cool the reaction with ice water, quench with 200-400 mL ice water, wash, and distill under reduced pressure to obtain tetraethylene glycol methacrylate; In the above process, the primary hydroxyl group of tetraethylene glycol attacks the carbonyl carbon of methyl acryloyl chloride to form tetraethylene glycol methacrylate.

[0014] S2: Dissolve the chain transfer agent, tetraethylene glycol methacrylate and azobisisobutyronitrile (AIBN) in tetrahydrofuran, and perform freezing, vacuumizing and thawing cycles under nitrogen atmosphere, then drop into cold ether after reaction, filter under reduced pressure, and dry at room temperature to constant weight to obtain an intermediate product; In the above process, the chain transfer agent and tetraethylene glycol methacrylate perform RAFT polymerization reaction.

[0015] S3: Dissolve the intermediate product, benzyl methacrylate and AIBN in methanol under nitrogen atmosphere, and perform freezing, vacuumizing and thawing cycles, then remove the solvent by rotary evaporation, dissolve in tetrahydrofuran again to obtain a 1 mg / mL block copolymer solution.

[0016] The structural formula of the block copolymer is as follows:

[0017] Preferably, in the S1, the amount ratio of tetraethylene glycol, triethylamine, dichloromethane and ice water is 50-100 g:26-52 g:300-600 mL; the nitrogen bubbling time is 8-12 min; the preparation method of the methyl acryloyl chloride solution is: adding 27-54 g of methyl acryloyl chloride into 200-400 mL of dichloromethane to obtain a methyl acryloyl chloride solution; the dropping speed is 2 mL / min; the cooling reaction time is 20-22 h; the washing method is: the organic phase is washed with 5 wt% dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine respectively once.

[0018] Preferably, in the S2, the chain transfer agent is 4-cyano-4-(phenylthiocarbonylthio) pentanoic acid; the ratio of the chain transfer agent, tetraethylene glycol methacrylate, AIBN, tetrahydrofuran, cold diethyl ether is 700-1400 mg:20-40 g:104-208 mg:100-200 mL:1-2 L; the number of cycles is 2-4 times; the reaction conditions are: the reaction temperature is 65-75℃, and the reaction time is 22-26 h.

[0019] Preferably, in the S3, the ratio of the intermediate product, benzyl methacrylate, AIBN, and methanol is 6-12 g:10-20 g:24-48 mg:66.6-138 mL; the number of cycles is 2-4 times; the reaction conditions are: the reaction temperature is 65-75℃, and the reaction time is 22-26 h.

[0020] Preferably, in the step (2), the preparation method of the chitosan solution is: adding glacial acetic acid into deionized water, stirring and treating, then adding chitosan powder under stirring conditions, and magnetically stirring at room temperature to obtain the chitosan solution.

[0021] Preferably, the ratio of the glacial acetic acid, deionized water, and chitosan powder is 10-20 mL:1-2 L:1-2 g; the stirring and treating time is 5-15 min; the stirring speed is 300-400 rpm; the magnetic stirring time is 4-6 h; and the degree of deacetylation of the chitosan is 80.0-95.0%.

[0022] In the step (2), the preparation method of the oleic acid modified diatomite includes the following steps: P1: dispersing diatomite in ethanol, filtering after sieving, evaporating the solvent to obtain pretreated diatomite, adding the pretreated diatomite into a mixed solution, reacting at room temperature, washing and drying to obtain activated diatomite; P2: mixing N,N-dimethylformamide and oleic acid with the activated diatomite, adding concentrated sulfuric acid dropwise under stirring, reacting with vigorous stirring, centrifuging, washing, and drying to obtain the oleic acid modified diatomite.

[0023] Preferably, in the P1, the ratio of the diatomite, ethanol, and the mixed solution is 10-20 g:1-2 L:200-400 mL; the sieving method is sieving 2-4 times through a 350-mesh sieve; the room temperature reaction time is 20-28 h; and the mixed solution is a mixture of 5 mol / L HCl and 30 wt% H2O2 in a volume ratio of 1:1.

[0024] Preferably, in the P2, the amount ratio of N,N-dimethylformamide, oleic acid, activated diatomite, concentrated sulfuric acid is 10-20 mL:1.5-3 g:1-2 g:3-6 drops; the reaction condition is that the reaction temperature is 55-65 DEG C, and the reaction time is 5-7 h; the centrifugation method is that centrifugation is carried out at a speed of 5000-7000 r / min for 15-25 min; the washing method is that each of ethanol and water is washed for 2-3 times; and the drying method is that drying is carried out at 40 DEG C for 10-14 h.

[0025] The fluoro-fipronil microcapsule suspending agent is prepared by the preparation method of the fluoro-fipronil microcapsule suspending agent.

[0026] In conclusion, due to the adoption of the technical solutions, the present application has the following advantages: 1. The fluoro-fipronil microcapsule suspending agent prepared by the present application is wrapped by the hydrophobic block of the block copolymer to form a stable drug-loaded core, and the hydrophilic block improves the dispersion stability of the fluoro-fipronil, so as to prevent the fluoro-fipronil from being precipitated and aggregated early, then the electrostatic layer-by-layer self-assembly of the positively charged chitosan and the negatively charged copolymer occurs in the acidic environment, so as to form a dense cationic chitosan shell on the surface to improve the stability of the system, and to form the first physical and electrostatic barrier for the outward diffusion of the fluoro-fipronil, then the sodium alginate is introduced and cross-linked with the chitosan layer to form a high-mechanical-strength gel wall, and the nanosheet structure of the added oleic acid modified diatomite is embedded in the wall material to enhance the density and mechanical properties of the wall material, and the hydrophobic surface of the oleic acid modification can enhance the adsorption of the fluoro-fipronil, prolong the diffusion path of the drug, inhibit the burst release, delay the penetration of water and the diffusion of the drug, and achieve long-acting and slow release. 2+ 2. The fluoro-fipronil microcapsule suspending agent prepared by the present application can release about 45-50% of the fluoro-fipronil in the early stage, quickly establish an effective insecticidal concentration, and slowly release the remaining fluoro-fipronil through the dense wall material in the later stage, so as to achieve a cumulative release rate of 92-95%, effectively improve the action time of the fluoro-fipronil, improve the stability of the drug efficacy, and have a good application prospect.

[0027] 2. The fluoro-fipronil microcapsule suspending agent prepared by the present application can release about 45-50% of the fluoro-fipronil in the early stage, quickly establish an effective insecticidal concentration, and slowly release the remaining fluoro-fipronil through the dense wall material in the later stage, so as to achieve a cumulative release rate of 92-95%, effectively improve the action time of the fluoro-fipronil, improve the stability of the drug efficacy, and have a good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0028] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art description. Obviously, the drawings in the following description only show some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without any creative effort.

[0029] Figure 1 is the column chart of the encapsulation efficiency of the fluoro-fipronil microcapsule suspending agent of the present application; Figure 2 is a drug loading fold line chart of the fipronil microcapsule suspension of the present application; Figure 3 is a sustained release efficiency fold line chart of the fipronil microcapsule suspension of the present application. DETAILED DESCRIPTION

[0030] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application. EMBODIMENT

[0031] The present embodiment discloses a preparation method of a block copolymer solution, comprising the following steps: S1: 75g of tetraethylene glycol and 29g of triethylamine are dissolved in 450mL of dichloromethane, nitrogen is bubbled for 10min, then a solution of methacryloyl chloride is added dropwise at a speed of 2mL / min, then the reaction is cooled with ice water for 21h, quenched and washed with 300mL of ice water, the organic phase is washed with 5wt% dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine respectively, and then distilled under reduced pressure to obtain tetraethylene glycol methacrylate; S2: 1050mg of chain transfer agent 4-cyano-4-(phenylthiocarbonylthio) pentanoic acid, 30g of tetraethylene glycol methacrylate and 156mg of AIBN are dissolved in 150mL of tetrahydrofuran, and then the solution is subjected to freezing, vacuumizing and thawing cycles for 3 times under nitrogen atmosphere, and then reacted at 70℃ for 24h, dropped into 1.5L of cold ether, filtered under reduced pressure, and dried at room temperature to constant weight to obtain an intermediate product; S3: 9g of the intermediate product, 15g of benzyl methacrylate and 36mg of AIBN are dissolved in 100mL of methanol, and then the solution is subjected to freezing, vacuumizing and thawing cycles for 3 times under nitrogen atmosphere, and then reacted at 70℃ for 24h, and then the solvent is removed by rotary evaporation, and then the solution is dissolved in tetrahydrofuran to obtain a 1mg / mL block copolymer solution.

[0032] The preparation method of the solution of methacryloyl chloride is as follows: 40g of methacryloyl chloride is added into 300mL of dichloromethane to obtain a solution of methacryloyl chloride. EMBODIMENT

[0033] The present embodiment discloses a preparation method of a chitosan solution, comprising the following steps: 15mL of glacial acetic acid is added into 1.5L of deionized water, stirred for 10min, and then 1.5g of chitosan powder is added under the condition of 350rpm rotation speed, and then the solution is magnetically stirred at room temperature for 5h to obtain a chitosan solution. EMBODIMENT

[0034] The embodiment discloses a preparation method of oil acid modified diatomite, comprising the following steps: P1: 15g diatomite is dispersed in 1.5L ethanol, filtered after being passed through a 350-mesh sieve for three times, the solvent is evaporated, and pretreated diatomite is obtained; the pretreated diatomite is added into 300mL mixed solution, and reacts for 24h at room temperature; and the activated diatomite is obtained after being washed and dried; the mixed solution is prepared by mixing 5mol / L HCl and 30wt% H2O2 at a volume ratio of 1:1.

[0035] P2: 15mL N,N-dimethylformamide, 2.2g oil acid and 1.5g activated diatomite are mixed, 4.5 drops of concentrated sulfuric acid are added dropwise under stirring, and the mixture is stirred at 60°C for 6h; then the mixture is centrifuged at a speed of 6000r / min for 20min; the precipitate is washed with ethanol and water for three times respectively; and the oil acid modified diatomite is obtained after the precipitate is dried at 40°C for 12h. Embodiment

[0036] The embodiment discloses a preparation method of fipronil microcapsule suspension, comprising the following steps: Step (1): 15mg fipronil is added into 30mL block copolymer solution with a concentration of 1mg / mL prepared in embodiment 1, and stirred for 15min; then the solution is added dropwise into 600mL water at a speed of 1mL / min under stirring, and stirred for 3h to obtain a copolymer fipronil dispersion; Step (2): 300mL copolymer fipronil dispersion is adjusted to pH 4.5 by using 0.1mol / L acetic acid, and 300mL chitosan solution prepared in embodiment 2 is added under stirring; the mixture is stirred for 45min at room temperature in dark, then centrifuged at a speed of 8000rpm for 18min, and the supernatant is discarded and dispersed in water to obtain a 1wt% chitosan copolymer fipronil suspension; Step (3): 75mg oil acid modified diatomite prepared in embodiment 3 is added into 750mL 0.3wt% sodium alginate aqueous solution, and 150mL chitosan copolymer fipronil suspension is added dropwise into the mixture at a speed of 1mL / min under the condition of a stirring speed of 600rpm; the mixture is obtained after being stirred for 30min by using a magnetic stirrer; and the mixture is added dropwise into a 0.15mol / L calcium chloride solution with the same volume as the mixture at a speed of 2mL / min under the condition of a stirring speed of 350rpm; the fipronil microcapsule is obtained after being stirred for 1.5h at a stirring speed of 250rpm, being passed through a 100-mesh sieve and being washed with water for four times; Step (4): 7% of an emulsifying dispersant based on the total weight of the final product is added into the fipronil microcapsule, and the water is added to 100% by weight, and the mixture is stirred for 60min at a stirring speed of 700rpm to obtain the fipronil microcapsule suspension.

[0037] The emulsifying dispersing aid is polyvinyl alcohol, sodium carboxymethyl cellulose, Tween 80, xanthan gum, and is compounded in a mass ratio of 2.5:1.3:0.7:0.4. Embodiment

[0038] The embodiment discloses a preparation method of a fipronil microcapsule suspension agent, and comprises the following steps: Step (1) 20 mg of fipronil is added into 20 mL of the block copolymer solution prepared in embodiment 1 with a concentration of 1 mg / mL, and after stirring treatment for 10 min, the solution is added dropwise into 800 mL of water at a speed of 1 mL / min under stirring, and stirring is continued for 2 h to obtain a copolymer fipronil dispersion liquid; Step (2) 400 mL of the copolymer fipronil dispersion liquid is adjusted to pH 4.5 by using 0.1 mol / L acetic acid, and 200 mL of the chitosan solution prepared in embodiment 2 is added under stirring, and stirring is continued for 50 min at room temperature in dark, and then centrifugation is carried out at a speed of 7000 rpm for 20 min, and after the supernatant is discarded, the copolymer fipronil suspension is dispersed in water again to obtain a 1 wt% chitosan copolymer fipronil suspension; Step (3) 50 mg of the oleic acid modified diatomite prepared in embodiment 3 is added into 1000 mL of a 0.3 wt% sodium alginate aqueous solution, and 200 mL of the chitosan copolymer fipronil suspension is added dropwise into the solution at a speed of 1 mL / min under stirring at a speed of 500 rpm, and a mixed solution is obtained after magnetic stirring for 25 min, and the mixed solution is added dropwise into a calcium chloride solution with the same volume as the mixed solution at a speed of 2 mL / min under stirring at a speed of 400 rpm, and stirring is continued for 2 h at a speed of 200 rpm, and then the fipronil microcapsule is obtained after being sieved through a 100 mesh sieve and washed with water for 3 times; Step (4) 8% of the emulsifying dispersing aid in the total weight of the final product is added into the fipronil microcapsule, and water is added to reach 100% by weight, and stirring treatment is carried out at a speed of 600 rpm for 65 min to obtain the fipronil microcapsule suspension agent.

[0039] The emulsifying dispersing aid is polyvinyl alcohol, sodium carboxymethyl cellulose, Tween 80, xanthan gum, and is compounded in a mass ratio of 2:1.5:0.5:0.5. Embodiment

[0040] The embodiment discloses a preparation method of a fipronil microcapsule suspension agent, and comprises the following steps: Step (1) 20 mg of fipronil is added into 20 mL of the block copolymer solution prepared in embodiment 1 with a concentration of 1 mg / mL, and after stirring treatment for 10 min, the solution is added dropwise into 800 mL of water at a speed of 1 mL / min under stirring, and stirring is continued for 2 h to obtain a copolymer fipronil dispersion liquid; Step (2) 200 mL copolymer fipronil dispersion solution was adjusted to pH 4.5 with 0.1 mol / L acetic acid, 400 mL chitosan solution prepared in Example 2 was added under stirring, and stirred at room temperature for 40 min in the dark, then centrifuged at 9000 rpm for 15 min, and the supernatant was discarded and then dispersed in water to obtain a 1 wt% chitosan copolymer fipronil suspension; Step (3) 100 mg of oleic acid modified diatomite prepared in Example 3 was added to 500 mL of 0.3 wt% sodium alginate aqueous solution, and 100 mL of chitosan copolymer fipronil suspension was added dropwise at a speed of 1 mL / min under the condition of 700 rpm, and a mixed solution was obtained after magnetic stirring for 35 min, and the mixed solution was added dropwise to a 0.15 mol / L calcium chloride solution with the same volume as the mixed solution at a speed of 2 mL / min under the condition of 300 rpm, and stirring was continued at a speed of 300 rpm for 1 h, and then sieved through a 100 mesh sieve and washed with water for 5 times to obtain fipronil microcapsules; Step (4) 5% of the total weight of the final product of emulsifying dispersant was added to the fipronil microcapsules, and water was added to 100% by weight, and then stirred at a speed of 800 rpm for 55 min to obtain fipronil microcapsule suspension.

[0041] The emulsifying dispersant is a mixture of polyvinyl alcohol, sodium carboxymethyl cellulose, Tween 80 and xanthan gum in a mass ratio of 3:1:1:0.3.

[0042] Comparative Example 1 Comparative Example 1 and Example 4, in the process of preparing fipronil microcapsule suspension, step (1) does not add block copolymer solution, the specific steps are as follows: 15 mg of fipronil was added to 20 mL of tetrahydrofuran, stirred for 15 min, and then added dropwise to 600 mL of water at a speed of 1 mL / min under stirring, and then stirred for 3 h to obtain a fipronil dispersion solution; other steps were unchanged.

[0043] Comparative Example 2 Comparative Example 2 and Example 4, in the process of preparing fipronil microcapsule suspension, there is no step (2) and step (3), that is, the copolymer fipronil dispersion solution obtained in step (1) is added to the emulsifying dispersant (8% of the total weight), and water is added to 100% by weight, and then stirred at a speed of 600 rpm for 65 min to obtain a suspension without microcapsule wall, and other conditions are unchanged.

[0044] Comparative Example 3 Comparative Example 3 and Example 4, in the process of preparing fipronil microcapsule suspension, no oleic acid modified diatomite is added, and other conditions are unchanged.

[0045] Comparative Example 4 Comparative Example 4 is the same as Example 4 except that the activated diatomite prepared in step P1 of Example 3 is used instead of the oleic acid modified diatomite in the preparation of the fipronil microcapsule suspension.

[0046] Experimental tests: the properties of the fipronil microcapsules and suspensions prepared in Examples 4-6 and Comparative Examples 1-4 were tested; the encapsulation efficiency / % = (the number of micrograms of fipronil encapsulated / the total number of micrograms of fipronil added) x 100%; the drug loading / % = (the mass of fipronil / microcapsule dry weight) x 100%, the microcapsule dry weight was obtained by weighing after freeze-drying; the average particle size and PDI were determined by using Zetasizer Nano ZS (Malvern Instruments Ltd, Worcestershire, UK) by dynamic light scattering (DLS) measurement to determine the average particle size and polydispersity index (PDI) of the fipronil microcapsules, and the test results are shown in Table 1; the sustained-release performance test: 30 mL of a mixed solution of 40% ethanol / water (v / v) was added to the fipronil microcapsule suspensions prepared in Examples 4-6 and Comparative Examples 1-4 containing 2 mg of fipronil, respectively, and incubated with constant shaking, 1.0 mL of the dissolved liquid was taken out every day, 1.0 mL of new 40% ethanol / water mixed solution was added at the same time, the absorbance was detected, the cumulative release amount was calculated, and the cumulative release rate of fipronil with time was obtained, and the relationship between the cumulative release rate and time is shown in Figure 3 Table 1.

[0047] Table 1

[0048] According to Table 1 and from Examples 4-6 and Comparative Examples 1-4, the fipronil microcapsule suspension prepared in Example 4 has good encapsulation efficiency, drug loading and sustained-release performance, and small particle size and good dispersibility. Comparative Example 1, compared with Example 4, does not add a block copolymer, the dispersibility and stability of the fipronil dispersion are poor, the drug loading is reduced, the encapsulation is poor, the particle size is large, aggregation is easy, and the sustained-release performance is poor; Comparative Example 2, compared with Example 4, is a block copolymer micelle, and has low performance and poor sustained-release performance; Comparative Examples 3-4, compared with Example 4, Comparative Example 3 does not add oleic acid modified diatomite, and Comparative Example 4 does not modify the diatomite, because the hydrophobic surface of the oleic acid modified diatomite can better adsorb and fix the hydrophobic drug fipronil, and the absence of addition or modification will reduce the encapsulation efficiency and sustained-release performance.

[0049] The above merely describes preferred embodiments of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art, within the technical scope disclosed by the present application, can make equivalent replacements or changes according to the technical scheme and inventive concept of the present application, which should be covered within the protection scope of the present application.

[0050] The preferred embodiments of the application disclosed above are only used to help explain the application. The preferred embodiments do not describe all the details and do not limit the application to the specific embodiments. Obviously, many modifications and changes can be made according to the content of the present application. The present application selects and describes these embodiments in order to better explain the principles and practical applications of the present application, so that those skilled in the art can well understand and utilize the present application. The present application is limited only by the claims and their full scope and equivalents.

Claims

1. A process for the preparation of a microcapsule suspension of fipronil characterized in that, The method comprises the following steps: Step (1) adding fipronil to the block copolymer solution, stirring and treating, then dropping into water under stirring and continuing stirring to obtain a copolymer fipronil dispersion; Step (2) adjusting the pH of the copolymer fipronil dispersion with acetic acid, then adding chitosan solution under stirring, stirring at room temperature in the dark, centrifuging, discarding the supernatant and then dispersing in water to obtain a 1wt% chitosan copolymer fipronil suspension; Step (3) adding oleic acid modified diatomite into sodium alginate aqueous solution, then dropping the chitosan copolymer fipronil suspension under stirring, obtaining a mixture after magnetic stirring, then dropping the mixture into an equal volume of calcium chloride solution under stirring, continuing stirring and removing impurities to obtain fipronil microcapsules; Step (4) adding an emulsifying dispersant to the fipronil microcapsules, making up to 100% by weight with water, stirring and treating to obtain fipronil microcapsule suspension.

2. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (1), the amount ratio of the block copolymer, fipronil and water is 20-40mL:10-20mg:400-800mL; the concentration of the block copolymer solution is 1mg / mL; the stirring and treating time is 10-20min; the dropping speed is 1mL / min; and the continuing stirring time is 2-4h.

3. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (2), the amount ratio of the copolymer fipronil dispersion and chitosan solution is 200-400mL:200-400mL; the concentration of acetic acid is 0.1mol / L; the pH value is adjusted to 4.5; the stirring time in the dark is 40-50min; and the centrifuging conditions are: the centrifuging speed is 7000-9000rpm and the centrifuging time is 15-20min.

4. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (3), the amount ratio of the oleic acid modified diatomite, sodium alginate aqueous solution and chitosan copolymer fipronil suspension is 50-100mg:500-1000mL:100-200mL; the mass fraction of the sodium alginate aqueous solution is 0.3wt%; the stirring speed when dropping the chitosan copolymer fipronil suspension is 500-700rpm and the dropping speed is 1mL / min; the magnetic stirring time is 25-35min; the re-dropping conditions are: the stirring speed is 300-400rpm and the dropping speed is 2mL / min; the concentration of the calcium chloride solution is 0.15mol / L; the continuing stirring conditions are: the stirring speed is 200-300rpm and the continuing stirring time is 1-2h; and the impurity removing method is: passing through a 100-mesh sieve and then washing with water for 3-5 times.

5. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (4), the emulsifying dispersant accounts for 5-8% of the total weight of the final product; the stirring and treating conditions are: the stirring and treating speed is 600-800rpm and the stirring and treating time is 55-65min; and the emulsifying dispersant is a compound of polyvinyl alcohol, sodium carboxymethyl cellulose, Tween 80 and xanthan gum with a mass ratio of 2-3:1.0-1.5:0.5-1.0:0.3-0.

5.

6. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (1), the preparation method of the block copolymer solution comprises the following steps: S1: tetraethylene glycol and triethylamine are dissolved in dichloromethane, nitrogen is bubbled, then a solution of methacryloyl chloride is added dropwise, after cooling reaction with ice water, 200-400 mL of ice water is added to quench, washed, distilled under reduced pressure to obtain tetraethylene glycol methacrylate; S2: chain transfer agent, tetraethylene glycol methacrylate and azobisisobutyronitrile (AIBN) are dissolved in tetrahydrofuran, and the reaction is carried out under nitrogen atmosphere by freezing, vacuumizing, thawing cycle, then drop into cold ether, vacuum filtration, and dried at room temperature to constant weight to obtain the intermediate product; S3: the intermediate product, benzyl methacrylate and AIBN are dissolved in methanol, and the reaction is carried out under nitrogen atmosphere by freezing, vacuumizing, thawing cycle, then remove the solvent by rotary evaporation, and then dissolved in tetrahydrofuran to obtain 1 mg / mL block copolymer solution.

7. The process for preparing the fipronil microcapsule suspension according to claim 6, characterized by, In the S1, the amount ratio of tetraethylene glycol, triethylamine, dichloromethane, ice water is 50-100 g:26-52 g:300-600 mL; the nitrogen bubbling time is 8-12 min; the preparation method of the methacryloyl chloride solution is: 27-54 g of methacryloyl chloride is added to 200-400 mL of dichloromethane to obtain a methacryloyl chloride solution; the dropwise adding speed is 2 mL / min; the cooling reaction time is 20-22 h; the washing method: the organic phase is washed with 5wt% dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine respectively; in the S2, the chain transfer agent is 4-cyano-4-(phenylthiocarbonylthio) pentanoic acid; the amount ratio of chain transfer agent, tetraethylene glycol methacrylate, AIBN, tetrahydrofuran, cold ether is 700-1400 mg:20-40 g:104-208 mg:100-200 mL:1-2 L; the cycle number is 2-4 times; the reaction condition: the reaction temperature is 65-75℃, and the reaction time is 22-26 h; in the S3, the amount ratio of intermediate product, benzyl methacrylate, AIBN, methanol is 6-12 g:10-20 g:24-48 mg:66.6-138 mL; the cycle number is 2-4 times; the reaction condition: the reaction temperature is 65-75℃, and the reaction time is 22-26 h.

8. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (2), the preparation method of the chitosan solution is: glacial acetic acid is added to deionized water, stirred and treated, then chitosan powder is added under stirring condition, and the mixture is stirred magnetically at room temperature to obtain the chitosan solution; the amount ratio of glacial acetic acid, deionized water, chitosan powder is 10-20 mL:1-2 L:1-2 g; the stirring and treating time is 5-15 min; the stirring speed is 300-400 rpm; the magnetic stirring time is 4-6 h.

9. The process for preparing the fipronil microcapsule suspension according to claim 1, characterized by, In the step (2), the preparation method of the oleic acid modified diatomite includes the following steps: P1: diatomite is dispersed in ethanol, sieved and filtered, the solvent is evaporated to obtain pretreated diatomite, the pretreated diatomite is added to a mixed solution, and the mixture is reacted at room temperature, washed and dried to obtain activated diatomite; P2: mixing N,N-dimethylformamide, oleic acid and activated diatomite, adding concentrated sulfuric acid dropwise under stirring, stirring the reaction vigorously, centrifuging, washing, drying to obtain oleic acid modified diatomite; in the P1, the amount ratio of diatomite, ethanol, mixed solution is 10-20g:1-2L:200-400mL; the sieving method is 2-4 times of sieving through a 350-mesh sieve; the reaction time at room temperature is 20-28h; the mixed solution is a mixture of 5mol / L HCl and 30wt% H2O2 in a volume ratio of 1:1; in the P2, the amount ratio of N,N-dimethylformamide, oleic acid, activated diatomite, concentrated sulfuric acid is 10-20mL:1.5-3g:1-2g:3-6 drops; the reaction condition is that the reaction temperature is 55-65℃ and the reaction time is 5-7h; the centrifuging method is centrifuging at a speed of 5000-7000r / min for 15-25min; the washing method is washing with ethanol and water for 2-3 times respectively; the drying method is drying at 40℃ for 10-14h.

10. A fipronil-containing microcapsule suspension prepared by the method according to any one of claims 1-9.

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