Compound anthelmintic granules for aquaculture, preparation method and application thereof

Abstract

The present invention belongs to the field of aquaculture technology and discloses a compound anthelmintic granule for aquaculture, a preparation method, and an application thereof. The compound anthelmintic granule is prepared from raw materials such as emamectin benzoate, flubendiamide, a surfactant, an antioxidant, a disintegrant, and a filler. The present invention selects emamectin benzoate and flubendiamide as active ingredients to kill crustacean parasites. Currently, there is no oral anthelmintic compounded with these two ingredients as active ingredients for aquaculture. Emamectin benzoate paralyzes the parasites and is metabolized slowly in the body. It is highly toxic to aquatic animals and is not suitable for large-scale or long-term use. Flubendiamide's main mechanism of action is to inhibit chitin synthesis, and although it has a slow onset of action, it is relatively safe for aquatic animals and is particularly effective against parasites resistant to organophosphorus and pyrethroids. Clinical verification has shown that the two compounds synergize and are far more effective in killing crustacean parasites than existing aquatic insecticides.

Description

Technical Field

[0001] The invention belongs to the technical field of aquaculture, and particularly relates to compound anthelmintic granules for aquaculture, and a preparation method and application thereof. Background Art

[0002] my country is a major aquaculture country, with an annual output exceeding 68 million tons, and freshwater aquaculture accounts for approximately 70% of the global total. In freshwater aquaculture, three major parasites are found: protozoa, helminths, and crustaceans. Crustacean parasites are particularly diverse, with high infection rates and the greatest potential for harm.

[0003] Crustaceans are a relatively primitive group of arthropods. Their main characteristic features are their heterorhythmically segmented bodies, divided into three parts: the head, thorax, and abdomen. They possess a chitinous exoskeleton, two pairs of pedipalps with jointed appendages, and an open-tubular circulatory system. Crustaceans are numerous, and while most are beneficial to humans, some also parasitize aquatic animals, impacting their growth and development and, in severe cases, causing mass mortality. Parasitic crustaceans primarily include copepods, branchioceras, cirripeds, isopods, and decapods. Representative parasites of freshwater aquaculture in my country include the Chinese mullet, anchorhead mullet, and silver carp. Crustacean parasites pose a significant threat to aquatic animals of all ages. They attach to the body or gills of aquatic animals, feeding on their host's blood and mucus, severely impacting their growth and health. Furthermore, the trauma they cause to host tissues makes it easier for bacteria and viruses to invade, causing complications or secondary diseases.

[0004] At present, national standard drugs for the prevention and control of aquaculture crustacean parasites are mainly divided into national standard products and non-national standard products. National standard products include pyrethroids (deltamethrin solution, high-efficiency cypermethrin solution, cypermethrin solution), organophosphates (phoxim solution) and trichlorfon (trichlorfon solution, refined trichlorfon powder). The main ingredients of these products are pesticides, which have poor safety and have certain impacts on the environment and food safety. In addition, because aquatic veterinary drugs have not been updated for many years, drug resistance has become generally serious, which has led to farmers often increasing the dosage during clinical use, which is prone to drug-related accidents. Non-national standard products are usually registered and sold in the form of non-drugs. The ingredients of these products are unknown, and they usually use organic reagents such as isopropyl alcohol, methanol, ethyl acetate, xylene, acetone, etc. as solvents. Their safety and effectiveness need to be further verified.

[0005] Whether they meet national standards or not, these insecticides are all external-use solutions, diluted with water before being added to aquaculture water. These insecticides are significantly affected by the environment during use, easily emulsifying and crystallizing in water, making them less effective. Furthermore, dosage is difficult to control, making them prone to pesticide-induced accidents and environmental pollution. Summary of the Invention

[0006] In order to solve the problems existing in the above-mentioned prior art, the first purpose of the present invention is to provide a compound anthelmintic granule for aquaculture. The compound anthelmintic granule of the present invention is administered orally, has good stability and rapid release in the body. Oral use can effectively prevent and treat crustacean parasites, is safe for aquatic animals, and is friendly to the breeding environment. It can also be made into spherical particles of different diameters according to the actual size of the feed, which is convenient for clinical mixing.

[0007] Another object of the present invention is to provide a method for preparing compound anthelmintic granules for aquaculture. The method is simple and easy to implement, and the operation is simple. The prepared compound anthelmintic granules have good stability and good water dispersibility, and the clinical dosage is much lower than the dosage of existing national standard or non-national standard crustacean parasiticides.

[0008] Another object of the present invention is to provide a compound anthelmintic granule for use in aquaculture to kill crustacean parasites that parasitize fish.

[0009] The technical solution adopted to achieve the above-mentioned purpose of the present invention is:

[0010] A compound anthelmintic granule for aquaculture, prepared from the following raw materials in the following weight percentages:

[0011]

[0012] Furthermore, the surfactant is at least one of sodium heavy alkylbenzene sulfonate, sodium secondary alkyl sulfonate, sodium secondary alkyl sulfate, sodium α-olefin sulfonate, sulfosuccinate, alkylphenol polyoxyethylene ether, and fatty alcohol polyoxyethylene ether.

[0013] Furthermore, the antioxidant is at least one of butylated hydroxyanisole, propyl gallate, and butylated hydroxytoluene.

[0014] Furthermore, the disintegrant is at least one of sodium carboxymethyl starch, hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone.

[0015] Furthermore, the filler is at least one of corn starch, pregelatinized starch, powdered sugar, lactose, dextrin, microcrystalline cellulose, and calcium carbonate.

[0016] Benzoic acid emamectin methylamino avermectin in the present invention is also called emamectin benzoate, emamectin benzoate, emamectin, is a kind of semi-synthetic antibiotic insecticide synthesized from fermentation product avermectin B1, soluble in acetone and methanol, slightly soluble in water, insoluble in hexane. Benzoic acid emamectin methylamino avermectin has stomach poison, contact killing effect, can enhance the effect of neurotic such as glutamic acid and gamma-aminobutyric acid (GABA), thereby making a large amount of chloride ions enter nerve cells, making cell function loss, disturbing nerve conduction, making irreversible paralysis occur in parasite, reaching the highest lethality within 3-4 days. Benzoic acid emamectin methylamino avermectin is usually made into emulsifiable concentrate, used on economic crops such as vegetables, tobacco, tea, cotton, fruit trees, for driving and killing pests such as mites, Lepidoptera, Coleoptera. Currently, registered domestic emulsifiable concentrates of emamectin benzoate include various concentrations, including 0.2%, 0.5%, 0.8%, 1%, 1.5%, 2%, 2.2%, 3%, 5%, and 5.7%. While research on the use of emamectin benzoate as a deworming agent for marine fish has been conducted abroad, there are no domestically approved insecticides for freshwater aquaculture.

[0017] Flubenzuron, a phenylformyl urea insecticide, is a stomach and contact toxicant with no systemic activity. It is a low-toxic insecticide, low-toxic to fish and birds, non-toxic to bees, and safe for crops. Flubenzuron's mechanism of action is primarily to inhibit chitin synthesis. Upon contact with insects, it disrupts chitin formation, thereby preventing further growth of the insect's exoskeleton.

[0018] Accordingly, the present invention also claims a method for preparing the aforementioned compound anthelmintic granules for aquaculture, which comprises the following steps:

[0019] S1. dispersing a surfactant in water to obtain an aqueous surfactant solution with a mass concentration of 20% to 30%;

[0020] S2, crushing and sieving emamectin benzoate and fenfluramide, and then adding them to the surfactant aqueous solution respectively, stirring evenly to obtain an emulsion;

[0021] S3. The disintegrant, antioxidant, and filler are mixed uniformly to obtain a mixed excipient. 70-85w% of the mixed excipient is added to a round pot granulator, atomized water is sprayed into the granulator, and spheronization is started under heating conditions to spheronize the material to form a base core;

[0022] S4. When the diameter of the base core reaches 0.5-1.5 mm, the emulsion is atomized and sprayed into a granulator (spraying pressure 0.1-0.2 MPa), and the remaining mixed auxiliary materials are added to the granulator to round the material into spherical particles, which are the compound anthelmintic granules for aquaculture.

[0023] Furthermore, in the step S3, the rotation speed during spheronization is 25-35 rpm and the temperature is 45-60°C.

[0024] Furthermore, the diameter of the base core is 0.5 to 1.5 mm, and the diameter of the compound anthelmintic granules for aquaculture is 2.0 to 3.5 mm.

[0025] Both emamectin benzoate and flubenzuron are insoluble in water. In the existing preparation technology, organic solvents such as toluene, xylene, and acetone are usually used to make emulsifiable concentrates. If emamectin benzoate or flubenzuron emulsifiable concentrates are directly used for aquatic insecticide, they form an emulsion after mixing with water and precipitate after being placed for 1-2 hours. They cannot have an effect on crustacean parasites in the water body, and the dosage is difficult to grasp. Moreover, due to the use of more pesticides and organic solvents, they are poorly safe and pollute the environment. The present invention first prepares the base core by mixing auxiliary materials, and then emamectin benzoate and flubenzuron are uniformly atomized and sprayed on the base core surface with a surfactant mixed solution, and the water is evaporated by heating to form drug particles. Compared to common emulsifiable concentrate formulations, the drug is more stable in a solid state. At the same time, due to being wrapped in the outer layer of the particles, it can be released and absorbed more quickly in vivo when used for oral anthelmintic of aquatic animals. Clinical verification has found that its killing effect on crustacean parasites is far superior to existing aquatic insecticides.

[0026] Accordingly, the present invention also claims the use of the aforementioned compound anthelmintic granules in aquaculture, and the use of the aforementioned compound anthelmintic granules in the preparation of anthelmintics or insecticides for aquaculture.

[0027] Furthermore, the worms are crustacean parasites that parasitize fish.

[0028] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0029] The present invention uses emamectin benzoate and flubendiamide as active ingredients to kill crustacean parasites. Currently, there are no oral anthelmintics formulated with these two active ingredients for use in aquaculture. Emamectin benzoate paralyzes and kills parasites, but its metabolism is slow, making it highly toxic to aquatic animals and unsuitable for large-scale or long-term use. Flubendiamide, which primarily acts by inhibiting chitin synthesis, has a slow onset but is relatively safe for aquatic animals and is particularly effective against parasites resistant to organophosphorus and pyrethroid insecticides. Clinical validation has shown that the two compounds work synergistically, resulting in far superior effectiveness against crustacean parasites than existing aquatic insecticides.

[0030] 2. The compound anthelmintic granules of the present invention can be orally administered for 3 to 5 consecutive days at a clinical dosage of 25 mg / kg bw to effectively kill crustacean parasites on fish. The dosage is much lower than the dosage of existing national standards for anti-crustacean parasites (30% trichlorfon solution: per 1m3 Water: 0.33-0.67g; 4.5% highly effective cypermethrin solution: per 1m 3 0.02~0.03ml water; 1% deltamethrin solution: per 1m 3 Water: 15-22 mg; 10% phoxim solution: per 1m 3 The compound anthelmintic granules of the present invention are non-irritating due to oral administration and are safe to aquatic animals and various aquatic organisms. In addition, since no organic solvent is used, the compound anthelmintic granules are environmentally friendly.

[0031] 3. The compound anthelmintic granules of the present invention have a reasonable formula design. Since both raw materials are insoluble in water and difficult to disperse in water, suitable surfactants are screened through experiments so that the two raw materials can be uniformly dispersed in the surfactant aqueous solution and sprayed with the solution atomized, thereby being evenly distributed on the surface of the base core. Since the drug is wrapped in the outer layer of the granules and has the presence of a disintegrant, it can be quickly released in the body. At this time, the surfactant plays the role of an absorption promoter. On the one hand, it can improve the apparent solubility of the drug, thereby improving the oral delivery efficiency of lipophilic drugs. On the other hand, it can reduce the metabolic effects of multiple enzymes on the drug, destroy the tight connection of the digestive tract, improve cell membrane fluidity, promote intestinal lymphatic transport and absorption, enhance the affinity of the drug with epithelial cells, and then increase the penetration efficiency of the drug in the digestive tract, thereby improving oral bioavailability.

[0032] 4. The raw materials of the compound anthelmintic granules of the present invention are easily available and inexpensive, the preparation method is simple and easy to operate, the preparation cost is low, and industrial large-scale production can be carried out. DETAILED DESCRIPTION

[0033] The present invention is described in detail below with reference to specific embodiments, but these embodiments are not to be construed as limiting the scope of protection of the present invention in any sense.

[0034] Example 1

[0035] A compound anthelmintic granule for aquaculture, prepared from the following raw materials in the following weight percentages:

[0036]

[0037] The preparation method of the above-mentioned compound anthelmintic granules for aquaculture is as follows:

[0038] 1. Disperse 8 g of disodium sulfosuccinate in water to obtain a disodium sulfosuccinate aqueous solution with a mass concentration of 22%.

[0039] 2. Grind 0.2 g of emamectin benzoate and 0.25 g of flubendiamide through a 100-mesh sieve, then add them to the aqueous solution of disodium sulfosuccinate, stir to form a uniform emulsion, and set aside.

[0040] 3. Mix 4 g of cross-linked polyvinyl pyrrolidone, 0.1 g of butylated hydroxyanisole, and 87.45 g of lactose to obtain a mixed excipient. Add 80 w% of the mixed excipient into a round pot granulator. Set the speed of the round pot granulator to 30 rpm and heat the round pot granulator to 55 ° C. Then spray an appropriate amount of atomized water and start spheronization at the same time to spheronize the material to form a base core.

[0041] 4. When the diameter of the base core reaches 0.5-1.5 mm, the emulsion is atomized and sprayed into a round pot granulator. The spray pressure is set to 0.2 MPa. At the same time, the remaining 20 w% of the mixed auxiliary materials are added to the granulator to round the material into spherical particles of 2.0-3.5 mm (water content below 5%), which are the compound anthelmintic granules for aquaculture.

[0042] Example 2

[0043] A compound anthelmintic granule for aquaculture, prepared from the following raw materials in the following weight percentages:

[0044]

[0045]

[0046] The preparation method of the above-mentioned compound anthelmintic granules for aquaculture is as follows:

[0047] 1. Disperse 10 g of sodium secondary alkyl sulfonate SAS-60 in water to obtain a sodium secondary alkyl sulfonate aqueous solution with a mass concentration of 30%.

[0048] 2. Grind 0.05 g of emamectin benzoate and 0.5 g of flubendiamide through a 100-mesh sieve, then add them to the aqueous solution of sodium secondary alkyl sulfonate, stir to form a uniform emulsion, and set aside.

[0049] 3. Mix 4 g of sodium carboxymethyl starch, 0.1 g of butylated hydroxytoluene and 85.45 g of pregelatinized starch to obtain a mixed auxiliary material. Add 80 w% of the mixed auxiliary material into a round pot granulator. Set the speed of the round pot granulator to 30 rpm and heat the round pot granulator to 55 ° C. Then spray an appropriate amount of atomized water and start spheronization at the same time to spheronize the material to form a base core.

[0050] 4. When the diameter of the base core reaches 0.5-1.5 mm, the emulsion is atomized and sprayed into a round pot granulator, and the spray pressure is set to 0.2 MPa. At the same time, the remaining 20 w% of the mixed auxiliary materials are added to the granulator to round the material into spherical particles of 2.0-3.5 mm (water content below 5%), which are the compound anthelmintic granules for aquaculture.

[0051] Example 3

[0052] A compound anthelmintic granule for aquaculture, prepared from the following raw materials in the following weight percentages:

[0053]

[0054] The preparation method of the above-mentioned compound anthelmintic granules for aquaculture is as follows:

[0055] 1. Disperse 7.5 g of fatty alcohol polyoxyethylene ether AEO-9 in water to obtain a fatty alcohol polyoxyethylene ether aqueous solution with a mass concentration of 20%.

[0056] 2. Grind 0.1 g of avermectin benzoate and 0.3 g of flubendiamide through a 100-mesh sieve, then add them to the fatty alcohol polyoxyethylene ether aqueous solution respectively, stir to form a uniform emulsion, and set aside.

[0057] 3. Mix 2 g of hydroxypropyl cellulose, 0.2 g of butylated hydroxyanisole, 39.9 g of microcrystalline cellulose and 50 g of corn starch to obtain a mixed excipient. Add 80 w% of the mixed excipient into a round pot granulator. Set the speed of the round pot granulator to 30 rpm and heat the round pot granulator to 55 ° C. Then spray an appropriate amount of atomized water and start spheronization at the same time to spheronize the material to form a base core.

[0058] 4. When the diameter of the base core reaches 0.5-1.5 mm, the emulsion is atomized and sprayed into a round pot granulator, and the spray pressure is set to 0.2 MPa. At the same time, the remaining 20 w% of the mixed auxiliary materials are added to the granulator to round the material into spherical particles of 2.0-3.5 mm (water content below 5%), which are the compound anthelmintic granules for aquaculture.

[0059] Example 4

[0060] A compound anthelmintic granule for aquaculture, prepared from the following raw materials in the following weight percentages:

[0061]

[0062] The preparation method of the above-mentioned compound anthelmintic granules for aquaculture is as follows:

[0063] 1. Disperse 5 g of heavy alkylbenzene sulfonate sodium OBS-50 in water to obtain a heavy alkylbenzene sulfonate aqueous solution with a mass concentration of 30%.

[0064] 2. Grind 0.25 g of emamectin benzoate and 0.1 g of flubendiamide through a 100-mesh sieve, then add them to the aqueous solution of sodium heavy alkylbenzene sulfonate, stir to form a uniform emulsion, and set aside.

[0065] 3. Mix 4 g of hydroxypropyl cellulose, 0.01 g of propyl gallate, 60.64 g of powdered sugar and 30 g of dextrin to obtain a mixed excipient. Add 80 w% of the mixed excipient into a round pot granulator. Set the speed of the round pot granulator to 30 rpm and heat the round pot granulator to 55 ° C. Then spray an appropriate amount of atomized water and start spheronization at the same time to spheronize the material to form a base core.

[0066] 4. When the diameter of the base core reaches 0.5-1.5 mm, the emulsion is atomized and sprayed into a round pot granulator, and the spray pressure is set to 0.2 MPa. At the same time, the remaining 20 w% of the mixed auxiliary materials are added to the granulator to round the material into spherical particles of 2.0-3.5 mm (water content below 5%), which are the compound anthelmintic granules for aquaculture.

[0067] Example 5

[0068] In June 2024, at a breeding base in Wuhan's Dongxihu District, where grass carp were the main species, an attack of anchor floccosis (a type of crustacean parasite) occurred. The compound anthelmintic granules prepared in Example 1 (divided into groups A, B, and C, depending on dosage) were used to treat anchor floccosis. A control group was also established, receiving a 4.5% highly effective cypermethrin solution and a 10% phoxim solution, respectively. Three days after administration, 10 fish were randomly sampled from each group. The results are shown in Table 1.

[0069] Table 1 Comparison of the efficacy of different insecticides against anchor flea disease

[0070]

[0071] As can be seen from Table 1, the compound anthelmintic granules prepared in Example 1 were mixed with feed at a dose of 25 mg / kg bw and fed to fish for 3 days, which effectively killed anchor fleas parasitic on the fish bodies. During the medication process, it was found that the fish in the compound anthelmintic granule groups B and C had no abnormal phenomena such as death or swimming around, no death in the compound anthelmintic granule group A and the high-efficiency chlorpyrifos group, a small number of fish swimming around, and more fish swimming around in the phoxim solution group and the no-dose group.

[0072] Example 6

[0073] In September 2024, at the same breeding base in Dongxihu District, Wuhan, an outbreak of anchor tungiasis reappeared in grass carp. The compound anthelmintic granules prepared in Example 1 were used to treat anchor tungiasis. Simultaneously, 0.45 wt% emamectin benzoate granules (with the same excipients and preparation method as in Example 1) and 0.45 wt% fenfluramide granules (with the same excipients and preparation method as in Example 1) were prepared as control groups. After three consecutive days of administration, 10 fish were randomly sampled from each group. The results are shown in Table 2.

[0074] Table 2 Comparison of the efficacy of different anthelmintics against anchor flea disease

[0075]

[0076] As shown in Table 2, at the same dosage, the compound anthelmintic granules prepared in Example 1 were effective in treating anchor tungiasis, with no mortality, limb-swimming, or other abnormal phenomena. The fenfluramide and emamectin benzoate groups showed no mortality, with a small number of fish limb-swimming, while the no-dose group showed a significant number of fish mortality and limb-swimming. The anthelmintic effect of the compound anthelmintic granules in Example 1 was superior to that of the anthelmintic prepared using emamectin benzoate and fenfluramide alone.

Claims

1. A compound anthelmintic granule for aquaculture, characterized in that It is prepared from the following raw materials in percentage by weight:

2. The compound anthelmintic granules for aquaculture according to claim 1, characterized in that: The surfactant is at least one of heavy alkylbenzene sodium sulfonate, secondary alkyl sodium sulfonate, secondary alkyl sodium sulfate, α-olefin sodium sulfonate, sulfosuccinate, alkylphenol polyoxyethylene ether and fatty alcohol polyoxyethylene ether.

3. The compound anthelmintic granules for aquaculture according to claim 1, characterized in that: The antioxidant is at least one of butylated hydroxyanisole, propyl gallate and butylated hydroxytoluene.

4. The compound anthelmintic granules for aquaculture according to claim 1, characterized in that: The disintegrant is at least one of sodium carboxymethyl starch, hydroxypropyl cellulose and cross-linked polyvinyl pyrrolidone.

5. The compound anthelmintic granules for aquaculture according to claim 1, characterized in that: The filler is at least one of corn starch, pregelatinized starch, powdered sugar, lactose, dextrin, microcrystalline cellulose and calcium carbonate.

6. A method for preparing the compound anthelmintic granules for aquaculture according to any one of claims 1 to 5, characterized in that The steps include: S1, dispersing a surfactant in water to obtain a surfactant aqueous solution; S2, crushing and sieving emamectin benzoate and fenfluramide, and then adding them to the surfactant aqueous solution respectively, stirring evenly to obtain an emulsion; S3. The disintegrant, antioxidant, and filler are uniformly mixed to obtain a mixed excipient, 70-85 wt% of the mixed excipient is added to a round pot granulator, atomized water is sprayed into the granulator, and spheronization is started under heating conditions to spheronize the material to form a base core; S4. When the diameter of the base core reaches 0.5-1.5 mm, the emulsion is atomized and sprayed into a granulator. At the same time, the remaining mixed auxiliary materials are added into the granulator to round the materials into spherical particles, which are the compound anthelmintic granules for aquaculture.

7. The method for preparing the compound anthelmintic granules for aquaculture according to claim 6, characterized in that: In the step S3, the rotation speed during spheronization is 25-35 rpm and the temperature is 45-60°C.

8. The method for preparing the compound anthelmintic granules for aquaculture according to claim 6, characterized in that: The diameter of the base core is 0.5-1.5 mm, and the diameter of the compound anthelmintic granules for aquaculture is 2.0-3.5 mm.

9. Use of the compound anthelmintic granules for aquaculture according to claim 1 in the preparation of an anthelmintic or an insecticide for aquaculture.

10. The use of the compound anthelmintic granules for aquaculture according to claim 9, characterized in that: The worms are crustacean parasites that parasitize fish bodies.

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