An albendazole ivermectin premix and its preparation method

Abstract

This invention relates to the field of veterinary drugs, specifically to an albendazole-ivermectin premix and its preparation method. The premix, by weight percentage (100%), comprises the following raw materials: albendazole 9.5-10.5%, ivermectin microcapsules 0.19-0.21%, sodium chloride 12-24%, and the balance being modified starch. The albendazole-ivermectin premix prepared by this invention can be uniformly mixed through a simple process, exhibiting high homogeneity.

Description

Technical Field

[0001] This invention relates to the field of veterinary drugs, specifically to an albendazole ivermectin premix and its preparation method. Background Technology

[0002] Albendazole is a highly effective imidazole derivative broad-spectrum anthelmintic, clinically used to treat roundworms, pinworms, tapeworms, whipworms, hookworms, and strongyloides stercoralis. The sulfur atom on the abendazole molecule can be metabolized into sulfoxides or sulfones in animals, thereby inhibiting the parasite's absorption of glucose, leading to glycogen depletion, or inhibiting the fumarate reductase system, hindering ATP production, and affecting the parasite's metabolism and reproduction.

[0003] Ivermectin is a novel, broad-spectrum, highly effective, and low-toxicity macrolide antiparasitic drug with good killing effects on both internal and external parasites. It can be used to treat onchocerciasis, strongyloidiasis, and infections caused by hookworms, roundworms, whipworms, and pinworms. Ivermectin increases the release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) from parasites, opens glutamate-controlled chloride ion channels, and enhances the permeability of nerve membranes to chloride ions, thereby interfering with nerve signal transmission, causing nerve paralysis in the parasite, loss of muscle cell contraction ability, and ultimately leading to parasite death or expulsion. However, the dosage of ivermectin is relatively small, and current preparation methods often result in uneven mixing, leading to insufficient dosage of the active ingredient according to the formula, thus affecting treatment efficacy.

[0004] Patent CN107349212B discloses an albendazole-ivermectin premix and its preparation method, comprising the following components: albendazole, ivermectin, medicinal charcoal, corn cob powder, plant extract for uterine protection and pregnancy maintenance, and starch. During preparation, the addition of plant extract for uterine protection and pregnancy maintenance to the formula effectively reduces the side effects of albendazole. However, this method requires multiple premixing steps with ivermectin and excipients, making the process cumbersome.

[0005] Patent CN106389456B discloses a veterinary albendazole-ivermectin premix and its preparation method, comprising the following components: albendazole, ivermectin, pharmaceutical charcoal, anhydrous glucose, corn starch, ivermectin pretreatment agent, and excipients. The ivermectin pretreatment agent in this invention contains paraffin, but paraffin may cause diseases such as gastric stones or gastrointestinal inflammation in cattle, leading to health problems.

[0006] Therefore, there is an urgent need for an albendazole ivermectin premix that is easy to prepare and suitable for a variety of animals. Summary of the Invention

[0007] To overcome the shortcomings of the prior art, the present invention provides an albendazole ivermectin premix and its preparation method. The prepared albendazole ivermectin premix can be mixed evenly through a simple process, with high uniformity and high drug utilization.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] The first aspect of the present invention provides an albendazole-ivermectin premix, comprising, by weight percentage 100%, the following raw materials: albendazole 9.5-10.5%, ivermectin microcapsules 0.19-0.21%, sodium chloride 12-24%, and the balance being modified starch.

[0010] In some embodiments, the method for preparing the ivermectin microcapsules includes the following steps:

[0011] (1) Dissolve ivermectin in methanol, add Span 80 to obtain the oil phase, then dissolve Tween 80 in water to obtain the aqueous phase, pour the aqueous phase into the oil phase, and stir at 300-400 rpm for 30-40 min to obtain the emulsion.

[0012] (2) Mix 2,5-dihydroxyterephthalic acid epoxide, chitosan and the emulsion obtained in step (1) evenly, adjust the pH to 8-10 with NaOH, stir the reaction at 45-55℃ and 300-400rpm for 1.5-2.5h, cool to room temperature, filter, and dry to obtain ivermectin microcapsules.

[0013] Preferably, the volume ratio of the aqueous phase to the oil phase is (1-2):1.

[0014] Albendazole is a broad-spectrum anthelmintic drug of the imidazole derivative class, while ivermectin is a broad-spectrum, highly effective, and low-toxicity anthelmintic drug. The combination of the two has a synergistic effect, resulting in a more significant anthelmintic effect. However, the addition amount of ivermectin is small, and the simple process makes it difficult to mix evenly, resulting in poor content uniformity and unstable efficacy. This invention prepares ivermectin microcapsules, which can be mixed evenly with albendazole and other excipients through a simple mixing process. This may be because the shell of the microcapsule contains a large number of polar groups that have good compatibility with albendazole, increasing the uniformity of the mixture. In addition, ivermectin microcapsules can reduce the destruction of the drug by gastric acid and increase the drug's utilization rate. This may be because the cross-linking structure of 2,5-dihydroxyterephthalic acid epoxide and chitosan slows down the decomposition of chitosan in animal gastric juice, preventing ivermectin from being destroyed by gastric acid, and allowing it to enter the intestine for absorption and utilization.

[0015] In some embodiments, the ivermectin microcapsules have a particle size of 1-2 μm.

[0016] This invention limits the particle size of ivermectin microcapsules, increasing the specific surface area of ​​the active pharmaceutical ingredient without causing aggregation, thereby increasing the drug's dissolution rate in vivo and improving its bioavailability.

[0017] In some embodiments, the mass ratio of the 2,5-dihydroxyterephthalic acid epoxide to chitosan is (0.2-0.4):1.

[0018] This invention limits the mass ratio of 2,5-dihydroxyterephthalic acid epoxide and chitosan to give chitosan a certain degree of cross-linking, which can slow down the decomposition of chitosan and reduce the damage of gastric acid to ivermectin.

[0019] In some embodiments, the method for preparing the 2,5-dihydroxyterephthalic acid epoxide includes the following steps:

[0020] I. Add 2,5-dihydroxyterephthalic acid to DMF and stir at 0-5℃ for 20-30 min. Then add anhydrous potassium carbonate and stir for 3-6 min. Then add bromopropylene dropwise and continue stirring for 25-35 min. Then raise the temperature to 30-35℃ and react for 47-49 h. Extract, wash and dry to obtain allylated 2,5-dihydroxyterephthalic acid.

[0021] II. Add the allylated 2,5-dihydroxyterephthalic acid obtained in step I to dichloromethane and stir at 0-5℃ for 20-30 min. Then, add 4-7 wt% of a dichloroperoxybenzoic acid solution in dichloromethane. After the addition is complete, continue the reaction for 55-70 min, raise the temperature to 35-45℃, and react for 47-49 h. Then, cool at -6 to 0℃ for 5.5-6.5 h, filter, wash, and dry to obtain 2,5-dihydroxyterephthalic acid epoxide.

[0022] In some embodiments, the mass ratio of 2,5-dihydroxyterephthalic acid, anhydrous potassium carbonate and bromopropylene in step I is 1:(2.8-3):(3-3.2).

[0023] In some embodiments, the mass ratio of the allylated 2,5-dihydroxyterephthalic acid to the 4-7 wt% dichloroperoxybenzoic acid solution in dichloromethane in step II is 1:(90-95).

[0024] This invention converts the -OH group of 2,5-dihydroxyterephthalic acid into a double bond by limiting the mass ratio of 2,5-dihydroxyterephthalic acid, anhydrous potassium carbonate, and bromopropylene, thereby allylating 2,5-dihydroxyterephthalic acid. Furthermore, by limiting the mass ratio of the allylated 2,5-dihydroxyterephthalic acid to a dichloromethane solution of m-chloroperoxybenzoic acid, the double bond is completely converted into an epoxy group, which then reacts with the amino group of chitosan to produce a cross-linked structure in chitosan.

[0025] In some embodiments, the method for preparing the modified starch includes the following steps:

[0026] 1) Add crotonic acid and starch to DMF, and add phosphoric acid solution while stirring. Stir at 70-80℃ for 5-6 hours. Then add sorbic acid and azobisisobutyronitrile, and continue stirring for 1-2 hours. Filter, wash and dry to obtain pre-modified starch.

[0027] 2) Add the pre-modified starch obtained in step 1), zinc gluconate, and NaOH to DMF and stir at 70-80℃ for 5-6 hours to obtain modified starch.

[0028] Preferably, the mass ratio of crotonic acid, sorbic acid and starch in step 1) is (0.5-0.7):(0.6-0.8):1.

[0029] Starch is stable, compatible with most drugs, and inexpensive, making it a common filler in pharmaceuticals. However, when used in premixes, it easily absorbs moisture after the outer packaging is opened, affecting drug quality. This invention modifies starch to reduce moisture absorption and increases compatibility with the active pharmaceutical ingredient, thus improving drug homogeneity. This may be due to two factors: firstly, crotonic acid consumes some of the hydrophilic hydroxyl groups on starch, and copolymerization with sorbic acid further increases the hydrophobicity of the alkane segments; secondly, the uniformly distributed carboxyl groups on the polymer react with the hydroxyl groups of zinc gluconate, resulting in uniform distribution of zinc gluconate along the branched chains; and thirdly, the electrostatic repulsion between modified starch molecules further enhances starch dispersibility, making the prepared premix more homogeneous. Additionally, the zinc ions of zinc gluconate can coordinate with both albendazole and ivermectin, further improving the homogeneity of the premix. Furthermore, the combination of zinc gluconate and sodium chloride can improve animal appetite, making the drug easier to administer.

[0030] In some embodiments, the mass ratio of the pre-modified starch to zinc gluconate in step 2) is 1:(0.3-0.5).

[0031] This invention limits the mass ratio of pre-modified starch to zinc gluconate in step 2), so that zinc gluconate is evenly distributed on the obtained modified starch, while improving the hygroscopicity of starch and zinc gluconate, and making the prepared medicine more uniform.

[0032] A second aspect of this invention provides a method for preparing an albendazole-ivermectin premix, comprising the following steps:

[0033] S1. Add sodium chloride, modified starch, and ivermectin microcapsules to a mixer and stir for 30-40 minutes to obtain a premix.

[0034] S2. Add albendazole to the premix obtained in step S1, continue stirring at 60-70℃ for 25-35 minutes, and continue stirring at room temperature for 15-25 minutes to obtain albendazole ivermectin premix.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] 1. The present invention provides an albendazole-ivermectin premix prepared by preparing ivermectin microcapsules and modifying starch, and then combining it with albendazole and sodium chloride. The premix can be mixed evenly through a simple process, with high uniformity and small deviation of the effective ingredients.

[0037] 2. The ivermectin microcapsules prepared by this invention contain a large number of polar groups in their shells, which have good compatibility with albendazole. They can be mixed evenly with albendazole and other excipients through a simple mixing process. In addition, 2,5-dihydroxyterephthalic acid epoxide and chitosan form a cross-linked structure, which slows down the decomposition of chitosan in animal gastric juice, prevents ivermectin from being destroyed by gastric acid, and then enters the intestine for absorption and utilization, thereby increasing the drug utilization rate.

[0038] 3. This invention modifies starch to make it less hygroscopic, while increasing its compatibility with the raw drug and further improving the uniformity of the drug. In addition, the combination of zinc gluconate and sodium chloride can improve the animal's appetite and make the drug easier to administer. Detailed Implementation

[0039] The present invention will be described below with reference to specific embodiments. It should be noted that the examples and comparative examples below are for illustrative purposes only and are not intended to limit the invention. Other combinations and various modifications within the scope of the invention can be made without departing from its spirit or scope.

[0040] To facilitate the implementation of this invention by those skilled in the art, the following description is provided regarding some of the raw materials and manufacturers used in the examples and comparative examples: The compounds and related reagents used in the following examples and comparative examples can all be purchased from the market, and the corn starch was purchased from Jinan Mingfeng Biotechnology Co., Ltd.

[0041] Preparation Example 1

[0042] The preparation method of 2,5-dihydroxyterephthalic acid epoxide-1 includes the following steps:

[0043] I. Add 5g of 2,5-dihydroxyterephthalic acid to 100ml of DMF and stir at 2℃ for 25min. Then add 14.5g of anhydrous potassium carbonate and stir for 5min. Then add 15.5g of bromopropene dropwise at a rate of 0.5g / min and continue stirring for 30min. Then raise the temperature to 32℃ and react for 48h. Extract, wash and dry to obtain allylated 2,5-dihydroxyterephthalic acid.

[0044] II. Add 5g of allylated 2,5-dihydroxyterephthalic acid obtained in step I to 100ml of dichloromethane and stir at 3℃ for 25min. Then, add 465g of a 5wt% dichloroperoxybenzoic acid solution in dichloromethane at a dropping rate of 15g / min. After the addition is complete, continue the reaction for 60min. Raise the temperature to 40℃ and react for 48h. Then, cool at -3℃ for 6h, filter, wash, and dry to obtain 2,5-dihydroxyterephthalic acid epoxide-1.

[0045] Preparation Example 2

[0046] The preparation method of 2,5-dihydroxyterephthalic acid epoxide-2 is the same as that in Preparation Example 1, except that the amount of bromopropene added is 13g.

[0047] Preparation Example 3

[0048] The preparation method of 2,5-dihydroxyterephthalic acid epoxide-3 is the same as that in Preparation Example 1, except that the amount of 5wt% dichloromethane solution of m-chloroperoxybenzoic acid added is 435g.

[0049] Preparation Example 4

[0050] The preparation method of ivermectin microcapsules-1 includes the following steps:

[0051] (1) Dissolve 1g of ivermectin in 20ml of anhydrous methanol, add 0.2ml of Span 80 to obtain the oil phase, then dissolve 0.2ml of Tween 80 in 30ml of deionized water to obtain the aqueous phase, pour 30ml of the aqueous phase into 20ml of the oil phase, and stir at 350rpm for 35min to obtain the emulsion.

[0052] (2) Mix 3g of 2,5-dihydroxyterephthalic acid epoxide-1, 10g of chitosan and 50ml of the emulsion obtained in step (1) evenly, adjust the pH to 9 with NaOH, stir and react for 2h at 50℃ and 350rpm, cool to room temperature, filter and dry to obtain ivermectin microcapsules-1.

[0053] Preparation Example 5

[0054] The preparation method of ivermectin microcapsules-2 is the same as that in preparation example 4, except that the amount of 2,5-dihydroxyterephthalic acid epoxide-1 added is 1g.

[0055] Preparation Example 6

[0056] The preparation method of ivermectin microcapsules-3 is the same as that in preparation example 4, except that 2,5-dihydroxyterephthalic acid epoxide-1 is replaced by an equal amount of 2,5-dihydroxyterephthalic acid epoxide-2.

[0057] Preparation Example 7

[0058] The preparation method of ivermectin microcapsules-4 is the same as that in preparation example 4, except that 2,5-dihydroxyterephthalic acid epoxide-1 is replaced by an equal amount of 2,5-dihydroxyterephthalic acid epoxide-3.

[0059] Preparation Example 8

[0060] The preparation method of modified starch-1 includes the following steps:

[0061] 1) Add 6g of crotonic acid and 10g of corn starch to 100ml of DMF, and add 3ml of 75wt% phosphoric acid solution while stirring. Stir at 75℃ for 5.5h, then add 7g of sorbic acid and 0.1g of azobisisobutyronitrile, and continue stirring for 1.5h. Filter, wash and dry to obtain pre-modified starch.

[0062] 2) Add 10g of the pre-modified starch obtained in step 1), 4g of zinc gluconate, and 0.1g of NaOH to 50ml of DMF and stir at 75℃ for 5.5h to obtain modified starch-1.

[0063] Preparation Example 9

[0064] The preparation method of modified starch-2 is the same as that in preparation example 8, except that the amount of zinc gluconate added is 6g.

[0065] Example 1

[0066] An albendazole-ivermectin premix, comprising, by weight percentage 100%, the following raw materials: albendazole 10%, ivermectin microcapsules-1 0.2%, sodium chloride 18%, and modified starch-1 71.8%.

[0067] The preparation method of albendazole ivermectin premix in this embodiment includes the following steps:

[0068] S1. Add sodium chloride, modified starch-1, and ivermectin microcapsules-1 to a mixer and stir at room temperature for 35 minutes to obtain a premix.

[0069] S2. Add albendazole to the premix obtained in step S1, continue stirring at 65°C for 30 minutes, and continue stirring at room temperature for 20 minutes to obtain albendazole ivermectin premix.

[0070] Example 2

[0071] An albendazole-ivermectin premix, comprising, by weight percentage 100%, the following raw materials: albendazole 9.5%, ivermectin microcapsules-1 0.19%, sodium chloride 12%, and modified starch-1 78.31%.

[0072] The preparation method of albendazole ivermectin premix in this embodiment includes the following steps:

[0073] S1. Add sodium chloride, modified starch-1, and ivermectin microcapsules-1 to a mixer and stir at room temperature for 30 minutes to obtain a premix.

[0074] S2. Add albendazole to the premix obtained in step S1, continue stirring at 60°C for 35 min, and continue stirring at room temperature for 15 min to obtain albendazole ivermectin premix.

[0075] Example 3

[0076] An albendazole-ivermectin premix, comprising, by weight percentage 100%, the following raw materials: albendazole 10.5%, ivermectin microcapsules-1 0.21%, sodium chloride 24%, and modified starch-1 65.29%.

[0077] The preparation method of albendazole ivermectin premix in this embodiment includes the following steps:

[0078] S1. Add sodium chloride, modified starch-1, and ivermectin microcapsules-1 to a mixer and stir at room temperature for 40 minutes to obtain a premix.

[0079] S2. Add albendazole to the premix obtained in step S1, continue stirring at 70°C for 25 minutes, and continue stirring at room temperature for 25 minutes to obtain albendazole ivermectin premix.

[0080] Example 4

[0081] An albendazole ivermectin premix and its preparation method are described. The specific implementation method is the same as in Example 1, except that ivermectin microcapsules-1 are replaced with ivermectin microcapsules-2 in equal amounts.

[0082] Example 5

[0083] An albendazole ivermectin premix and its preparation method are described. The specific implementation method is the same as in Example 1, except that ivermectin microcapsules-1 are replaced with ivermectin microcapsules-3 in equal amounts.

[0084] Example 6

[0085] An albendazole ivermectin premix and its preparation method are described. The specific implementation method is the same as in Example 1, except that ivermectin microcapsules-1 are replaced with ivermectin microcapsules-4 in equal amounts.

[0086] Example 7

[0087] An albendazole ivermectin premix and its preparation method are described. The specific implementation method is the same as in Example 1, except that modified starch-1 is replaced with modified starch-2 in an equal amount.

[0088] Comparative Example 1

[0089] An albendazole ivermectin premix and its preparation method are described. The specific implementation method is the same as in Example 1, except that the ivermectin microcapsules are replaced with an equal amount of ivermectin.

[0090] Comparative Example 2

[0091] An albendazole ivermectin premix and its preparation method are described. The specific implementation method is the same as in Example 1, except that the modified starch is replaced with corn starch in an equal amount.

[0092] Performance testing

[0093] 1. Content and uniformity testing

[0094] The content of ivermectin in the above examples and comparative examples was determined by liquid chromatography according to the detection method of ivermectin in the Chinese Veterinary Pharmacopoeia (2015 edition). The uniformity was also determined by referring to the content uniformity test method in the appendix. The quality standard requires that the content of ivermectin should be 90-110% of the labeled amount and the content uniformity should be ≤15.0.

[0095] 2. Animal experiments

[0096] Nine hundred sheep weighing between 50-80 kg, suffering from mixed parasitic infections, were randomly divided into nine groups of 100 sheep each. All sheep were fed the premixes prepared in the above examples and comparative proportions. The average dosage was 0.05 g / kg per sheep per day. Treatment effectiveness was assessed after 10 days. Ineffective: no significant change in symptoms, parasite count, and fecal egg count remained unchanged or increased after 10 days. Effective: no significant change in symptoms, and a decrease or disappearance of parasite count and fecal egg count after 10 days. Cured: disappearance of parasite count and fecal egg count after 10 days.

[0097] The experimental results are shown in Table 1.

[0098] Table 1

[0099]

[0100] A comparison of the experimental data from Examples 1-3 in Table 1 shows that the ivermectin in this albendazole-ivermectin premix has good uniformity and therapeutic effect. A comparison of Example 4 with Example 1 shows that changes in the ratio of 2,5-dihydroxyterephthalic acid epoxide to chitosan may lead to a decrease in the cross-linking degree of the capsule shell and a decline in therapeutic effect. A comparison of Examples 5 and 6 with Example 1 shows that the ratio of 2,5-dihydroxyterephthalic acid, anhydrous potassium carbonate, and allyl bromopropene, as well as the ratio of allylated 2,5-dihydroxyterephthalic acid to 4... The change in the ratio of -7wt% m-chloroperoxybenzoic acid in dichloromethane solution may lead to a decrease in the stability of the microcapsule shell and a decrease in therapeutic effect; a comparison between Example 7 and Example 1 shows that the change in the ratio of pre-modified starch to zinc gluconate leads to a decrease in both the uniformity and therapeutic effect of the premix; a comparison between Example 1 and Comparative Example 1 shows that the uniformity and therapeutic effect of directly adding ivermectin are both poor; a comparison between Example 1 and Comparative Example 2 shows that the compatibility between unmodified starch and the original drug is poor, and all properties of the premix decrease.

[0101] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An albendazole-ivermectin premix, characterized in that, The product comprises, by weight percentage (100%), the following raw materials: albendazole 9.5-10.5%, ivermectin microcapsules 0.19-0.21%, sodium chloride 12-24%, and the balance being modified starch; the preparation method of the ivermectin microcapsules includes the following steps: (1) Dissolve ivermectin in methanol, add Span 80 to obtain the oil phase, then dissolve Tween 80 in water to obtain the aqueous phase, pour the aqueous phase into the oil phase, and stir at 300-400 rpm for 30-40 min to obtain the emulsion. (2) Mix 2,5-dihydroxyterephthalic acid epoxide, chitosan and the emulsion obtained in step (1) evenly, adjust the pH to 8-10 with NaOH, stir the reaction at 45-55℃ and 300-400rpm for 1.5-2.5h, cool to room temperature, filter, dry, and obtain ivermectin microcapsules; The preparation method of the 2,5-dihydroxyterephthalic acid epoxide includes the following steps: I. Add 2,5-dihydroxyterephthalic acid to DMF and stir at 0-5℃ for 20-30 min. Then add anhydrous potassium carbonate and stir for 3-6 min. Then add bromopropylene dropwise and continue stirring for 25-35 min. Then raise the temperature to 30-35℃ and react for 47-49 h. Extract, wash and dry to obtain allylated 2,5-dihydroxyterephthalic acid. II. The allylated 2,5-dihydroxyterephthalic acid obtained in step I was added to dichloromethane and stirred at 0-5℃ for 20-30 min. Then, a 4-7 wt% solution of m-chloroperoxybenzoic acid in dichloromethane was added dropwise. After the addition was complete, the reaction was continued for 55-70 min. The temperature was raised to 35-45℃ and the reaction was carried out for 47-49 h. Then, the mixture was cooled at -6~0℃ for 5.5-6.5 h. The mixture was filtered, washed, and dried to obtain 2,5-dihydroxyterephthalic acid epoxide. The method for preparing the modified starch includes the following steps: 1) Add crotonic acid and starch to DMF, and add phosphoric acid solution while stirring. Stir at 70-80℃ for 5-6 hours. Then add sorbic acid and azobisisobutyronitrile, and continue stirring for 1-2 hours. Filter, wash and dry to obtain pre-modified starch. 2) Add the pre-modified starch, zinc gluconate, and NaOH obtained in step 1) to DMF and stir at 70-80℃ for 5-6 hours to obtain modified starch.

2. The albendazole-ivermectin premix according to claim 1, characterized in that, The ivermectin microcapsules have a particle size of 1-2 μm.

3. The albendazole-ivermectin premix according to claim 1, characterized in that, The mass ratio of 2,5-dihydroxyterephthalic acid epoxide to chitosan is (0.2-0.4):

1.

4. The albendazole-ivermectin premix according to claim 1, characterized in that, The mass ratio of 2,5-dihydroxyterephthalic acid, anhydrous potassium carbonate and bromopropylene in step I is 1:(2.8-3):(3-3.2).

5. The albendazole-ivermectin premix according to claim 1, characterized in that, In step II, the mass ratio of the allylated 2,5-dihydroxyterephthalic acid to the 4-7 wt% dichloroperoxybenzoic acid solution in dichloromethane is 1:(90-95).

6. The albendazole-ivermectin premix according to claim 1, characterized in that, The mass ratio of the pre-modified starch to zinc gluconate in step 2) is 1:(0.3-0.5).

7. A method for preparing the albendazole-ivermectin premix according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Add sodium chloride, modified starch, and ivermectin microcapsules to a mixer and stir at room temperature for 30-40 minutes to obtain a premix. S2. Add albendazole to the premix obtained in step S1 and continue stirring at 60-70℃ for 25-35 minutes, then continue stirring at room temperature for 15-25 minutes to obtain albendazole ivermectin premix.

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