Water suspension type albendazole and ivermectin premix and preparation method thereof

Abstract

The invention relates to the field of veterinary drugs, in particular to a water suspension type albendazole and ivermectin premix and a preparation method thereof.The water suspension type albendazole and ivermectin premix is prepared from, by mass, 9.5%-10.5% of albendazole, 0.19%-0.21% of ivermectin microcapsules, 12%-24% of sodium chloride, 20%-25% of modified montmorillonite, 7%-10% of modified polyvinyl alcohol and the balance modified starch. The water suspension type albendazole and ivermectin premix prepared by the invention has high stability in water, can be directly added into water to feed animals, is convenient to use and has small toxic and side effects.

Description

Technical Field

[0001] The invention relates to the field of veterinary drugs, and in particular to a water-suspended albendazole-ivermectin premix and a preparation method thereof. Background Art

[0002] Albendazole has a strong expelling and killing effect on pig nematodes, liver flukes of cattle and sheep, etc., but has little effect on sheep fly disease, pig and cattle mite disease, and schistosomiasis infection. It has a strong expelling and killing effect on roundworms, pinworms, tapeworms, whipworms, hookworms, and fecal strongyloides. Ivermectin premix has a good therapeutic effect on lice, mites, and schistosomiasis of horses, cattle, pigs, and sheep. It is often necessary to use the two drugs in combination to achieve a good anthelmintic effect. However, the small dosage of ivermectin makes it difficult to mix evenly. Therefore, how to mix albendazole, ivermectin and other excipients evenly to reduce drug waste has become a problem of concern to people in this field.

[0003] Patent CN103356714B discloses a compound pharmaceutical composition containing albendazole and ivermectin for veterinary use, and relates to the field of veterinary drug technology preparations. It is composed of the following ingredients: albendazole, ivermectin, sulfamethoxazole, lactobacillus, and soluble starch. The veterinary antiparasitic pharmaceutical composition of the present invention is easy to use, synergistic, has a wide anti-insect spectrum, good anti-insect efficacy, can enhance gastric motility, increase feed intake, and is beneficial to the growth of poultry and livestock. The pharmaceutical compound of the invention can be a dry suspension, which can be directly added to an automatic drinking fountain in proportion, and is easy to use, but it ignores the problem that ivermectin is easy to settle in water, which easily causes insufficient or excessive dosage during feeding.

[0004] Patent CN115554308B discloses an albendazole-ivermectin premix, comprising the following components in parts by weight: 6 parts of albendazole, 0.25 parts of ivermectin, 10 parts of polyethylene glycol 6000, 41.75-75.75 parts of sugar, and 10-40 parts of potassium pivalate; the preparation method of the premix is ​​as follows: albendazole, ivermectin and polyethylene glycol 6000 are placed in an emulsifier according to the proportion, heated and stirred until completely mixed, and then the corresponding proportion of potassium pivalate-sucrose aqueous solution is slowly added, and after the addition is completed, stirring is continued until completely mixed, and the product is granulated using a spray granulator. The premix obtained by the invention has low toxicity, and the preparation process is environmentally friendly and safe, but the premix obtained by the invention is suitable for mixed administration with feed, and is not suitable for direct administration in drinking water.

[0005] Therefore, there is an urgent need for an albendazole-ivermectin premix that has good suspension in water and is convenient for administration. Summary of the invention

[0006] In order to overcome the above-mentioned deficiencies of the prior art, the present invention provides an albendazole-ivermectin premix which has high stability in water, can be directly added to water and fed to animals, is easy to use, and has little toxic and side effects.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides a water-suspended albendazole-ivermectin premix, which comprises the following raw materials, calculated by mass percentage of 100%, 9.5-10.5% of albendazole, 0.19-0.21% of ivermectin microcapsules, 12-24% of sodium chloride, 20-25% of modified montmorillonite, 7-10% of modified polyvinyl alcohol, and the balance is modified starch.

[0009] In some embodiments, the method for preparing the modified polyvinyl alcohol comprises the following steps:

[0010] A1. Add polyvinyl alcohol to acrylic acid, stir and react at 90-100°C for 5-6h, then add ethylene and tetrabutyl titanate, continue to react at 0.1-0.5MPa for 2-3h, wash and dry to obtain a polymer;

[0011] A2. Add the polymer obtained in step A1, allylmalonic acid and azobisisobutyronitrile to ethanol, react at 80-90° C. for 1-2 hours, wash and dry to obtain modified polyvinyl alcohol.

[0012] Polyvinyl alcohol has good dispersibility and stability, can effectively improve the uniformity and stability of the system, in drug manufacturing, can be evenly dispersed in liquid medium by drug particles, improve the bioavailability of medicine. Although polyvinyl alcohol has good water solubility, the process of dissolution usually requires heating or other external forces to assist, and the polyvinyl alcohol without dissolution can form a gel in water, affecting the dispersibility of other substances in the system. The present invention increases the water solubility of polyvinyl alcohol by modifying polyvinyl alcohol, and can make albendazole ivermectin form a stable suspension system in water at the same time, the possible reason is that the modified polyvinyl alcohol increases the side chain, forms a comb-type structure, the end of the side chain has multiple carboxyl groups, increases the solubility in water, can quickly and fully wet solid particles, the carboxyl groups at the ends of the long side chains in addition have the same charge, can produce repulsion each other, and the comb-type polymer has a strong adhesive force that can prevent particles from re-aggregating, keeps the long-term stability of the suspension system.

[0013] In some embodiments, the mass ratio of polyvinyl alcohol, acrylic acid and ethylene in step A1 is 1:(0.4-0.6):(0.2-0.4).

[0014] In some embodiments, the mass ratio of the polymer to allylmalonic acid in step A2 is 1:(0.1-0.3).

[0015] The invention limits the mass ratio of polyvinyl alcohol, acrylic acid and ethylene so that the polyvinyl alcohol side chain has an appropriate length, and limits the mass ratio of the polymer to allylmalonic acid so that the end of the side chain is grafted with a hydrophilic carboxyl group, so that the obtained comb-shaped modified polyvinyl alcohol has good water solubility and suspension.

[0016] In some embodiments, the number average molecular weight of the modified polyvinyl alcohol is 20,000-25,000.

[0017] The invention limits the number average molecular weight of the modified polyvinyl alcohol and reduces the interaction force between polyvinyl alcohol molecules, so that the obtained modified polyvinyl alcohol is more easily dissolved in water and the suspension system is more stable.

[0018] In some embodiments, the method for preparing the modified montmorillonite comprises the following steps:

[0019] B1, adding montmorillonite and silane coupling agent into ethanol, stirring at 50-60° C. for 5-6 hours, and then adding sodium hydroxide to obtain silane coupling agent modified montmorillonite;

[0020] B2. Add the silane coupling agent modified montmorillonite obtained in step B1, sodium glutamate and phosphoric acid into ethylene dichloride, react at 70-80° C. for 5-6 hours, wash and dry to obtain modified montmorillonite.

[0021] Preferably, the silane coupling agent is γ-glycidyloxypropyltrimethoxysilane.

[0022] Albendazole has certain toxic and side effects, and feeding pregnant animals may cause malformation or stillbirth. Conventional albendazole and ivermectin premixes are not suitable for pregnant animals. The present invention adds montmorillonite, which has a large specific surface area, will not be absorbed by the human body, has no toxic effects, and has a strong covering ability. It can adhere to the intestine to form a protective barrier, reduce the direct contact between the intestine and albendazole, reduce toxic and side effects, and have good efficacy. However, montmorillonite is easy to settle after being dispersed in water, which is easy to cause differences in dosing. The applicant modifies the montmorillonite so that the modified montmorillonite can be evenly dispersed in the water and will not settle for a long time. The possible reason is that the hydrophilic and hydrophobic segments appear alternately on the surface of the modified montmorillonite, the hydrophilic amino group and the modified polyvinyl alcohol segment attract each other, and the -COO - The terminal carboxyl groups of modified polyvinyl alcohol repel each other, thereby improving the suspension of montmorillonite. In addition, the layered structure of montmorillonite has a certain "lifting" effect, which synergizes with the comb-like structure of modified polyvinyl alcohol to further improve the stability of the suspension system.

[0023] In some embodiments, the mass ratio of the silane coupling agent modified montmorillonite to sodium glutamate in step B2 is 1:(0.5-0.6).

[0024] The invention limits the mass ratio of the silane coupling agent-modified montmorillonite and sodium glutamate, so that the obtained modified montmorillonite is not easy to settle, thereby increasing the suspension property of the system.

[0025] In some embodiments, the method for preparing the ivermectin microcapsules comprises the following steps:

[0026] (1) dissolving ivermectin in methanol, adding Span 80 to obtain an oil phase, then dissolving Tween 80 in water to obtain an aqueous phase, pouring the aqueous phase into the oil phase, and stirring at a speed of 300-400 rpm for 30-40 minutes to obtain an emulsion;

[0027] (2) 2,5-dihydroxyterephthalic acid epoxide, chitosan and the emulsion obtained in step (1) are mixed uniformly, the pH is adjusted to 8-10 with NaOH, the mixture is stirred at 45-55° C. and 300-400 rpm for 1.5-2.5 h, cooled to room temperature, filtered and dried to obtain ivermectin microcapsules.

[0028] Preferably, the volume ratio of the water phase to the oil phase is (1-2):1.

[0029] In some embodiments, the particle size of the ivermectin microcapsules is 1-2 μm.

[0030] In some embodiments, the mass ratio of the 2,5-dihydroxyterephthalic acid epoxide to chitosan is (0.2-0.4):1.

[0031] In some embodiments, the method for preparing 2,5-dihydroxyterephthalic acid epoxide comprises the following steps:

[0032] The preparation method of 2,5-dihydroxyterephthalic acid epoxide comprises the following steps:

[0033] Ⅰ. Add 2,5-dihydroxyterephthalic acid to DMF, stir at 0-5°C for 20-30 minutes, then add anhydrous potassium carbonate, stir for 3-6 minutes, then drop propylene bromide, continue stirring for 25-35 minutes, then heat to 30-35°C, react for 47-49 hours, extract, wash, and dry to obtain allylated 2,5-dihydroxyterephthalic acid;

[0034] Ⅱ. Add the allylated 2,5-dihydroxyterephthalic acid obtained in step Ⅰ to dichloromethane, stir at 0-5°C for 20-30 minutes, then add dropwise a 4-7wt% dichloroperbenzoic acid solution in dichloromethane, continue the reaction for 55-70 minutes after the addition is complete, heat to 35-45°C, react for 47-49 hours, then cool at -6 to 0°C for 5.5-6.5 hours, filter, wash, and dry to obtain 2,5-dihydroxyterephthalic acid epoxide.

[0035] In some embodiments, the mass ratio of 2,5-dihydroxyterephthalic acid, anhydrous potassium carbonate and propylene bromide in step I is 1:(2.8-3):(3-3.2).

[0036] In some embodiments, the mass ratio of the allylated 2,5-dihydroxyterephthalic acid to the 4-7 wt % m-chloroperbenzoic acid dichloromethane solution in step II is 1:(90-95).

[0037] In some embodiments, the method for preparing the modified starch comprises the following steps:

[0038] 1) crotonic acid and starch are added to DMF, and phosphoric acid solution is added while stirring, and the mixture is stirred at 70-80° C. for 5-6 hours, and then sorbic acid and azobisisobutyronitrile are added, and the mixture is stirred for 1-2 hours, filtered, washed, and dried to obtain pre-modified starch;

[0039] 2) adding the pre-modified starch obtained in step 1), zinc gluconate and NaOH into DMF, stirring at 70-80° C. for 5-6 hours to obtain modified starch.

[0040] Preferably, in step 1), the mass ratio of crotonic acid, sorbic acid and starch is (0.5-0.7):(0.6-0.8):1.

[0041] The second aspect of the present invention provides a method for preparing a water-suspended albendazole-ivermectin premix, comprising the following steps:

[0042] S1. Add sodium chloride, ivermectin microcapsules, modified polyvinyl alcohol and modified montmorillonite into a mixer and stir at room temperature for 30-40 minutes to obtain a premix;

[0043] S2. Add albendazole and modified starch into the premix obtained in step S1 and stir at 30-40° C. for 50-70 min to obtain a water-suspended albendazole-ivermectin premix.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] 1. The present invention prepares a water-suspended albendazole-ivermectin premix by using modified polyvinyl alcohol, modified montmorillonite and an albendazole-ivermectin premix with high uniformity, which can be directly added to water and fed to animals, is easy to use, and has little toxic and side effects.

[0046] 2. The present invention modifies polyvinyl alcohol, and the modified polyvinyl alcohol adds side chains to form a comb-type structure. The end of the side chain has multiple carboxyl groups, which increases the solubility in water and can quickly and fully wet solid particles. In addition, the carboxyl groups at the end of the long side chains have the same charge and can generate repulsion between each other. The comb-type polymer has strong adhesion to prevent the particles from reaggregating and maintain the long-term stability of the suspension system.

[0047] 3. The present invention adds montmorillonite, which has a large specific surface area, will not be absorbed by the human body, has no toxic effects, and has a strong covering ability. It can adhere to the intestine to form a protective barrier, reduce the direct contact between the intestine and albendazole, reduce toxic side effects, and have good efficacy.

[0048] 4. The present invention modifies montmorillonite so that the modified montmorillonite can be evenly dispersed in the medium and does not settle for a long time. The hydrophilic and hydrophobic segments on the surface of the modified montmorillonite appear alternately. The hydrophilic amino groups and the modified polyvinyl alcohol segments attract each other, and the -COO - The terminal carboxyl groups of modified polyvinyl alcohol repel each other, thereby improving the suspension of montmorillonite. In addition, the layered structure of montmorillonite has a certain "lifting" effect, which synergizes with the comb-like structure of modified polyvinyl alcohol to further improve the stability of the suspension system. DETAILED DESCRIPTION

[0049] The present invention will be described below in conjunction with specific embodiments. It should be noted that the following examples and comparative examples are only used to illustrate the present invention and are not intended to limit the present invention. Other combinations and various modifications within the concept of the present invention may be performed without departing from the spirit or scope of the present invention.

[0050] In order to facilitate those skilled in the art to implement the present invention, some raw materials and manufacturers of the embodiments and comparative examples are described as follows:

[0051] The compounds and related reagents used in the following examples and comparative examples can all be purchased from the market, among which polyvinyl alcohol was purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd. with a number average molecular weight of 23,000; corn starch was purchased from Jinan Mingfeng Biotechnology Co., Ltd.; montmorillonite was purchased from Inner Mongolia Longqing Bentonite Technology Co., Ltd. with a mesh size of 325.

[0052] Preparation Example 1

[0053] The preparation method of modified polyvinyl alcohol-1 comprises the following steps:

[0054] A1. Add 10 g of polyvinyl alcohol to 5 g of acrylic acid, stir and react at 95°C for 5.5 h, then add 3 g of ethylene and 0.1 g of tetrabutyl titanate, continue to react at 0.3 MPa for 2.5 h, wash and dry to obtain a polymer;

[0055] A2. Add 10 g of the polymer obtained in step A1, 2 g of allylmalonic acid and 0.01 g of azobisisobutyronitrile to 50 ml of anhydrous ethanol, react at 85° C. for 1.5 h, wash, dry and grind to obtain modified polyvinyl alcohol-1 with a number average molecular weight of 24312.

[0056] Preparation Example 2

[0057] The preparation method of modified polyvinyl alcohol-2 is the same as that of Preparation Example 1, except that the amount of acrylic acid added is 8 g.

[0058] Preparation Example 3

[0059] The preparation method of modified polyvinyl alcohol-3 is the same as that of Preparation Example 1, except that the amount of ethylene added is 6 g.

[0060] Preparation Example 4

[0061] The preparation method of modified polyvinyl alcohol-4 is the same as that of Preparation Example 1, except that the amount of allylmalonic acid added is 4 g.

[0062] Preparation Example 5

[0063] The preparation method of modified polyvinyl alcohol-5 is the same as that of Preparation Example 1, except that the reaction time of step A2 is 3 hours, and the number average molecular weight of the obtained modified polyvinyl alcohol-5 is 29312.

[0064] Preparation Example 6

[0065] The preparation method of modified montmorillonite-1 comprises the following steps:

[0066] B1. Add 10 g of montmorillonite and 5 g of γ-glycidyloxypropyltrimethoxysilane into 60 ml of anhydrous ethanol, stir at 55° C. for 5.5 h, and then add 0.3 g of sodium hydroxide to obtain silane coupling agent-modified montmorillonite;

[0067] B2. Add 10 g of the silane coupling agent modified montmorillonite obtained in step B1, 5.5 g of sodium glutamate and 5 ml of 75 wt% phosphoric acid into 100 g of ethylene dichloride, react at 75° C. for 5.5 h, wash and dry to obtain modified montmorillonite-1.

[0068] Preparation Example 7

[0069] The preparation method of modified montmorillonite-1 is the same as that of Preparation Example 6, except that the amount of sodium glutamate added is 7 g.

[0070] Preparation Example 8

[0071] The preparation method of 2,5-dihydroxyterephthalic acid epoxide comprises the following steps:

[0072] Ⅰ. Add 5g of 2,5-dihydroxyterephthalic acid to 100ml of DMF, stir at 2°C for 25min, then add 14.5g of anhydrous potassium carbonate, stir for 5min, then drop 15.5g of propylene bromide at a rate of 0.5g / min, continue stirring for 30min, then heat to 32°C, react for 48h, extract, wash, and dry.

[0073] Obtaining allylated 2,5-dihydroxyterephthalic acid;

[0074] Ⅱ. Add 5 g of the allylated 2,5-dihydroxyterephthalic acid obtained in step Ⅰ to 100 ml of dichloromethane, stir at 3°C ​​for 25 min, then add dropwise 465 g of a 5 wt% solution of m-chloroperbenzoic acid in dichloromethane at a rate of 15 g / min. After the addition is complete, continue the reaction for 60 min, heat to 40°C, react for 48 h, then cool at -3°C for 6 h, filter, wash, and dry to obtain 2,5-dihydroxyterephthalic acid epoxide.

[0075] Preparation Example 9

[0076] The preparation method of ivermectin microcapsules comprises the following steps:

[0077] (1) Dissolve 1 g of ivermectin in 20 ml of anhydrous methanol, add 0.2 ml of Span 80 to obtain an oil phase, then dissolve 0.2 ml of Tween 80 in 30 ml of deionized water to obtain an aqueous phase, pour 30 ml of the aqueous phase into 20 ml of the oil phase, and stir at 350 rpm for 35 min to obtain an emulsion;

[0078] (2) 3 g of 2,5-dihydroxyterephthalic acid epoxide-1, 10 g of chitosan, and 50 ml of the emulsion obtained in step (1) were mixed uniformly, the pH was adjusted to 9 with NaOH, and the mixture was stirred at 50° C. and 350 rpm for 2 h. The mixture was cooled to room temperature, filtered, and dried to obtain ivermectin microcapsules.

[0079] Preparation Example 10

[0080] The preparation method of modified starch comprises the following steps:

[0081] 1) 6 g of crotonic acid and 10 g of corn starch were added to 100 ml of DMF, and 3 ml of 75 wt% phosphoric acid solution was added while stirring, and the mixture was stirred at 75° C. for 5.5 h, and then 7 g of sorbic acid and 0.1 g of azobisisobutyronitrile were added, and the mixture was stirred for 1.5 h, filtered, washed, and dried to obtain pre-modified starch;

[0082] 2) 10 g of the pre-modified starch obtained in step 1), 4 g of zinc gluconate and 0.1 g of NaOH were added to 50 ml of DMF and stirred at 75° C. for 5.5 h to obtain modified starch.

[0083] Example 1

[0084] A water-suspended albendazole-ivermectin premix comprises the following raw materials, calculated by mass percentage of 100%, 10% albendazole, 0.2% ivermectin microcapsules, 18% sodium chloride, 23% modified montmorillonite-1, 18% modified polyvinyl alcohol, and 40.8% modified starch.

[0085] The preparation method of the water-suspended albendazole-ivermectin premix in this embodiment comprises the following steps:

[0086] S1, adding sodium chloride, ivermectin microcapsules, modified polyvinyl alcohol-1, and modified montmorillonite-1 into a mixer and stirring at room temperature for 35 minutes to obtain a premix;

[0087] S2. Add albendazole and modified starch into the premix obtained in step S1 and stir at 35° C. for 60 min to obtain a water-suspended albendazole-ivermectin premix.

[0088] Example 2

[0089] A water-suspended albendazole-ivermectin premix comprises the following raw materials, calculated by mass percentage of 100%, 9.5% of albendazole, 0.19% of ivermectin microcapsule-1, 12% of sodium chloride, 20% of modified montmorillonite-1, 7% of modified polyvinyl alcohol-1 and 51.31% of modified starch.

[0090] The preparation method of the water-suspended albendazole-ivermectin premix in this embodiment comprises the following steps:

[0091] S1, adding sodium chloride, ivermectin microcapsules, modified polyvinyl alcohol-1, and modified montmorillonite-1 into a mixer and stirring at room temperature for 30 minutes to obtain a premix;

[0092] S2. Add albendazole and modified starch into the premix obtained in step S1 and stir at 30° C. for 70 min to obtain a water-suspended albendazole-ivermectin premix.

[0093] Example 3

[0094] A water-suspended albendazole-ivermectin premix comprises the following raw materials, calculated by mass percentage of 100%, 10.5% albendazole, 0.21% ivermectin microcapsules, 24% sodium chloride, 25% modified montmorillonite-1, 10% modified polyvinyl alcohol-1 and 30.29% modified starch.

[0095] The preparation method of the water-suspended albendazole-ivermectin premix in this embodiment comprises the following steps:

[0096] S1, adding sodium chloride, ivermectin microcapsules, modified polyvinyl alcohol-1, and modified montmorillonite-1 into a mixer and stirring at room temperature for 40 minutes to obtain a premix;

[0097] S2. Add albendazole and modified starch into the premix obtained in step S1 and stir at 40° C. for 50 min to obtain a water-suspended albendazole-ivermectin premix.

[0098] Example 4

[0099] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified polyvinyl alcohol-1 is replaced by modified polyvinyl alcohol-2.

[0100] Example 5

[0101] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified polyvinyl alcohol-1 is replaced by modified polyvinyl alcohol-3.

[0102] Example 6

[0103] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified polyvinyl alcohol-1 is replaced by modified polyvinyl alcohol-4.

[0104] Example 7

[0105] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified polyvinyl alcohol-1 is replaced by modified polyvinyl alcohol-5.

[0106] Example 8

[0107] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified montmorillonite-1 is replaced by modified montmorillonite-2.

[0108] Comparative Example 1

[0109] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified polyvinyl alcohol-1 is replaced by polyvinyl alcohol.

[0110] Comparative Example 2

[0111] A water-suspended albendazole-ivermectin premix and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of modified montmorillonite-1 is replaced by montmorillonite.

[0112] Performance Testing

[0113] 1. Stability test

[0114] The water-suspended albendazole ivermectin premix of each embodiment and comparative example was subjected to a high temperature, high humidity and strong light accelerated test according to the drug stability test method in the appendix of the 2015 edition of the Chinese Pharmacopoeia of Veterinary Medicine. The premix was placed in a drug stability test box at a temperature of 40±2°C, a relative humidity of 75±5%, and an illumination of 4500±500LX for 6 months according to commercial packaging. Samples were taken at the end of the first, third, and sixth months during the experiment to detect the properties and content of the premix, wherein the ivermectin should be 90-110% of the labeled amount.

[0115] 2. Suspension

[0116] 1 g of the water-suspended albendazole-ivermectin premix of each example and comparative example was added into 20 ml of deionized water and stirred for 5 min. The mixture was allowed to stand and the time for sedimentation to occur was recorded.

[0117] The test results are shown in Table 1.

[0118] Table 1

[0119]

[0120]

[0121] By comparing the data of Examples 1-3 in Table 1, it can be seen that the water-suspended albendazole ivermectin premix has good stability; compared with Example 1, Examples 4 and 5 show that the ratio of polyvinyl alcohol, acrylic acid and ethylene is changed, and the suspensibility of the water-suspended albendazole ivermectin premix decreases; compared with Example 1, Example 6 shows that the ratio of the polymer to allylmalonic acid is changed, resulting in a decrease in the water solubility of the modified polyvinyl alcohol, a decrease in the stability and suspensibility of the water-suspended albendazole ivermectin premix; By comparing Example 7 with Example 1, it can be seen that the molecular weight of the modified polyvinyl alcohol changes, resulting in a decrease in the suspendability of the water-suspended albendazole ivermectin premix; by comparing Example 8 with Example 1, it can be seen that the ratio of the silane coupling agent-modified montmorillonite to sodium glutamate changes, and the montmorillonite is easy to settle in water, resulting in a decrease in the suspendability of the water-suspended albendazole ivermectin premix; by comparing Comparative Examples 1 and 2 with Example 1, it can be seen that the stability and suspendability of the water-suspended albendazole ivermectin premix are both reduced by directly using polyvinyl alcohol or montmorillonite.

[0122] 3. Safety Experiment

[0123] 250 healthy pregnant sows of the same parity were selected and randomly divided into 5 groups, 50 in each group, and the water-suspended albendazole ivermectin premix prepared in Examples 1-3 and Comparative Examples 1-2 was added to water and fed to pregnant sows for one week. The mass ratio of water to the water-suspended albendazole ivermectin premix was 1000:1, and the number of sows with stillbirths, deformed piglets and weak piglets during the test was counted. The test started on the 45th day of sow gestation and ended after the sow gave birth.

[0124] The test results are shown in Table 2.

[0125] Table 2

[0126]

[0127]

[0128] By comparing the data of Examples 1-3 and Comparative Examples 1 and 2 in Table 2, it can be seen that the water-suspended albendazole-ivermectin premix prepared by the present invention will not cause stillbirth, deformed piglets and weak piglets in sows, and can be used for pregnant animals.

[0129] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with this profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A water-suspended albendazole-ivermectin premix, characterized in that: The mass percentage is 100%, including the following raw materials: The invention discloses albendazole 9.5-10.5%, ivermectin microcapsule 0.19-0.21%, sodium chloride 12-24%, modified montmorillonite 20-25%, modified polyvinyl alcohol 7-10%, and the balance is modified starch.

2. The water-suspended albendazole-ivermectin premix according to claim 1, characterized in that: The preparation method of the modified polyvinyl alcohol comprises the following steps: A1. Add polyvinyl alcohol to acrylic acid, stir and react at 90-100°C for 5-6h, then add ethylene and tetrabutyl titanate, continue to react at 0.1-0.5MPa for 2-3h, wash and dry to obtain a polymer; A2. Add the polymer obtained in step A1, allylmalonic acid and azobisisobutyronitrile to ethanol, react at 80-90° C. for 1-2 hours, wash and dry to obtain modified polyvinyl alcohol.

3. The water-suspended albendazole-ivermectin premix according to claim 2, characterized in that: The mass ratio of polyvinyl alcohol, acrylic acid and ethylene in step A1 is 1:(0.4-0.6):(0.2-0.4).

4. The water-suspended albendazole-ivermectin premix according to claim 2, characterized in that: The mass ratio of the polymer to allylmalonic acid in step A2 is 1:(0.1-0.3).

5. The water-suspended albendazole-ivermectin premix according to claim 2, characterized in that: The number average molecular weight of the modified polyvinyl alcohol is 20,000-25,000.

6. The water-suspended albendazole-ivermectin premix according to claim 1, characterized in that: The preparation method of the modified montmorillonite comprises the following steps: B1, adding montmorillonite and silane coupling agent into ethanol, stirring at 50-60° C. for 5-6 hours, and then adding sodium hydroxide to obtain silane coupling agent modified montmorillonite; B2. The silane coupling agent-modified montmorillonite obtained in step B1, sodium glutamate and phosphoric acid are added to ethylene dichloride, reacted at 70-80° C. for 5-6 hours, and washed and dried to obtain modified montmorillonite.

7. The water-suspended albendazole-ivermectin premix according to claim 5, characterized in that: The mass ratio of the silane coupling agent modified montmorillonite to sodium glutamate in step B2 is 1:(0.5-0.6).

8. The water-suspended albendazole-ivermectin premix according to claim 1, characterized in that: The preparation method of the ivermectin microcapsules comprises the following steps: (1) dissolving ivermectin in methanol, adding Span 80 to obtain an oil phase, then dissolving Tween 80 in water to obtain an aqueous phase, pouring the aqueous phase into the oil phase, and stirring at a speed of 300-400 rpm for 30-40 minutes to obtain an emulsion; (2) 2,5-dihydroxyterephthalic acid epoxide, chitosan and the emulsion obtained in step (1) are mixed uniformly, the pH is adjusted to 8-10 with NaOH, the mixture is stirred at 45-55° C. and 300-400 rpm for 1.5-2.5 h, cooled to room temperature, filtered and dried to obtain ivermectin microcapsules.

9. The water-suspended albendazole-ivermectin premix according to claim 1, characterized in that: The preparation method of the modified starch comprises the following steps: 1) crotonic acid and starch are added to DMF, and phosphoric acid solution is added while stirring, and the mixture is stirred at 70-80° C. for 5-6 hours, and then sorbic acid and azobisisobutyronitrile are added, and the mixture is stirred for 1-2 hours, filtered, washed, and dried to obtain pre-modified starch; 2) adding the pre-modified starch obtained in step 1), zinc gluconate and NaOH into DMF, stirring at 70-80° C. for 5-6 hours to obtain modified starch.

10. A method for preparing the water-suspended albendazole-ivermectin premix according to any one of claims 1 to 9, characterized in that: The following steps are involved: S1. Add sodium chloride, ivermectin microcapsules, modified polyvinyl alcohol and modified montmorillonite into a mixer and stir at room temperature for 30-40 minutes to obtain a premix; S2. Add albendazole and modified starch into the premix obtained in step S1 and stir at 30-40° C. for 50-70 min to obtain a water-suspended albendazole-ivermectin premix.

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