WO2018161291A1 - Eprinomectin nanoemulsion and preparation method and use thereof - Google Patents

Abstract

Provided in the present invention is an eprinomectin nanoemulsion, the eprinomectin nanoemulsion containing eprinomectin, a solvent and a long-chain monoester; the monoester is represented by the formula R-COO-R', wherein R is selected from alkyl groups containing 10-16 carbon atoms, while R' is an alkyl group containing 1-5 carbon atoms, and the alkyl group containing 1-5 carbon atoms is preferably ethyl, propyl, isopropyl, butyl or isobutyl. Provided in the present invention is a method for preparing the eprinomectin nanoemulsion. The method comprises the following steps: (1) mixing the eprinomectin evenly with a solvent to obtain a first mixture; (2) mixing the first mixture evenly with a long-chain monoester and an emulsifier to obtain a second mixture; and (3) mixing the second mixture evenly with water to obtain a third mixture. Further provided in the present invention is an eprinomectin nanoemulsion which is prepared and obtained by means of said method and a use thereof in killing parasites within animal bodies and parasites on surfaces of animal bodies.

Description

Acetylamino avermectin nanoemulsion and preparation method and use thereof Technical field

The present invention relates to the field of animal medicine, and in particular to an acetamido avermectin nanoemulsion, a preparation method of the acetylamino avermectin nanoemulsion, and the use of the acetylamino avermectin nanoemulsion.

Background technique

The surface of livestock and pets often breeds parasites such as arthropods such as cockroaches, cockroaches and mites. These surface parasites are not only detrimental to the health of livestock and pets, but also affect the health of people who are in contact with livestock and pets. Therefore, it is necessary to develop a method for effectively killing parasites of livestock and pets. Among them, the use of drugs such as acetamido avermectin is an important means of killing parasites in livestock and pets.

Eplinomectin, also known as eplecapone, has the molecular formula C ₅₀ H ₇₅ NO ₁₄ (eprinomectin B _1a )+C ₄₉ H ₇₃ NO ₁₄ (eprinomectin B _1b ), B _1a and B _1b unique The difference is that B _1a has an isopropyl group attached to the methylene group (-CH ₂ -) of C25. CAS No. 123997-26-2, chemical name 4"-episo-acetamido-4"-deoxy Avermectin, is a new type of avermectin, which is introduced into the 4" end of avermectin. Acetylamine is a kind of 16-membered macrolide antibiotic. It has high lipophilicity and is soluble in organic solvents due to its strong lipophilic group in its molecular structure. Such as methanol, ethanol, propylene glycol, ethyl acetate, etc., the solubility in propylene glycol is the largest (more than 400g / L), almost insoluble in water. Similar to other avermectins, the mechanism of action of acetobia avermectin is in drugs Binding to specific receptors in synaptic or neuromuscular synapses of worm neurons, stimulating nerve endings to release the neurotransmitter inhibitor gamma-aminobutyric acid (GABA) and opening glutamate-controlled Cl ^- channels, ultimately making the worms Paralysis, refusal to eat, death. Acetyl avermectin has a strong killing effect on the surface and endoparasites parasitic on animals and plants. The internal parasites are mainly nematodes, and surface parasites include cockroaches, cockroaches, cockroaches and It is known as one of the most active insecticides in the world today. Because of its unique mechanism of action, it has no cross-resistance with other insect-resistant drugs. It is especially important that the acetamido avermectin has a very low milk/blood concentration ratio. Therefore, acetamibine can be used in all cows. It includes lactating cows and does not require a drug holiday.

When acetamido avermectin is used to kill parasites on livestock and pets, the dosage form is usually a pour-on agent. The pour-on agent has a high production cost due to the use of a large amount of organic solvent, and has high conditions for packaging and transportation. In addition, the transdermal absorption of the pour-on animal is relatively poor, and in order to maintain the therapeutic effect, a long-term use of a larger dose is required. The long-term use of acetamido avermectin has an effect on the environment, and its various degradation products in the environment have the toxicity equivalent to or higher than the acetomycin. When used on livestock and pet surface parasites, acetamidomycin can be left in the fur of livestock and pets by spraying, which poses a health hazard to humans.

CN104095866 discloses an acetylamino avermectin transdermal agent, which comprises 30-70 parts by weight of 95% medical alcohol in the examples, which is highly irritating to animal skin and has a safety hazard in transportation. It is still barely viable for small animals, but it still has poor transdermal absorbability for large animals such as cattle. Therefore, there is still a need to further improve the transdermal absorbability of acetamido avermectin.

Summary of the invention

In order to overcome the defect that the transdermal absorbability of the acetamido avermectin pour-on agent is poor, the present invention provides an acetamido avermectin nanoemulsion capable of further improving transdermal absorbability, a preparation method thereof and use thereof. The acetamido avermectin nanoemulsion preparation provided by the invention adopts an oil-in-water system, can penetrate the skin of an animal well, has a transdermal transmittance of more than 70%, uses less organic solvent, and reduces irritation to animals. . Moreover, the concentration of the original drug is low, and water is used as an auxiliary material, which greatly reduces the cost.

In one aspect, the present invention provides an acetylamino avermectin nanoemulsion, wherein the acetamibium avermectin nanoemulsion comprises an acetamido avermectin, a solvent and a long-chain monoester, wherein the mono-ester is R-COO-R' represents wherein R is selected from an alkyl group having 10 to 16 carbon atoms, and R' is an alkyl group having 1 to 5 carbon atoms, wherein an alkyl group having 1 to 5 carbon atoms is preferred. Ethyl, propyl, isopropyl, butyl or isobutyl.

In another aspect, the present invention provides a method for preparing acetamido avermectin nanoemulsion, wherein the method comprises the following steps: (1) mixing acetamido avermectin with a solvent to obtain a first mixture (2) mixing the first mixture and the long-chain monoester and the emulsifier uniformly to obtain a second mixture; (3) uniformly mixing the second mixture with water to obtain a third mixture.

In another aspect, the invention also provides an acetamido avermectin nanoemulsion prepared by the method described above.

In still another aspect, the present invention provides the use of the acetamido avermectin nanoemulsion as described above for killing parasites and surface parasites in animals.

According to the above technical solution, the acetamido avermectin nanoemulsion of the present invention can significantly increase the permeation amount Q and the transmissibility of transdermal absorption in the transdermal absorbability test in fresh cowhide.

Other features and advantages of the invention will be described in detail in the detailed description which follows.

detailed description

Specific embodiments of the present invention will be described in detail below. It is to be understood that the specific embodiments described herein are merely illustrative and not restrictive.

In one aspect, the present invention provides an acetylamino avermectin nanoemulsion, wherein the acetylamino avermectin nanoemulsion comprises acetylamino avermectin, a solvent and a monoester, and the monoester is represented by the formula R- COO-R' represents wherein R is selected from an alkyl group having 10 to 16 carbon atoms, and R' is an alkyl group having 1 to 5 carbon atoms, wherein the alkyl group having 1 to 5 carbon atoms is preferably Ethyl, propyl, isopropyl, butyl or isobutyl.

In the present invention, the acetamido avermectin nanoemulsion is an oil-in-water (O/W) type, a water-in-oil (W/O) type or a bicontinuous type. The type of acetamido avermectin nanoemulsion of the present invention was identified by the water-soluble dye methylene blue and the fat-soluble dye Sudan Red III staining method.

In one embodiment of the present invention, the acetamiphorin nanoemulsion may have a concentration of acetamido avermectin of 0.1 to 2% by weight, preferably 0.2 to 1.5% by weight, most preferably 0.4- 1.2% by weight based on the total weight of the acetylamino avermectin nanoemulsion.

In another embodiment of the present invention, in the acetamido avermectin nanoemulsion, the solvent may be contained in an amount of 1 to 10 parts by weight, preferably 5 to 1 part by weight of the acetamido avermectin. 8 parts by weight.

In still another embodiment of the present invention, the acetylamino avermectin nanoemulsion may have a monoester content of 5 to 30 parts by weight, preferably 10%, per part by weight of the acetoamectin. -20 parts by weight.

In still another embodiment of the present invention, the acetamido avermectin nanoemulsion may further contain an emulsifier and water, wherein the emulsifier is in an amount of 8 parts by weight with respect to 1 part by weight of the active ingredient. 30 parts by weight, the content of water is 30-85 parts by weight. Preferably, the emulsifier is contained in an amount of 10 to 15 parts by weight and the water is contained in an amount of 45 to 80 parts by weight based on 1 part by weight of the active ingredient.

According to a particularly preferred embodiment of the present invention, the weight ratio of the monoester to the emulsifier in the nanoemulsion is 1: (0.5-1.5). In this preferred embodiment, the pharmaceutical composition has a very excellent transdermal effect.

According to an embodiment of the present invention, in the acetamido avermectin nanoemulsion, the monobasic ester may be ethyl laurate, ethyl myristate, ethyl palmitate, isopropyl laurate, lauric acid. N-propyl ester, isopropyl myristate, n-propyl myristate, isopropyl palmitate, isobutyl laurate, n-butyl laurate, isobutyl myristate, n-butyl myristate, At least one of isobutyl palmitate and n-butyl palmitate.

According to an embodiment of the present invention, the acetylamino avermectin nanoemulsion, the solution The agent may be selected from at least one of methanol, ethanol, propanol, propylene glycol, dimethylformamide, dimethyl sulfoxide and ethyl acetate; particularly preferably, the solvent is ethanol or propylene glycol or ethyl acetate.

According to an embodiment of the present invention, in the acetamido avermectin nanoemulsion, the emulsifier may be an alkylphenol ethoxylate emulsifier, such as nonylphenol ethoxylate (NPEO), octyl Phenolic polyoxyethylene ether (OPEO), dodecylphenol polyoxyethylene ether (DPEO) and dinonyl phenol ethoxylate (DNPEO), polyoxyethylene castor oil emulsifier, or dodecyl benzene sulfonic acid Calcium, or a mixture of two or more emulsifiers as described above. Particularly preferably, the emulsifier is an alkylphenol ethoxylate emulsifier.

According to an embodiment of the present invention, in the acetamido avermectin nanoemulsion, the acetamiphorin nanoemulsion further contains an auxiliary agent including a transdermal agent, a preservative, an antioxidant, and a pigment. At least one of them.

In a preferred embodiment, the transdermal agent may be selected from at least one of eucalyptus oil, azone, peppermint oil, and silicone oil; the transdermal agent may be included in an amount of 2 to 8% by weight, The total weight of the acetamido avermectin nanoemulsion is based on the total weight.

BIT20防腐剂、奥麒

GXL防腐剂和科莱恩

BIT20防腐剂中的至少一种；所述防腐剂的含量可以为0.5-2重量％，以所述乙酰氨基阿维菌素纳米乳的总重量为基准。In a preferred embodiment, the selection and content of the preservative are not particularly required and may be a conventional selection and content, for example, the preservative may be selected from the group consisting of Dow.

BIT20 preservative, Austrian

GXL Preservatives and Clariant

At least one of BIT20 preservatives; the preservative may be included in an amount of from 0.5 to 2% by weight based on the total weight of the acetamiphorin nanoemulsion.

In a preferred embodiment, the choice of the antioxidant is not particularly required and may be a conventional selection and content, for example, the antioxidant may be selected from 2,6-di-tert-butyl-4-methylphenol ( Also known as dibutylhydroxytoluene, BHT), butylated hydroxyanisole (BHA), tert-butyl hydroquinone, methylene-4,4'-bis-(2,6-tert-butylphenol) and At least one of 2,6-diisopropylphenol; preferably The antioxidant is 2,6-di-tert-butyl-4-methylphenol (BHT); the antioxidant may be included in an amount of 0.5 to 3% by weight based on the total weight of the acetylamino avermectin nanoemulsion As the benchmark.

In a preferred embodiment, the selection and content of the pigment are not particularly required, and may be a conventional selection and content. Pigments conventionally used in the field of pesticides can be used in the present invention, and can be freely added or not added according to commercial needs. . For example, the pigment may be selected from at least one of Sudan red, capsicum red, carmine, indigo, and tartrazine; the concentration of the pigment may be a trace amount as long as the acetamido avermectin nanoemulsion is provided A specific color can be.

In another aspect, the present invention provides a method for preparing acetamido avermectin nanoemulsion, wherein the method comprises the following steps: (1) mixing acetamido avermectin with a solvent to obtain a first mixture (2) mixing the first mixture and the long-chain monoester and the emulsifier uniformly to obtain a second mixture; (3) uniformly mixing the second mixture with water to obtain a third mixture.

According to an embodiment of the present invention, in the method of the present invention, the long-chain monobasic ester may be used in an amount of 5 to 30 parts by weight, preferably 10 to 20 parts by weight, per part by weight of the acetoamectin. The emulsifier may be used in an amount of 8 to 30 parts by weight, preferably 10 to 15 parts by weight; the solvent may be used in an amount of 1 to 10 parts by weight, preferably 5 to 8 parts by weight; and the amount of water may be 30 to 85 parts by weight. It is preferably 45-80 parts by weight. The weight ratio of the long-chain monoester to the emulsifier may be 1: (0.5 - 1.5), preferably 1: (0.5 - 1), particularly preferably 1: 0.8. The amount of the long-chain monobasic ester is preferably 10-20 parts by weight, the content of the emulsifier is preferably 10-15 parts by weight, and the solvent is preferably used in an amount of 5-8 parts by weight, based on 1 part by weight of the acetamido avermectin. When the amount of water used is preferably from 45 to 80 parts by weight, the acetamido avermectin nanoemulsion of the above method has a better transdermal effect.

According to one embodiment of the invention, in the method of the invention, mixing uniformly means that the mixed material is a relatively stable, uniform liquid. Wherein, in the steps (1)-(3), the mixing conditions may independently comprise: a temperature of 30-40 ° C, a relative humidity of 60-80%, and a mixed material having a pH of 5-7; Ground, in steps (1)-(3), the conditions of mixing are independent The site includes: a temperature of 33-37 ° C, a relative humidity of 50-80%, and a mixed material having a pH of 5.5-6.5. Most preferably, in the steps (1)-(3), the mixing conditions include a temperature of 35 ° C, a relative humidity of 70%, and a pH of the mixed material of 6.

According to an embodiment of the present invention, in the method of the present invention, the long-chain monobasic ester may be ethyl laurate, ethyl myristate, ethyl palmitate, isopropyl laurate, lauric acid Propyl ester, isopropyl myristate, n-propyl myristate, isopropyl palmitate, isobutyl laurate, n-butyl laurate, isobutyl myristate, n-butyl myristate, palm At least one of isobutyl acrylate and n-butyl palmitate.

According to an embodiment of the present invention, in the method of the present invention, the solvent may be selected from at least methanol, ethanol, propanol, propylene glycol, dimethylformamide, dimethyl sulfoxide and ethyl acetate. One; particularly preferably, the solvent is ethanol or propylene glycol or ethyl acetate.

According to an embodiment of the present invention, in the method of the present invention, the emulsifier may be an alkylphenol ethoxylate emulsifier, including nonylphenol ethoxylate (NPEO), octylphenol polyoxyl Vinyl ether (OPEO), dodecylphenol polyoxyethylene ether (DPEO) and dinonyl phenol ethoxylate (DNPEO) or mixtures thereof, polyoxyethylene castor oil emulsifier, or dodecyl benzene sulfonic acid Calcium, or a mixture of two or more emulsifiers as described above. Particularly preferably, the emulsifier is an alkylphenol ethoxylate emulsifier.

According to an embodiment of the present invention, in the method of the present invention, the acetyl avermectin nanoemulsion further contains an auxiliary agent comprising at least at least a transdermal agent, a preservative, an antioxidant, and a pigment. One.

In a preferred embodiment, the transdermal agent may be selected from at least one of eucalyptus oil, azone, peppermint oil, and silicone oil; the transdermal agent may be included in an amount of 2 to 8% by weight, The total weight of the acetamido avermectin nanoemulsion is based on the total weight.

BIT20防腐剂、奥麒

GXL防腐剂和科莱恩

BIT20防腐剂中的至少一种；所述防腐剂的浓度可以为0.5-2重量％，以所述乙酰氨基阿维菌素纳米乳的总重量为基准。In a preferred embodiment, the selection and content of the preservative are not particularly required and may be a conventional selection and content, for example, the preservative may be selected from the group consisting of Dow.

BIT20 preservative, Austrian

GXL Preservatives and Clariant

At least one of BIT20 preservatives; the preservative may be present in a concentration of from 0.5 to 2% by weight based on the total weight of the acetamiphorin nanoemulsion.

In a preferred embodiment, the choice of the antioxidant is not particularly required and may be a conventional selection and content, for example, the antioxidant may be selected from 2,6-di-tert-butyl-4-methylphenol ( Also known as dibutylhydroxytoluene, BHT), butylated hydroxyanisole (BHA), tert-butyl hydroquinone, methylene-4,4'-bis-(2,6-tert-butylphenol) and At least one of 2,6-diisopropylphenol; preferably the antioxidant is 2,6-di-tert-butyl-4-methylphenol (BHT); the concentration of the antioxidant may be 0.5-3 % by weight based on the total weight of the acetamido avermectin nanoemulsion.

In a preferred embodiment, the selection and content of the pigment are not particularly required, and may be a conventional selection and content. Pigments conventionally used in the field of pesticides can be used in the present invention, and can be freely added or not added according to commercial needs. For example, the pigment may be selected from at least one of Sudan red, capsicum red, carmine, indigo, and tartrazine; the concentration of the pigment may be a trace amount as long as the acetamido avermectin nanoemulsion can be made There is a specific color.

In another aspect, the invention also provides an acetamido avermectin nanoemulsion prepared by the method described above.

In another aspect, the present invention also provides the use of an acetamido avermectin nanoemulsion as described above for killing parasites and surface parasites in animals.

In one embodiment of the present invention, the acetamido avermectin nanoemulsion may be applied to a pasture, a farm, a pet hospital, a zoo, etc., and the animal may be various birds and mammals. Endoparasites can include, but are not limited to, nematodes, which can include, but are not limited to, at least one of sputum, sputum, sputum, and sputum.

The acetylamino avermectin nanoemulsion of the present invention has outstanding advantages in killing surface parasites of large animals including, but not limited to, ostriches, pigs, cows, sheep, dogs, horses, donkeys, and camels. At least one of them.

The invention will now be described in further detail by way of examples.

Examples 1-8 and Comparative Examples 1-2

The acetamido avermectin nanoemulsion is prepared according to the following steps: (1) mixing acetyl avermectin with a solvent to obtain a first mixture; (2) combining the first mixture with a long-chain monoester and an emulsifier Mixing uniformly to obtain a second mixture; (3) mixing the second mixture with water to obtain a third mixture, adding a preservative, an antioxidant, and a pigment to the third mixture, and stirring well until the solution is transparent and clear . In the steps (1) to (3), the mixing conditions include a temperature of 35 ° C, a relative humidity of 70%, and a pH of the mixed material of 6. The selection and amount of the long-chain monoester, solvent, emulsifier, preservative and antioxidant are shown in Table 1. In Table 1, the long-chain monobasic ester, solvent, emulsifier, preservative, antioxidant and water are all used in parts by weight relative to 1 part by weight of acetamido avermectin; BHT means 2,6-di-uncle Butyl-4-methylphenol.

Table 1

Comparative example 1

其每毫升包含5mg乙酰氨基阿维菌素(5mg/mL)。Commercially available products: 0.5% pouring of Merial

It contains 5 mg of acetamidobacmin (5 mg/mL) per ml.

Comparative example 2

According to the teaching of Example 1 of CN104095866A, a pouring agent containing 10 mg/mL of acetamido avermectin was prepared by adding 2 mL of azone, 6 mL of oleic acid, 8 mL of propylene glycol, 40 mL to a 100 mL volumetric flask at a temperature of 25 °C. Dimethyl sulfoxide, 44 mL of 95% medical alcohol, and 1 g of acetamido avermectin were thoroughly mixed and then dispensed in a 5 mL vial.

Test Example 1

According to the design requirements of the GLP test, the transdermal diffusion cell was used to study its transmittance by high performance liquid chromatography. The instruments and equipment used include: YB-P6 intelligent transdermal tester, Tianjin Pharmacopoeia Standard Instrument Factory; LC-2010A high performance liquid chromatograph, Shimadzu Corporation, Japan.

浇泼剂作为对比1，其所用剂量为样品1-8以及对比例2的 两倍，对比例2得到的乙酰氨基阿维菌素纳米乳作为对比2。透皮实验所用的牛皮采自呼和浩特市清真屠宰场，去净皮下脂肪，浸于生理盐水中，于冰箱中4℃保存待用。The acetamido avermectin nanoemulsion obtained in Example 1-8 was used as a sample 1-8, and the commercial product of Comparative Example 1

The pour-on agent was used as the comparison 1, and the dose used was twice that of the samples 1-8 and the comparative example 2, and the acetamido avermectin nanoemulsion obtained in the comparative example 2 was used as the comparison 2. The cowhide used in the transdermal experiment was collected from the Hohhot halal slaughterhouse in Hohhot, and the skin was subcutaneously fat, immersed in physiological saline, and stored in a refrigerator at 4 ° C for use.

The test group consisted of two dose groups (20 μL, 30 μL, and acetamibium avermectin concentration of 5.2 μg/μL). The dosing regimen includes: using the Franz cell diffusion method, the transdermal barrier of the isolated bovine skin, and the physiological saline as the receiving medium, and determining the content of acetamido avermectin in the receiving solution by HPLC.

Specifically, fresh cowhide (taken from the back of the cow), washed with physiological saline, remove the coat by electric hairpin, remove the subcutaneous fat and adhesion, and then wash with physiological saline, check the skin before use, no damage can be used in vitro Transdermal test. Franz small pool diffusion method, the upper chamber is the diffusion chamber, the lower chamber is the receiving chamber, the receiving chamber has a volume of 16.5mL, the effective diffusion area is 1.56cm ² , the constant temperature water bath (37±0.2) °C is heated, and the magnetic force is constant at 400r.pm. Stirring at a speed. During the test, the receiving chamber was filled with the receiving liquid, and the processed cowhide was fixed between the two chambers with the stratum corneum facing upward, so that the dermis layer was in full contact with the receiving liquid to eliminate air bubbles.

The detection method and the cumulative permeation (Q) and transmittance were calculated as follows: After the cowhide was stabilized for 30 min, the 8 samples and 2 comparative samples for the test were uniformly applied to the cowhide at 20 μL and 30 μL, respectively. 2 mL of the receiving solution was taken out of the receiving chamber at 24 h and 48 h, and an equal amount of blank receiving solution was immediately replenished. The taken-out solution was filtered through a 0.45 μm micropore filter, and the filtrate was a sample solution. The sample solution was subjected to high performance liquid chromatography (liquid chromatography conditions: column supelcosil TMLC-18250 mm × 4.6 mm, 5 μm; mobile phase acetonitrile: methanol: water, 40:38:22 (V:V); flow rate 1.0 mL/ Min; detection wavelength: 215 nm; injection volume: 5 μm) The concentration of acetamido avermectin was measured. Calculate the cumulative transmission amount (Q) of each sample according to the formula (Q=C _x ×V×receiving liquid dilution coefficient), and calculate the transmittance according to the formula (transmittance %=Q/C ₀ ×100%). C _x is the concentration of the sample at different times; V is the volume of the receiving chamber; C ₀ is the amount of the coating. The results are shown in Table 2.

Table 2

According to the data of Table 2, Samples 1-8 have higher transmittance and permeation Q than Comparatives 1 and 2. Further, preferably, the amount of the long-chain monobasic ester is 10-20 parts by weight, the amount of the emulsifier is 10-15 parts by weight, and the solvent is used in an amount of 5-8 with respect to 1 part by weight of acetylamino avermectin. The amount of water is 45-80 parts by weight, and the long-chain monoester and the emulsifier are used. In the case where the weight ratio is 1: (0.5-1), the acetylamino avermectin nanoemulsion of the present invention has a better transdermal effect.

Test Example 2 - Animal skin irritation test

Test animals: 10 adult healthy white rabbits weighing 2 - 2.5 kg.

Animal pre-treatment: The back sides were divided into 4 areas to remove hair 24 h before the test, and the depilation range of each area was 3 cm × 3 cm.

Test operation: The rabbits were tested for Baoding, and the test was compared with the left and right sides. The left side of the rabbit's back is used as the control area, and the right side is used as the experimental area. There are two front and back areas on each side. The front is the damaged skin test area, and the back is the intact skin test area: the damaged skin test area is disinfected and the needle is used to draw the "well". The word is broken and the damaged area is 3cm×3cm. After the complete skin test area was sterilized, the area of 3 cm × 3 cm was marked with a marker. Each test zone on the right side of the rabbit was administered to Examples 1-8 at a dose of 2 g/kg, and an equivalent amount of Comparative Example 1 and Comparative Example 2 were compared; the same amount of physiological saline was administered as a control on the left side, and It is fixed with non-irritating gauze, tape, etc. After 24 hours of administration, the test substance was wiped off, washed with warm water, and the test article was removed for 30 min, 1 h, 24 h, 48 h, and 72 h to observe the presence or absence of erythema and edema at the application site, and the recovery time and condition of the above changes. The coating site was calculated according to the scoring standard of Table 2, and the average score of the reaction of the test group and the control of each group at each observation point was calculated, and the stimulation intensity was evaluated according to Table 3. The skin irritation test results are shown in Table 4.

Table 2 scoring standards

Stimulating response Score No erythema 0 Mild erythema ( barely visible) 1 Moderate erythema (apparently visible) 2 Severe erythema 3 Purple red erythema to mild eschar formation 4

No edema 0 Mild edema ( barely visible) 1 Moderate edema (significant bulge) 2 Severe edema (skin uplift 1mm, clear outline) 3 Severe edema (skin bulge more than 1mm and enlarged) 4 Maximum total score 8

table 3

Table 4 skin irritation test results

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solutions of the present invention within the scope of the technical idea of the present invention. These simple variants All fall within the scope of protection of the present invention.

It should be further noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention has various possibilities. The combination method will not be described separately.

In addition, any combination of various embodiments of the invention may be made as long as it does not deviate from the idea of the invention, and it should be regarded as the disclosure of the invention.

Claims (28)

An acetamido avermectin nanoemulsion characterized in that the acetamibium avermectin nanoemulsion comprises acetylamino avermectin, a solvent and a long-chain monoester, and the monoester is represented by the formula R-COO-R 'Expression wherein R is selected from an alkyl group having 10 to 16 carbon atoms, and R' is an alkyl group having 1 to 5 carbon atoms. The acetamido avermectin nanoemulsion according to claim 1, wherein R' is an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group. The acetylamino avermectin nanoemulsion according to claim 1, wherein the acetamiphorin nanoemulsion has a solvent content of from 1 to 10% by weight based on 1 part by weight of acetamido avermectin. The long chain monoester content is 5-30 parts by weight. The acetylamino avermectin nanoemulsion according to claim 3, wherein the acetamiphorin nanoemulsion has a solvent content of 5-8 by weight relative to 1 part by weight of acetamibium avermectin. The content of the long-chain monoester is 10-20 parts by weight. The acetobia avermectin nanoemulsion according to any one of claims 1 to 4, wherein the acetamido avermectin nanoemulsion further contains an emulsifier and water. The acetyl avermectin nanoemulsion according to claim 5, wherein the acetamiphorin nanoemulsion has an emulsifier content of 8 to 30% by weight based on 1 part by weight of the active ingredient. The water content is 30-85 parts by weight. The acetyl avermectin nanoemulsion according to claim 6, wherein the acetamiphorin nanoemulsion has an emulsifier content of 1 part by weight of the active ingredient. 10-15 parts by weight, the content of water is 45-80 parts by weight. The acetyl avermectin nanoemulsion according to claim 7, wherein a weight ratio of the monoester to the emulsifier in the acetamiphorin nanoemulsion is 1: (0.5 - 1.5). The acetamiphorin nanoemulsion according to claim 7, wherein the acetamido avermectin nanoemulsion further contains at least one of a transdermal agent, a preservative, an antioxidant, and a pigment. The acetylamino avermectin nanoemulsion according to any one of claims 1 to 4, wherein the monoester is at least one selected from the group consisting of ethyl laurate, ethyl myristate, palm Ethyl acetate, isopropyl laurate, n-propyl laurate, isopropyl myristate, n-propyl myristate, isopropyl palmitate, isobutyl laurate, n-butyl laurate, nutmeg Isobutyl acrylate, n-butyl myristate, isobutyl palmitate and n-butyl palmitate. The acetylamino avermectin nanoemulsion according to any one of claims 1 to 4, wherein the solvent is at least one selected from the group consisting of methanol, ethanol, propanol, propylene glycol, and dimethyl Amide, dimethyl sulfoxide and ethyl acetate. The acetylamino avermectin nanoemulsion according to claim 5, wherein the emulsifier is an alkylphenol ethoxylate emulsifier, a polyoxyethylene castor oil emulsifier, or a calcium dodecylbenzenesulfonate. , or a mixture of two or more of the above emulsifiers. The acetylamino avermectin nanoemulsion according to any one of claims 1 to 4, wherein the acetylamino avermectin is based on the total weight of the acetamibium avermectin nanoemulsion The content is from 0.1 to 2% by weight. The acetylamino avermectin nanoemulsion according to claim 13, wherein the acetylamino avermectin is contained in an amount of 0.2 to 1.5% by weight based on the total weight of the acetamibium avermectin nanoemulsion. . A method for preparing acetamido avermectin nanoemulsion, characterized in that the method comprises the following steps: (1) mixing acetyl avermectin with a solvent to obtain a first mixture; (2) mixing the first mixture and the long-chain monoester and the emulsifier uniformly to obtain a second mixture; the long-chain mono-ester is represented by the formula R-COO-R', wherein R is selected from the group consisting of 10-16 An alkyl group of one carbon atom, R' is an alkyl group having 1 to 5 carbon atoms; (3) The second mixture is uniformly mixed with water to obtain a third mixture. The method of claim 15 wherein R' is ethyl, propyl, isopropyl, butyl or isobutyl. The method according to claim 16, wherein the solvent is used in an amount of from 1 to 10 parts by weight, the long-chain monoester is used in an amount of from 5 to 30 parts by weight, based on 1 part by weight of the acetyl avermectin, and the amount of the emulsifier is used. The amount of water is from 30 to 85 parts by weight, based on 8 to 30 parts by weight. The method according to claim 17, wherein the acetamiphorin nanoemulsion is used in an amount of 5-8 parts by weight, based on 1 part by weight of acetamido avermectin, of a long-chain monoester. The amount of the emulsifier is 10-15 parts by weight, the amount of water is 45-80 parts by weight, and the weight ratio of the long-chain monoester to the emulsifier is 1: ( 0.5-1.5). The method according to any one of claims 15-18, wherein steps (1) - (3) The mixing conditions each independently include: a temperature of 30-40 ° C, a relative humidity of 60-80%, and a mixed material having a pH of 5-7. The method according to claim 19, wherein in the steps (1) to (3), the conditions of the mixing each independently comprise: a temperature of 33 to 37 ° C, a relative humidity of 50 to 70%, and a pH of the mixed material. The value is 5.5-6.5. The method according to claim 20, wherein the solvent is selected from at least one of the group consisting of methanol, ethanol, propanol, propylene glycol, dimethylformamide, dimethyl sulfoxide, and ethyl acetate. The method according to claim 21, wherein said monoester is at least one selected from the group consisting of ethyl laurate, ethyl myristate, ethyl palmitate, isopropyl laurate, and lauric acid. Propyl ester, isopropyl myristate, n-propyl myristate, isopropyl palmitate, isobutyl laurate, n-butyl laurate, isobutyl myristate, n-butyl myristate, palm Isobutyl acid, and n-butyl palmitate. The method according to any one of claims 15 to 18, wherein the emulsifier is an alkylphenol ethoxylate emulsifier, a polyoxyethylene castor oil emulsifier, or a calcium dodecylbenzenesulfonate. Or a mixture of two or more of the above emulsifiers. The method according to claim 23, wherein the emulsifier is an alkylphenol ethoxylate emulsifier. The method according to claim 15, wherein the method further comprises uniformly mixing the third mixture with an auxiliary agent comprising at least one of a transdermal agent, a preservative, an antioxidant, and a pigment. The acetamido avermectin nanoemulsion prepared by the method of any one of claims 15-18. The use of the acetylamino avermectin nanoemulsion according to any one of claims 1 to 4, or 6 to 10 or 13 for killing animal surface parasites and endoparasites. The use according to claim 27, wherein said animal comprises at least one of ostrich, pig, cow, sheep, dog, horse, donkey and camel; said surface parasite including cockroach, cockroach, cockroach and cockroach At least one of the classes; the endoparasite includes a nematode.