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WO2018161291A1 - Nanoémulsion d'éprinomectine, son procédé de préparation et son utilisation - Google Patents

Nanoémulsion d'éprinomectine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2018161291A1
WO2018161291A1 PCT/CN2017/076074 CN2017076074W WO2018161291A1 WO 2018161291 A1 WO2018161291 A1 WO 2018161291A1 CN 2017076074 W CN2017076074 W CN 2017076074W WO 2018161291 A1 WO2018161291 A1 WO 2018161291A1
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Prior art keywords
avermectin
nanoemulsion
weight
emulsifier
acetamido
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Ceased
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PCT/CN2017/076074
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English (en)
Chinese (zh)
Inventor
吴一凡
布里斯托J•T
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Jiangsu Rotam Chemical Co Ltd
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Jiangsu Rotam Chemical Co Ltd
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Priority to PCT/CN2017/076074 priority Critical patent/WO2018161291A1/fr
Priority to CN201780088184.3A priority patent/CN110494129B/zh
Publication of WO2018161291A1 publication Critical patent/WO2018161291A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • 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.
  • 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.
  • 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.
  • acetobia avermectin 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.
  • GABA neurotransmitter inhibitor
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. .
  • the concentration of the original drug is low, and water is used as an auxiliary material, which greatly reduces the cost.
  • 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.
  • 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.
  • the invention also provides an acetamido avermectin nanoemulsion prepared by the method described above.
  • the present invention provides the use of the acetamido avermectin nanoemulsion as described above for killing parasites and surface parasites in animals.
  • 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.
  • 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.
  • 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.
  • 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.
  • the solvent in the acetamido avermectin nanoemulsion, 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.
  • 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.
  • 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.
  • 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.
  • the weight ratio of the monoester to the emulsifier in the nanoemulsion is 1: (0.5-1.5).
  • the pharmaceutical composition has a very excellent transdermal effect.
  • the monobasic ester may be ethyl laurate, ethyl myristate, ethyl palmitate, isopropyl laurate, lauric acid.
  • 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.
  • the emulsifier in the acetamido avermectin nanoemulsion, 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.
  • the emulsifier is an alkylphenol ethoxylate emulsifier.
  • the acetamiphorin nanoemulsion further contains an auxiliary agent including a transdermal agent, a preservative, an antioxidant, and a pigment. At least one of them.
  • 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.
  • 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.
  • 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
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • mixing uniformly means that the mixed material is a relatively stable, uniform liquid.
  • 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.
  • the mixing conditions include a temperature of 35 ° C, a relative humidity of 70%, and a pH of the mixed material of 6.
  • 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.
  • the solvent in the method of the present invention, may be selected from at least methanol, ethanol, propanol, propylene glycol, dimethylformamide, dimethyl sulfoxide and ethyl acetate.
  • the solvent is ethanol or propylene glycol or ethyl acetate.
  • 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.
  • the emulsifier is an alkylphenol ethoxylate emulsifier.
  • the acetyl avermectin nanoemulsion further contains an auxiliary agent comprising at least at least a transdermal agent, a preservative, an antioxidant, and a pigment.
  • an auxiliary agent comprising at least at least a transdermal agent, a preservative, an antioxidant, and a pigment.
  • 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.
  • 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.
  • 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.
  • BHT dibutylhydroxytoluene
  • BHA butylated hydroxyanisole
  • BHT 2,6-diisopropylphenol
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • 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.
  • 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.
  • the invention also provides an acetamido avermectin nanoemulsion prepared by the method described above.
  • the present invention also provides the use of an acetamido avermectin nanoemulsion as described above for killing parasites and surface parasites in animals.
  • 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 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 .
  • the mixing conditions include a temperature of 35 ° C, a relative humidity of 70%, and a pH of the mixed material of 6.
  • Table 1 The selection and amount of the long-chain monoester, solvent, emulsifier, preservative and antioxidant are shown in Table 1.
  • 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.
  • 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.
  • 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.
  • 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
  • the dose used was twice that of the samples 1-8 and the comparative example 2
  • 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 ⁇ L, 30 ⁇ L, and acetamibium avermectin concentration of 5.2 ⁇ g/ ⁇ L).
  • 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.
  • 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 ⁇ L and 30 ⁇ L, 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 ⁇ m 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 ⁇ m; mobile phase acetonitrile: methanol: water, 40:38:22 (V:V); flow rate 1.0 mL/ Min; detection wavelength: 215 nm; injection volume: 5 ⁇ m)
  • concentration of acetamido avermectin was measured.
  • 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.
  • Table 2 The results are shown in Table 2.
  • Samples 1-8 have higher transmittance and permeation Q than Comparatives 1 and 2.
  • 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
  • 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.
  • the weight ratio is 1: (0.5-1)
  • the acetylamino avermectin nanoemulsion of the present invention has a better transdermal effect.
  • 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.
  • 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.
  • 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.

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  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une nanoémulsion d'éprinomectine, la nanoémulsion d'éprinomectine contenant de l'éprinomectine, un solvant et un monoester à longue chaîne; le monoester est représenté par la formule R-COO-R', dans laquelle R est choisi parmi les groupes alkyle contenant 10 à 16 atomes de carbone, tandis que R' est un groupe alkyle contenant 1 à 5 atomes de carbone, et le groupe alkyle contenant 1 à 5 atomes de carbone est de préférence l'éthyle, le propyle, l'isopropyle, le butyle ou l'isobutyle. La présente invention concerne également un procédé de préparation de la nanoémulsion d'éprinomectine. Le procédé comprend les étapes suivantes : (1) mélanger l'éprinomectine uniformément avec un solvant pour obtenir un premier mélange; (2) mélanger le premier mélange uniformément avec un monoester à longue chaîne et un émulsifiant pour obtenir un deuxième mélange; et (3) mélanger le deuxième mélange uniformément avec de l'eau pour obtenir un troisième mélange. La présente invention concerne en outre une nanoémulsion d'éprinomectine qui est préparée et obtenue au moyen dudit procédé et une utilisation de celle-ci pour tuer des parasites dans des corps d'animaux et des parasites sur des surfaces de corps d'animaux.
PCT/CN2017/076074 2017-03-09 2017-03-09 Nanoémulsion d'éprinomectine, son procédé de préparation et son utilisation Ceased WO2018161291A1 (fr)

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CN201780088184.3A CN110494129B (zh) 2017-03-09 2017-03-09 一种乙酰氨基阿维菌素纳米乳及其制备方法和用途

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CN101309587A (zh) * 2005-11-18 2008-11-19 凯米诺瓦有限公司 阿维菌素类的水包油制剂
US20090258065A1 (en) * 2006-10-12 2009-10-15 Galderma S.A. Dermatological compositions comprising avermectin nanocapsules
CN104095866A (zh) * 2013-04-03 2014-10-15 华中农业大学 一种依普菌素透皮剂及制备方法及应用
CN105769751A (zh) * 2016-04-01 2016-07-20 江苏农牧科技职业学院 一种埃普利诺菌素乳剂凝胶及其制备方法
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