Parasite repellent preparation as well as preparation method and application thereof

Abstract

The invention relates to an insect repellent preparation as well as a preparation method and application thereof, and the insect repellent preparation comprises the following components: fluralan, a flavoring agent, a surfactant, a phagostimulant, a lubricant, a forming agent and a filler. The phagostimulant is a mixture of chicken powder, chicken heart powder and chicken liver powder, and the mass ratio of the chicken powder to the chicken heart powder to the chicken liver powder is 1: (1-3): (0.5-1.5). The flurala chewable tablets comprise the following components in parts by mass: 10-25 parts of flurala, 5-15 parts of a flavoring agent, 0.1-5 parts of a surfactant, 5-40 parts of a phagostimulant, 10-40 parts of a lubricant, 10-35 parts of a forming agent and 10-30 parts of a filling agent. The fluralan insecticide is good in stability, high in safety, good in curative effect, simple and convenient in preparation method and suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary drugs, and in particular to an anthelmintic drug preparation and a preparation method and application thereof. Background Art

[0002] Control the parasite infection of animal groups, especially internal parasites (threads, silk, hooks, roundworms, whips, pinworms, suckers, tapeworms) parasitize in pets, depriving them of nutrients. In severe cases, pets may show clinical symptoms such as stomach pain, diarrhea, cough, anemia, itching, and even die. Therefore, regular deworming of pets is an important measure to ensure the healthy growth of pets.

[0003] Fluralaner, a new type of highly effective isoxazoline insecticide, interferes with the parasite's γ-aminobutyric acid (GABA)-gated chloride ion channels, causing the parasite's nervous system to become overexcited and die. Compared with traditional insecticides, isoxazoline insecticides have significant differences in target, molecular structure, selectivity, etc. Isoxazoline insecticides are mainly used to treat parasites such as fleas and ticks in pet cats or dogs, and red mites in poultry.

[0004] Patent CN105992517B discloses a method for preventing adult fleas from infesting animals and their environment by systemic administration of an isoxazoline compound (flurelan). The drug is only used to prevent external parasites of dogs and cats, such as fleas, and is ineffective against internal parasites.

[0005] The isoxazoline composition disclosed in patent CN103705509A can be used to prevent and treat parasites such as fleas, ticks, mites, etc. outside the body of animals, but is ineffective against parasites inside the body of animals.

[0006] In summary, there is an urgent need in this field to develop an anthelmintic preparation with good solubility of active pharmaceutical ingredients, high insecticidal activity, good safety, fast release rate, high bioavailability and strong palatability. Summary of the invention

[0007] In view of the above-mentioned technical limitations, based on existing research, the present invention provides an anthelmintic drug preparation and a preparation method thereof, which uses various solid materials to be sieved through a specific mesh number and prepared at a specific temperature, and the synergistic effect makes the drug of the present invention have strong palatability and good material compatibility, thereby overcoming the above-mentioned defects.

[0008] The invention provides an anthelmintic drug preparation, the ingredients of which include flurana, a flavoring agent, a surfactant, an attractant, a lubricant, a molding agent and a filler; the attractant is a mixture of chicken powder, chicken heart powder and chicken liver powder, and the mass ratio of the chicken powder, chicken heart powder and chicken liver powder is 1:(1-3):(0.5-1.5).

[0009] Further, in terms of parts by mass of the components of the anthelmintic drug preparation, fluralaner is 10 - 25 parts, the flavoring agent is 5 - 15 parts, the surfactant is 0.1 - 5 parts, the attractant is 5 - 40 parts, the lubricant is 10 - 40 parts, the molding agent is 10 - 35 parts, and the filler is 10 - 30 parts.

[0010] Further, the flavoring agent is selected from any one or a combination of glucose, lactose, and granulated sugar; preferably granulated sugar.

[0011] Further, the surfactant is selected from any one of sodium lauryl sulfate, sodium dodecylbenzenesulfonate, and polyvinyl alcohol.

[0012] Further, the lubricant includes lubricant 1 and lubricant 2; wherein the mass ratio of lubricant 1 to lubricant 2 is (0.1 - 5):(10 - 35);

[0013] Lubricant 1 is selected from any one of magnesium stearate and calcium stearate;

[0014] Preferably, lubricant 2 is selected from any one or a combination of glycerol, castor oil, dimethyl silicone oil, propylene glycol, soybean oil, and peanut oil.

[0015] Further, the molding agent is selected from any one or a combination of starch paste, gelatin, polyethylene glycol, stearate, and stearoyl polyoxyethylene glycerol ester.

[0016] Preferably, the filler is selected from any one of corn starch, tapioca starch, and potato starch.

[0017] Further, the drug preparation includes oral administration, and the dosage form for oral administration is selected from powder, granule, tablet, pill, capsule, soft capsule, and cachet, preferably tablet.

[0018] The present invention also provides a preparation method of an anthelmintic drug preparation, and the specific steps are as follows:

[0019] 1) Weigh the main components fluralaner, flavoring agent, surfactant, attractant, lubricant 1, lubricant 2, molding agent, and filler respectively according to parts by mass;

[0020] 2) Crushing: Crush the solid materials in the main components weighed in step 1) respectively, pass through a sieve, and set aside;

[0021] 3) Mixing process: Add the flavoring agent, surfactant, lubricant 1, fluralaner, attractant, and filler into a trough mixer, and start stirring.

[0022] 4) Preparation of soft mass: Slowly add lubricant 2 into a trough mixer, stir, and at the same time turn on the heating function of the trough mixer, keep temperature 1 unchanged, and continue stirring until a mass is formed.

[0023] 5) Total mixing: Dissolve the molding agent in advance, quickly add the dissolved molding agent into the trough mixer and stir until evenly mixed and separated from the wall. After mixing well, keep temperature 2 of the trough mixer unchanged.

[0024] 6) Tabletting and forming: Turn on the temperature control devices of the hopper of the rotary roller printing machine and the tablet press in advance, and keep temperature 3 unchanged. Place the mass in the tablet press for tabletting and forming. After the tabletting and forming is completed, the described anthelmintic drug preparation is obtained.

[0025] Furthermore, in step 2), the solid material flavoring agent is crushed and sieved through a 75 - 85 mesh sieve, and the solid materials fluralaner, surfactant, attractant, lubricant 1, and filler are sieved through a 45 - 55 mesh sieve;

[0026] In step 3), the stirring time is 1 - 4 hours;

[0027] In step 4) for preparing the soft mass, the set temperature 1 is 50 - 70 °C;

[0028] In step 5) for total mixing, the set temperature 2 is 30 - 50 °C;

[0029] In step 6) for tabletting and forming, the set temperature 3 is 30 - 50 °C.

[0030] The present invention also provides an application of the above - described drug preparation or the drug preparation prepared as claimed in the above in the preparation of drugs for preventing and treating parasites in animals.

[0031] Compared with the prior art, the advantages of the present invention:

[0032] The preparation of the present invention is for oral administration, taking into account both compressibility and palatability, and having good material compatibility, good stability under high temperature, high humidity and light, greatly expanding the clinical application range of fluralaner. Therefore, the fluralaner insecticide of the present invention has good stability, high safety, good efficacy, and a simple preparation method, and is suitable for large - scale production.

[0033] Specific embodiments

[0034] To make the purpose, technical solutions and advantages of the present application clearer, the present application will be further described in detail below. However, it should be understood that the description herein is only used to explain the present application and not to limit the scope of the present application.

[0035] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present application, and the terms used herein in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The reagents and instruments used herein are all commercially available, and the characterization means involved can refer to the relevant descriptions in the prior art, which will not be repeated herein.

[0036] In order to further understand the present application, the present application is further described in detail below in conjunction with the best embodiment.

[0037] Example 1

[0038] The present embodiment provides an anthelmintic drug preparation, the ingredients of which include flurellana, a flavoring agent, a surfactant, an attractant, a lubricant, a molding agent, and a filler; the attractant is a mixture of chicken meal, chicken heart meal, and chicken liver meal, wherein the mass ratio of the chicken meal, chicken heart meal, and chicken liver meal is 1:(1-3):(0.5-1.5);

[0039] Preferably, the attractant not only affects the adsorption balance and stability, but also affects the uniformity when it is added to the feed. According to the results of clinical efficacy trials, by determining a mixture of chicken meal, chicken heart meal and chicken liver meal in a mass ratio of 1:2:1, the palatability of the drug can be improved, and the success rate of treatment can be increased by optimizing the taste.

[0040] As a further embodiment, the anthelmintic drug preparation comprises, by weight, 10-25 parts of fluphenazine, 5-15 parts of flavoring agent, 0.1-5 parts of surfactant, 5-40 parts of attractant, 10-40 parts of lubricant, 10-35 parts of molding agent, and 10-30 parts of filler.

[0041] The following is a further description of the above main components and their mass fractions:

[0042] Fluerana is a broad-spectrum insecticide that has good insecticidal activity against pests such as ticks, sphinotidae, pedicel, hemiptera and diptera. Its toxicity is higher than that of Chemicalbook or equivalent to that of commonly used insecticides. Fluerana not only has no significant cross-resistance with existing insecticides, but also has good insecticidal activity against some resistant pests. Its molecular formula is C 22 H 17 C l2 F6N3O3, molecular weight 556.29, CAS number: 864731-61-3, structural formula is as follows:

[0043]

[0044] Preferably, the mass fraction of fluralaner can be taken as: for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 parts or any value between any two values.

[0045] Flavoring agent: A flavoring agent refers to a pharmaceutical excipient used in drugs to improve or mask the unpleasant odor and taste of the drug, making it difficult for patients to detect the strong bitter taste (or other unpleasant odors such as spicy, irritating, etc.) of the drug. Preferably, the mass fraction of the flavoring agent can be taken as: for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 parts or any value between any two values.

[0046] Preferably, the flavoring agent is selected from any one or a combination of glucose, lactose, and granulated sugar; preferably granulated sugar.

[0047] Surfactant: Surfactants have functions such as wetting, emulsifying, and solubilizing, and are thus widely used as pharmaceutical excipients, especially in the pharmaceutical microemulsion technology developed in recent years. In drug synthesis, surfactants can be used as phase transfer catalysts, which can change the degree of solvation of ions, thereby increasing the reaction activity of ions, enabling the reaction to proceed in a heterogeneous system, and greatly improving the reaction efficiency. In pharmaceutical analysis, especially in pharmaceutical fluorescence spectrometry, surfactants are often used as solubilizing and sensitizing agents. In the fields of preoperative skin disinfection, wound or mucosal disinfection, instrument disinfection, and environmental disinfection in the pharmaceutical industry, surfactants can strongly interact with bacterial biofilm proteins, causing them to denature or lose their function, and are widely used as bactericides and disinfectants. Preferably, the mass fraction of the surfactant can be taken as: for example, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 parts or any value between any two values.

[0048] Preferably, the surfactant is selected from any one of sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, and polyvinyl alcohol.

[0049] Preferably, the attractant is a mixture of chicken powder, chicken heart powder, and chicken liver powder, and the mass fraction of the mixture can be taken as: for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 parts or any value between any two values.

[0050] Lubricant: A lubricant is an important tablet excipient that can reduce the friction and extrusion force between powders and reduce the adhesion of powders in tablet production, so as to improve the quality of tablets.

[0051] The lubricant includes lubricant 1 and lubricant 2; the mass ratio of lubricant 1 to lubricant 2 is (0.1 - 5):(10 - 35).

[0052] Preferably, the amount of lubricant 1 by mass can be taken as: for example, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 parts or any value between any two values.

[0053] Preferably, the lubricant 1 is selected from any one of magnesium stearate and calcium stearate.

[0054] Preferably, the amount of the lubricant by mass can be taken as: for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 parts or any value between any two values.

[0055] Preferably, the lubricant 2 is selected from any one or a combination of glycerol, castor oil, dimethyl silicone oil, propylene glycol, soybean oil, or peanut oil.

[0056] Tablet former: The tablet former is an auxiliary material that strictly controls the quality of tablets during the tablet preparation process. The role of the tablet former is to increase the binding force and hardness of the tablets. Preferably, the amount of the tablet former by mass can be taken as: for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 parts or any value between any two values.

[0057] Preferably, the tablet former is selected from any one or a combination of starch paste, gelatin, polyethylene glycol, stearate, and stearoyl polyoxyethylene glycerol ester.

[0058] Filler: The filler is an auxiliary material that does not contain any active ingredients in the plate containing the drug. Preferably, the amount of the filler by mass can be taken as: for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 parts or any value between any two values.

[0059] Preferably, the filler is selected from any one of corn starch, tapioca starch, and potato starch.

[0060] As a further embodiment, the pharmaceutical preparation includes oral administration, and the dosage form for oral administration is selected from powder, granule, tablet, pill, capsule, soft capsule, and sachet, preferably a tablet.

[0061] The route of administration of the pharmaceutical formulations provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and cachets may be acceptable as solid dosage forms.

[0062] Example 2

[0063] This example provides a method for preparing an anthelmintic pharmaceutical formulation, and the specific steps are as follows:

[0064] 1) Weigh the main ingredient fluralaner, flavoring agent, surfactant, palatability enhancer, lubricant 1, lubricant 2, shaping agent, and filler respectively by mass parts;

[0065] 2) Crushing: Crush the solid materials among the main ingredients weighed in step 1) respectively, sieve through a mesh sieve, and reserve;

[0066] 3) Mixing process: Add the flavoring agent, surfactant, lubricant 1, fluralaner, palatability enhancer, and filler into a trough mixer, and start stirring.

[0067] 4) Preparing soft mass: Slowly add lubricant 2 into the trough mixer, stir, and at the same time turn on the heating function of the trough mixer, set the temperature 1 to remain unchanged, and continue stirring until a mass is formed.

[0068] 5) Total mixing: Dissolve the shaping agent in advance, quickly add the dissolved shaping agent into the trough mixer and stir until evenly mixed and separated from the wall. After mixing well, set the temperature 2 of the trough mixer to remain unchanged.

[0069] 6) Tableting and shaping: Turn on the temperature control devices of the hopper of the rotary roller imprinting machine and the tablet press in advance, and set the temperature 3 to remain unchanged. Place the mass in the tablet press for tableting and shaping. After the tableting and shaping are completed, the anthelmintic pharmaceutical formulation is obtained.

[0070] As a further implementation method, the solid material flavoring agent in step 2) is crushed and sieved through a 75 - 85 mesh sieve, preferably the flavoring agent is crushed and sieved through an 80 mesh sieve. The solid materials fluralaner, surfactant, palatability enhancer, lubricant 1, and filler are sieved through a 45 - 55 mesh sieve, preferably through a 50 mesh sieve. The treatment method in step 2) improves the palatability and compressibility of the drug, greatly expanding the clinical application range of the drug.

[0071] As a further implementation method, the stirring time in step 3) is 1 - 4 hours;

[0072] As a further implementation method, the set temperature 1 in step 4) for preparing the soft mass is 50 - 70 °C;

[0073] As a further embodiment, the temperature 2 set in step 5) of the total mixing is 30 to 50 °C;

[0074] As a further embodiment, the temperature 3 set in step 6) of the tabletting is 30 to 50 °C.

[0075] In the above preparation method, the control of the temperature adjustment in each step, and the synergistic effect with each step make the materials of the present invention have good compatibility.

[0076] Example 3

[0077] Use of a drug preparation as described above or a drug preparation prepared as described above in the preparation of a drug for preventing and treating parasites in animals.

[0078] Example 4

[0079] According to the content of the present application, the drug preparations of the examples are prepared, and the specific description is as follows:

[0080] For those not specifying specific experimental steps or conditions in the examples, the operations or conditions of the conventional experimental steps described in the literature in the art can be followed. For reagents or instruments without indicating the manufacturer, they are all conventional reagent products that can be obtained through commercial purchase.

[0081] The present invention will be further described in detail below with specific examples, and these examples should not be construed as limiting the scope claimed by the present invention.

[0082] Test Example 1

[0083] Composition of a anthelmintic drug preparation: 25 g of fluralaner, 12 g of flavoring agent granulated sugar, 3 g of surfactant sodium dodecylbenzenesulfonate, 36 g of attractant chicken meat powder, chicken heart powder and chicken liver powder mixture, including 9 g of chicken meat powder, 18 g of chicken heart powder and 9 g of chicken liver powder, 2 g of lubricant 1 magnesium stearate, 35 g of lubricant 2 glycerol, 33 g of molding agent stearic acid ester, 29 g of filler corn starch.

[0084] Preparation method:

[0085] 1) Weigh 25 g of the main ingredient fluralaner, 12 g of flavoring agent granulated sugar, 3 g of surfactant sodium dodecylbenzenesulfonate, 36 g of attractant chicken meat powder, chicken heart powder and chicken liver powder mixture, including 9 g of chicken meat powder, 18 g of chicken heart powder and 9 g of chicken liver powder, 2 g of lubricant 1 magnesium stearate, 35 g of lubricant 2 glycerol, 33 g of molding agent stearic acid ester, 29 g of filler corn starch respectively.

[0086] 2) Crushing: Take the flavoring agent granulated sugar powder and sieve it through an 80-mesh sieve, and sieve the remaining all solid materials, including fluralaner, sodium dodecylbenzenesulfonate, chicken meat powder, chicken heart powder and chicken liver powder, magnesium stearate, and corn starch through a 50-mesh sieve.

[0087] 3) Mixing process: Place white granulated sugar, sodium dodecylbenzenesulfonate, magnesium stearate, fluralaner, chicken powder, chicken heart powder, chicken liver powder, and corn starch into a trough-type mixer, turn on the stirring, and stir for 3 hours.

[0088] 4) Soft material preparation: Slowly add 2 g of glycerol to the trough-type mixer and stir. At the same time, turn on the heating function of the trough-type mixer, set the temperature to remain constant at 60 °C, and continue stirring until a mass is formed.

[0089] 5) Overall mixing: Melt the stearate ester in advance, quickly add the melted stearate ester to the trough-type mixer and stir until evenly mixed and separated from the wall. After mixing well, set the temperature of the trough-type mixer to remain constant at 40 °C.

[0090] 6) Tablet pressing and forming: Open the hopper of the rotary roller printing and forming machine and the temperature control of the tablet press in advance to remain constant at 45 °C. Place the mass into the tablet press for tablet pressing and forming. After the tablet pressing and forming is completed, the described anthelmintic drug preparation, namely 100 chewable tablets, is obtained.

[0091] Test Example 2

[0092] Composition of an anthelmintic drug preparation: 25 g of fluralaner, 15 g of white granulated sugar as a flavoring agent, 3 g of sodium dodecylbenzenesulfonate as a surfactant, 35 g of a mixture of chicken powder, chicken heart powder, and chicken liver powder as a feeding attractant, including 9 g of chicken powder, 18 g of chicken heart powder, and 8 g of chicken liver powder, 1.5 g of calcium stearate as lubricant 1, 35 g of soybean oil as lubricant 2, 20 g of gelatin and 10 g of starch paste as forming agents, and 30 g of tapioca starch as a filler.

[0093] Preparation method:

[0094] 1) Weigh the main components separately: 25 g of fluralaner, 15 g of white granulated sugar as a flavoring agent, 3 g of sodium dodecylbenzenesulfonate as a surfactant, 35 g of a mixture of chicken powder, chicken heart powder, and chicken liver powder as a feeding attractant, including 9 g of chicken powder, 18 g of chicken heart powder, and 8 g of chicken liver powder, 1.5 g of calcium stearate as lubricant 1, 35 g of soybean oil as lubricant 2, 20 g of gelatin and 10 g of starch paste as forming agents, and 30 g of tapioca starch as a filler.

[0095] 2) Crushing: Crush the white granulated sugar as a flavoring agent through an 80-mesh sieve, and pass the rest of all solid materials through a 50-mesh sieve.

[0096] 3) Mixing process: Place white granulated sugar, sodium dodecylbenzenesulfonate, calcium stearate, fluralaner, chicken powder, chicken heart powder, chicken liver powder, and tapioca starch into a trough-type mixer, turn on the stirring, and stir for 2 hours.

[0097] 4) Preparation of soft material: Slowly add soybean oil to a trough mixer, stir, and at the same time turn on the heating function of the trough mixer, set the temperature to remain constant at 70 °C, and continue stirring until a mass is formed.

[0098] 5) Total mixing: Dissolve gelatin and starch paste in advance, quickly add the dissolved gelatin and starch paste to a trough mixer and stir until evenly mixed and separated from the wall. After mixing, set the temperature of the trough mixer to remain constant at 40 °C.

[0099] Tablet pressing and forming: Open the hopper of the rotary roller printing and forming machine and the temperature control of the tablet press in advance to remain constant at 40 °C. Place the mass in the tablet press for tablet pressing and forming. After the tablet pressing and forming is completed, the described anthelmintic drug preparation is obtained, that is, 100 chewable tablets are obtained.

[0100] Test Example 3

[0101] Composition of an anthelmintic drug preparation: 20 g of fluralaner, 10 g of flavoring agent white granulated sugar, 3 g of surfactant polyvinyl alcohol, 28 g of mixture of attractants chicken powder, chicken heart powder and chicken liver powder, including 7 g of chicken powder, 14 g of chicken heart powder, 7 g of chicken liver powder, 2 g of lubricant 1 magnesium stearate, 15 g of lubricant 2 peanut oil, 20 g of soybean oil, 30 g of molding agent stearoyl polyoxyethylene glycerol ester, 25 g of filler potato starch.

[0102] Preparation method:

[0103] 1) Weigh the main components separately: 20 g of fluralaner, 10 g of flavoring agent white granulated sugar, 3 g of surfactant polyvinyl alcohol, 28 g of mixture of attractants chicken powder, chicken heart powder and chicken liver powder, including 7 g of chicken powder, 14 g of chicken heart powder, 7 g of chicken liver powder, 2 g of lubricant 1 magnesium stearate, 15 g of lubricant 2 peanut oil, 20 g of soybean oil, 30 g of molding agent stearoyl polyoxyethylene glycerol ester, 25 g of filler potato starch.

[0104] 2) Crushing: Crush the flavoring agent white granulated sugar through an 80-mesh sieve, and pass the rest of all solid materials through a 50-mesh sieve.

[0105] 3) Mixing process: Place white granulated sugar, polyvinyl alcohol, magnesium stearate, fluralaner, chicken powder, chicken heart powder, chicken liver powder, and potato starch in a trough mixer, turn on the stirring, and stir for 4 hours.

[0106] 4) Preparation of soft material: Slowly add peanut oil and soybean oil to a trough mixer, stir, and at the same time turn on the heating function of the trough mixer and set the temperature to remain constant at 50 °C, and continue stirring until a mass is formed.

[0107] 5) Total mixing: Melt stearoyl polyoxyethylene glycerol ester in advance, quickly add the melted stearoyl polyoxyethylene glycerol ester into a trough mixer and stir until evenly mixed and separated from the wall. After mixing well, set the temperature of the trough mixer to remain unchanged at 50 °C.

[0108] Tablet pressing and forming: Open the hopper of the rotary roller printing and forming machine and the temperature control of the tablet press in advance to remain unchanged at 50 °C. Place the mass in the tablet press for tablet pressing and forming. After the tablet pressing and forming is completed, the described anthelmintic drug preparation is obtained, that is, 100 chewable tablets are obtained.

[0109] In Comparative Example 1, the temperature cannot reach

[0110] Composition of an anthelmintic drug preparation: The same components and weights as in Test Example 1 are adopted.

[0111] Preparation method

[0112] Steps 1), 2), 3) are the same as those in Test Example 1.

[0113] 4) Preparation of soft material: Slowly add 2 g of glycerol into a trough mixer and stir. At the same time, turn on the heating function of the trough mixer, set the temperature to remain unchanged at 40 °C, and continue to stir until a mass is formed.

[0114] 5) Total mixing: Melt stearate in advance, quickly add the melted stearate into a trough mixer and stir until evenly mixed and separated from the wall. After mixing well, set the temperature of the trough mixer to remain unchanged at 25 °C.

[0115] 6) Tablet pressing and forming: Open the hopper of the rotary roller printing and forming machine and the temperature control of the tablet press in advance to remain unchanged at 25 °C. Place the mass in the tablet press for tablet pressing and forming. After the tablet pressing and forming is completed, the described anthelmintic drug preparation is obtained, that is, 100 chewable tablets.

[0116] In Comparative Example 2, sieving does not meet the requirements

[0117] Composition of an anthelmintic drug preparation: The same components and weights as in Test Example 1 are adopted.

[0118] Preparation method:

[0119] Steps 1), 3), 4), 5), 6) are the same as those in Test Example 1.

[0120] 2) Pulverization: Take the flavoring agent white granulated sugar and pulverize it through a 50-mesh sieve, and sieve the remaining all solid materials through a 50-mesh sieve.

[0121] Comparative Example 3 Existing technology

[0122] An anthelmintic drug preparation: The formulation and preparation method in Example 1 of a compound soft chewable anti-parasitic drug preparation and its preparation method and application with patent (application number CN202110824752.X) are adopted, as follows: Ingredients (total 175 g): Fluralaner 5.88%, Milbemycin 1.18%, Praziquantel 2.94%, Sucrose 8%, Starch 17%, Soybean oil 15%, Propylene glycol 7%, Lauroyl polyoxyethylene-32 glycerol ester 20 g%, Liver powder 23%.

[0123] The specific preparation steps are as follows:

[0124] (1) Dry mixing: Mix Fluralaner, Praziquantel, Milbemycin with Sucrose, Starch, and attractant in a mixer to obtain a premixed material.

[0125] (2) Wet mixing: Add the liquid components sequentially or after mixing into the mixer, and mix with the premixed material obtained in step (1) to prepare a wet material.

[0126] (3) Addition of molding agent: After heating and melting the molding agent, quickly add it to the wet material obtained in step (2) (control the temperature of the wet material at 35 - 45 °C), and mix quickly to prepare an intermediate material.

[0127] (4) Compression: Use a molding machine to extrude and form the intermediate material obtained in step (3) to obtain the product of Comparative Example 3.

[0128] Comparative Example 4 Existing technology

[0129] An anthelmintic drug preparation: The formulation and preparation method in a novel fluralaner tablet, preparation method and application with patent (patent number CN202311820119.9) are adopted, specifically as follows: Ingredients: Fluralaner 15 g, Liver powder 10 g, Sodium cyclamate 1.5 g, Silicon dioxide 2 g, Calcium carboxymethylcellulose 5 g, Hydroxypropyl methylcellulose 5 g, Hydroxypropyl cellulose 5 g, Polyoxyethylene-8 glyceryl behenate 5 g, Lactose 5 g, Silicified microcrystalline cellulose 5 g, Mannitol 5 g.

[0130] The specific preparation steps are as follows:

[0131] 1) Crush Fluralaner so that the particle size of the obtained Fluralaner powder is 50 mm;

[0132] 2) After passing the Fluralaner powder obtained in step 1 and hydroxypropyl methylcellulose, lactose through a 50-mesh sieve, put them into a fluidized bed, control the temperature at 40 °C - 50 °C, and mix evenly;

[0133] 3) Spray purified water into the first mixture obtained in step 2 so that the first mixture powder gradually binds into small particles and finally forms coarse particles;

[0134] 4) Dry the coarse particles obtained in step 3 in a fluidized bed, control the temperature at 40°C to 50°C, control the moisture content of the material at 4% to 5%, and then screen and size the particles through a 40-mesh sieve;

[0135] 5) After uniformly mixing the particles obtained in step 4 with hydroxypropyl cellulose, silicified microcrystalline cellulose, mannitol, sodium cyclamate, liver powder, and silicon dioxide, add polyoxyethylene-8 glyceryl behenate and mix;

[0136] 6) Compress the second mixture obtained in step 5 into tablets to obtain the product of Comparative Example 4.

[0137] Comparative Example 5 Existing technology

[0138] An anthelmintic drug preparation: Use the formula and preparation method in the patent (Patent No. CN202210137143.1) Fluralaner soft chewable composition, soft chewable tablets and their preparation methods and applications, specifically as follows: Ingredients (total 175 g): Fluralaner 26.25 g, corn starch 26.25 g, soy protein powder 21.875 g, chicken liver powder 38.375 g, hydroxypropyl cellulose 7.875 g, polyethylene glycol 3350 14 g, polyethylene glycol 15 hydroxystearate 4.375 g, glycerol 13.125 g, soybean oil 21.875 g.

[0139] Specific preparation steps are as follows:

[0140] 1) Crush fluralaner so that the particle size D90 of the obtained fluralaner powder is ≤ 35 mm;

[0141] 2) Mix the fluralaner powder obtained in step (1) with soy protein powder, chicken liver powder, and hydroxypropyl cellulose polyethylene glycol 3350 in a wet granulator for 10 minutes to obtain a mixed material;

[0142] 3) Mix glycerol and polyethylene glycol 15 hydroxystearate, uniformly and slowly add them to the mixed material obtained in step (2), stir and shear for 2 minutes to mix evenly, then add soybean oil, and stir and shear for 1 minute to mix evenly to obtain a fluralaner soft chewable composition with moderate flexibility;

[0143] 4) Put the fluralaner soft chewable composition obtained in step (3) of the soft chewable composition preparation method into a hydraulic molding machine and compress it into tablets to obtain the product of Comparative Example 5.

[0144] Comparative Example 6 Sieving over 80

[0145] An anthelmintic drug preparation ingredient: Use the same components and weights as in Test Example 1.

[0146] Preparation method:

[0147] Steps 1), 3), 4), 5), 6) are the same as those in Test Example 1.

[0148] Step 2) Take the flavoring agent white granulated sugar, crush it and sieve it through a 150-mesh sieve, and sieve the rest of all solid materials through a 50-mesh sieve.

[0149] In Comparative Example 7, the attractant is pure chicken liver powder

[0150] Composition of an anthelmintic drug preparation: 25 g of fluralaner, 12 g of flavoring agent white granulated sugar, 3 g of surfactant sodium dodecylbenzenesulfonate, 36 g of attractant chicken liver powder, including 9 g of chicken meat powder, 18 g of chicken heart powder and 9 g of chicken liver powder, 2 g of lubricant 1 magnesium stearate, 35 g of lubricant 2 glycerol, 33 g of molding agent stearic acid ester, 29 g of filler corn starch.

[0151] The preparation method is the same as that of Test Example 1.

[0152] In Comparative Example 8, the flavoring agent is sucrose

[0153] Composition of an anthelmintic drug preparation: 25 g of fluralaner, 12 g of flavoring agent sucrose, 3 g of surfactant sodium dodecylbenzenesulfonate, 36 g of attractant mixture of chicken meat powder, chicken heart powder and chicken liver powder, including 9 g of chicken meat powder, 18 g of chicken heart powder and 9 g of chicken liver powder, 2 g of lubricant 1 magnesium stearate, 35 g of lubricant 2 glycerol, 33 g of molding agent stearic acid ester, 29 g of filler corn starch.

[0154] The preparation method is the same as that of Test Example 1.

[0155] Experimental Example 1

[0156] Examine the content uniformity of the samples of Test Example 1 and Comparative Examples 1-2. Take 10 tablets of the samples of Test Example 1 and Comparative Examples 1-2, quantitatively transfer them to a stoppered conical flask respectively, accurately add 50 ml of acetonitrile, stir for 1 h, cool, filter through a 0.22 μm filter membrane, take the subsequent filtrate as the test sample, inject 20 μL into a high performance liquid chromatograph to record the chromatogram, calculate the content according to the peak area of the control and calculate. The results are shown in Table 1.

[0157] Table 1 Content uniformity of the samples of Test Example 1 and Comparative Examples 1-2

[0158]

[0159] The test results prove that: due to the temperature and the crushing mesh number of the flavoring agent not meeting the requirements, the content uniformity of the products obtained in Comparative Examples 1-2 cannot meet the requirements.

[0160] Experimental Example 2

[0161] Examine the stability of the influencing factors of the samples of Test Example 1 and Comparative Examples 3-5.

[0162] High-temperature test: Take the samples of Test Example 1 and Comparative Examples 3-5, place them open in an incubator at 60 °C for 10 days, and take samples for testing on the 5th and 10th days.

[0163] High-humidity test: Take the samples of Test Example 1 and Comparative Examples 3-5, place them open in a stability chamber with a humidity of 75% for 10 days, and take samples for testing on the 5th and 10th days.

[0164] Light exposure test: Take the samples of Test Example 1 and Comparative Examples 3-5, place them under the condition of illuminance of 4500 lx ± 500 lx for 10 days, and take samples for testing on the 5th and 10th days.

[0165] Table 2 Stability of the samples of Test Example 1 and Comparative Examples 3-5

[0166]

[0167] The results show that the sample of Test Example 1 has good stability under high-temperature, high-humidity and light exposure conditions. In Comparative Examples 3-5, the content decreased. The decrease in content may be due to the interaction between the raw materials and excipients. The decrease in content may affect the quality and stability of the drug, and further affect its safety and effectiveness. Therefore, it is proved that the compatibility of the products - chewable tablets in the comparative examples is poor. Since the product contents of Comparative Example 1 and Comparative Example 2 are uneven, it is impossible to intuitively confirm the influence of the influencing factors.

[0168] Experimental Example 3

[0169] The palatability of Test Examples 1-3 of the present invention and Comparative Examples 3-8 was evaluated. The test method was as follows: Select 90 healthy test dogs with normal spirit and appetite and who had not used related products for treatment in the past 3 months. There were a total of 9 groups, with 10 dogs in each group. Each group used the corresponding drug and dose for the palatability test. The weight of each test dog was evaluated before the test, and the drug was administered according to the weight (see Table 3). Take the sample tablets of Test Examples 1-3 and Comparative Examples 3-8 for the palatability test. The test personnel put the drug into the food bowl and induced the dog to eat it voluntarily or put the drug in the palm and feed it. The stopwatch was used to time for 2 minutes, and the feeding situation of each dog for the test sample was observed.

[0170] Table 3 Drug administration dose table

[0171]

[0172] The main criteria for judging palatability are as follows: 1. Actively eat: finish eating all within 1 minute; 2. Eat all: finish eating all within 2 minutes; 3. Eat partially: eat part within 2 minutes; 4. Refuse to eat: vomit after eating into the mouth or completely reject.

[0173] Table 4 Palatability of the test dogs for each group of preparations

[0174] Drug Actively eat Completely eat Partially eat Refuse to eat Test Example 1 6 3 1 0 Test Example 2 7 2 1 0 Test Example 3 7 3 0 0 Comparative Example 3 4 5 1 0 Comparative Example 4 2 5 2 1 Comparative Example 5 0 6 3 1 Comparative Example 6 1 4 5 0 Comparative Example 7 0 7 2 1 Comparative Example 8 4 4 2 0

[0175] The test results show that: in Comparative Example 6, due to the too fine grinding mesh number of the flavoring agent, the palatability of the product is poor, and there is a large difference from the results of Test Examples 1-3. Compared with Comparative Examples 3-8, the overall acceptance rate of the pharmaceutical preparations prepared in Test Examples 1-3 is high.

[0176] Experimental Example 4

[0177] The hardness of the samples of Test Example 1 and Comparative Examples 1-2, 6-8 was investigated. Five tablets of the samples of Test Example 1 and Comparative Examples 1-2, 6-8 were taken. They were placed in a constant temperature incubator that had been balanced at 25 ± 0.5 °C for 20 minutes and balanced for 30 minutes, and then detected using a hardness tester. The average pressure of each chewable tablet should be within the range of 15-25 N. The results are shown in Table 5.

[0178] Table 5 Hardness of the samples of Test Example 1, Comparative Examples 1-2, 6-8

[0179]

[0180] The test results prove that: due to the temperature and the grinding mesh number of the flavoring agent not meeting the requirements, the hardness of the products obtained in Comparative Examples 1-2 and Comparative Example 6 cannot meet the requirements, proving that the temperature and the grinding mesh number of the flavoring agent have a great influence on tabletting; the hardness of the product obtained in Comparative Example 7 is not much different from that of the product in Test Example 1, proving that the attractant has little influence on the hardness, but the hardness of the product in Comparative Example 8 is close to the limit, proving that the flavoring agent also has a significant influence on tabletting.

[0181] This is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions, or improvements made within the spirit and principle of the present application shall be included within the protection scope of the present application.

Claims

1. An anthelmintic drug preparation, characterized in that: Its ingredients include flurana, flavoring agent, surfactant, attractant, lubricant, molding agent and filler; the attractant is a mixture of chicken powder, chicken heart powder and chicken liver powder, and the mass ratio of the chicken powder, chicken heart powder and chicken liver powder is 1:(1-3):(0.5-1.5).

2. The pharmaceutical preparation according to claim 1, characterized in that The anthelmintic drug preparation comprises, by weight, 10-25 parts of flurellana, 5-15 parts of flavoring agent, 0.1-5 parts of surfactant, 5-40 parts of attractant, 10-40 parts of lubricant, 10-35 parts of molding agent and 10-30 parts of filler.

3. The pharmaceutical preparation according to claim 1, characterized in that The flavoring agent is selected from any one or more combinations of glucose, lactose, and white sugar; preferably white sugar.

4. The pharmaceutical preparation according to claim 1, characterized in that: The surfactant is selected from any one of sodium dodecyl sulfate, sodium dodecylbenzene sulfonate and polyvinyl alcohol.

5. The pharmaceutical preparation according to claim 1, characterized in that The lubricant includes lubricant 1 and lubricant 2; wherein the mass ratio of lubricant 1 to lubricant 2 is (0.1-5):(10-35); The lubricant 1 is selected from any one of magnesium stearate and calcium stearate; Preferably, the lubricant 2 is selected from any one or more combinations of glycerin, castor oil, dimethicone, propylene glycol, soybean oil, and peanut oil.

6. The pharmaceutical preparation according to claim 1, characterized in that The molding agent is selected from any one or more combinations of starch slurry, gelatin, polyethylene glycol, stearate, and stearyl polyoxyethylene glyceride. Preferably, the filler is selected from any one of corn starch, tapioca starch and potato starch.

7. The pharmaceutical preparation according to any one of claims 1 to 6, characterized in that The pharmaceutical preparation includes oral administration, and the dosage form for oral administration is selected from powder, granules, tablets, pills, capsules, soft capsules and caplets, preferably tablets.

8. A method for preparing the anthelmintic pharmaceutical preparation according to any one of claims 1 to 6, characterized in that: The specific steps are as follows: 1) Weigh the main ingredients of flurellana, flavoring agent, surfactant, appetite attractant, lubricant 1, lubricant 2, shaping agent, and filler respectively according to their mass proportions; 2) Crushing: crush the solid materials of the main components weighed in step 1) respectively, sieve through a mesh sieve, and set aside; 3) Mixing process: Add flavoring agent, surfactant, lubricant 1, flurellanine, attractant, and filler into a trough mixer and start stirring. 4) Preparation of soft material: slowly add lubricant 2 into the trough mixer, stir, turn on the heating function of the trough mixer, set the temperature 1 to remain unchanged, and continue stirring to form a mass. 5) Total mixing: melt the molding agent in advance, quickly add the melted molding agent into the trough mixer and stir until it is evenly mixed and separated from the wall. After mixing, set the temperature of the trough mixer to remain unchanged. 6) Tablet forming: Open the temperature control device of the rotary roller press hopper and the tablet press in advance, set the temperature 3 to remain unchanged, put the mass into the tablet press, and perform tablet forming. After the tablet forming is completed, the anthelmintic drug preparation is obtained.

9. The preparation method according to claim 8, characterized in that: The solid material flavoring agent in step 2) is crushed and passed through a 75-85 mesh sieve, and the solid material flurellanine, surfactant, attractant, lubricant 1, and filler are passed through a 45-55 mesh sieve; The stirring time in step 3) is 1-4 hours; Step 4) The temperature 1 in preparing the soft material is set to 50-70° C.; Step 5) The setting temperature 2 in the total mixing is 30-50° C.; In step 6), the setting temperature 3 in tableting is 30-50°C.

10. Use of the pharmaceutical preparation according to any one of claims 1 to 7 or the pharmaceutical preparation prepared according to any one of claims 8 to 9 in preparing drugs for preventing and treating parasites in animals.

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