CN112006981A - A kind of long-acting compound anthelmintic drug liquid preparation and preparation method and application thereof - Google Patents

Abstract

The invention relates to a long-acting compound anthelmintic medicinal liquid preparation, a preparation method and application thereof, and belongs to the field of veterinary medicinal preparations. The compound preparation is mainly composed of anti-parasitic active ingredients mirbeoxime, benzimidazoles and juvenile hormones, and in mass percentage: 0.5-1% of mirbexime, 5-10% of benzimidazoles, Juvenile hormones 3-5%, macromolecular suspending agent 0.1-5%, wetting agent 0.1-5%, antioxidant 0.01-1%, and the balance is dispersion medium. The invention combines the anti-parasitic drugs to expand the anti-parasitic spectrum and plays a comprehensive and efficient role of both internal and external driving.

Description

A kind of long-acting compound anthelmintic drug liquid preparation and preparation method and application thereof

technical field

The invention belongs to the technical field of veterinary drugs, and particularly relates to a long-acting compound anthelmintic drug liquid preparation and a preparation method and application thereof.

Background technique

Parasites can cause mechanical damage to pets by consuming nutrients in pets, causing pets to grow slowly, stagnant, thin, anemia, and weight loss due to lack of nutrients; or miscarriage, stillbirth, loss of fertility; or appear rough skin, Dermatitis, itching, hair loss, frailty, decreased immunity and disease resistance, prone to diseases, infectious diseases, etc. After animals suffer from parasitic diseases, due to frequent contact with humans, most of the parasites can be transmitted to humans through pets, which seriously threatens the health of children and adults.

Milbeoxime is a macrolide antibody internal and external parasite drug, which is mainly used as an anthelmintic for dogs; it can effectively prevent and treat heartworms, effectively control internal parasites such as hookworms, roundworms, whipworms, roundworms, and hair follicles. , scabies, lice, fleas and other ectoparasites, and its toxicity to abamectin-sensitive dogs is less, therefore, its application and research more and more attention. At present, most of the mirbeoxime circulating in the market are oral tablets; mirbeoxime has high fat solubility and is easily soluble in organic solvents such as methanol, ethanol and acetone.

Benzimidazole anthelmintic with broad-spectrum anthelmintic effect. Nematodes are sensitive to it, and it also has a strong effect on tapeworms and flukes, but the required dose is large. The mechanism of action of benzimidazole anthelmintics is mainly by binding to the tubulin of nematodes. Binding of benzimidazoles to β-tubulin prevents its multimerization with α-tubulin to assemble into microtubules. Microtubules are the basic structural units of many organelles and are necessary for cellular reproduction processes such as mitosis, protein assembly, and energy metabolism. Benzimidazoles have a significantly higher affinity for nematode tubulin than mammalian tubulin, and therefore have little toxicity to mammals. This product not only has a strong effect on adults, but also has a strong effect on immature worms and larvae, as well as killing eggs.

The growth, development and maturation of insects are all regulated or influenced by the steroid ecdysone and the sesquiterpenoid juvenile hormone. Juvenile hormone is a new type of chitin synthesis inhibitor, and its mechanism of action is mainly based on the coordination of the following three aspects: (1) Through the retention of high concentrations in hemolymph, it accelerates the secretion of insect prothymic sex hormones and interferes with the epidermis. The biosynthesis of ecdysone in ecdysone; (2) the chitin synthase of insects is inhibited, causing the synthesis of chitin in the epidermis to be blocked and continuously reduced. Death; (3) The insect lacks the stimuli needed to lay eggs, resulting in the production of non-viable eggs or inhibiting the hatching of eggs.

The invention solves the problem that a single anthelmintic drug has a narrow anti-insect spectrum, a large dosage, and is easy to produce drug resistance; and the existing anthelmintic preparation is effective for deworming in a short term, and has a weak effect on the eggs, and the eggs are in a certain incubation period. After growing into larvae and adults, continue to infect the main body, the recurrence rate is high, and the technical problems that cannot meet the market demand, from the perspective of the whole to the local, macro and micro, it is more reasonable to compound the use of anti-parasitic drugs to expand the anti-parasitic drugs. The insect spectrum has a better therapeutic effect, and provides a long-acting compound anthelmintic medicinal preparation and a preparation method thereof.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a long-acting compound anthelmintic drug liquid preparation and a preparation method and application thereof, utilizing mirbeoxime to continuously and long-actly drive and kill nematodes in animals, benzimidazole drugs to drive and kill tapeworms in animals, and The in vitro insecticidal effect of juvenile hormone drugs is combined with synergistic deworming. The combination of the compound preparation is reasonable, safe and reliable, and the anti-insect spectrum is expanded, thereby comprehensively preventing and treating parasites inside and outside the dog.

The active ingredients in the long-acting compound anthelmintic drug liquid preparation of the present invention are milbe oxime, benzimidazole drugs, and juvenile hormone drugs.

Described benzimidazole class medicine is selected from a kind of in albendazole, mebendazole, fenbendazole, ofendazole, conbendazole, bubendazole, triclabendazole, nitorbimine ; Preferably, the benzimidazole drug is a kind of albendazole, conbendazole, triclbendazole; more preferably, the benzimidazole drug is albendazole.

The juvenile hormone drug is one of methoprene, pyriproxyfen, pyridoxine, and dioxycarb; preferably, the juvenile hormone drug is pyriproxyfen, methoprene, dioxycarb one of; more preferably, the juvenile hormone drug is pyriproxyfen.

The long-acting compound anthelmintic drug liquid preparation of the present invention further contains a macromolecule suspending agent, a wetting agent, an antioxidant, and a dispersion medium. Each component in the compound preparation is calculated in mass percentage: 0.5-1% of milbe oxime, 5-10% of benzimidazoles, 3-5% of juvenile hormones, 0.1-5% of macromolecular suspending agent, moisturizing agent Wet agent 0.1-5%, antioxidant 0.01-1%, and the balance is dispersion medium. Preferably, the long-acting compound anthelmintic drug liquid preparation is calculated in mass percentage as: 0.5-1% of milbe oxime, 5-10% of benzimidazoles, 3-5% of juvenile hormones, and macromolecular suspension 2 to 4% of the agent, 1 to 2% of the wetting agent, 0.1 to 0.3% of the antioxidant, and the balance is the dispersion medium.

The macromolecular suspending agent of the present invention is selected from hydroxypropyl methylcellulose, xanthan gum, gelatin, aluminum monostearate, aluminum distearate, hydrogenated castor oil, microcrystalline wax, yellow wax, stearic acid One or more of glycerides.

The wetting agent is selected from one or more of lecithin, soybean lecithin, hydroxylated lecithin, Tween 80, Span 40 and Span 60.

The antioxidant is selected from one or more of α-tocopherol, p-hydroxy-tert-butyl anisole (BHA), and di-tert-butyl-p-cresol (BHT).

Described dispersion medium is selected from one in ethyl lactate, propylene glycol, soybean oil, ethyl oleate, N,N-dimethylformamide, isopropyl myristate, acetal formaldehyde, glycerol monooleate. species or several.

The preparation method of the long-acting compound anthelmintic medicinal liquid preparation is:

(1) Weigh each raw material component according to the formula, and treat the dispersion medium at a high temperature of 100～180℃ for 0.5～2h.

(2) Preparation by low temperature method: take the dispersion medium that accounts for 50-70% of the total volume of the injection, add a macromolecule suspending agent to the dispersion medium at 60-100°C, and maintain it for 0.5-1h to make the macromolecular suspending agent suspend. The agent is completely gelled; cooled to below 40°C, added wetting agent, antioxidant, milbe oxime, benzimidazole drugs, juvenile hormone drugs, high-speed shearing treatment.

Or, prepare by high temperature method: take the dispersion medium that accounts for 50-70% of the total volume of the injection, add a polymer suspending agent to the dispersion medium at 100-140°C, and maintain it for 0.5-1h to make the polymer suspending agent After complete gelation; add antioxidants, dissolve and stir evenly, then quickly cool to below 40°C, add wetting agent, milbe oxime, benzimidazole drugs, juvenile hormone drugs, and high-pressure homogenization treatment.

(3) Take the mixture obtained in step (2), cool it to room temperature, and use a small amount of dispersing medium to make up the volume to the mark; after the semi-finished product is tested qualified, it is divided into packaging, and that is obtained.

The pressure of the high-pressure homogenization described in the step (2) is 20000-26000 psi, and the time is 0.5-1 h; the rotating speed of the high-speed shearing is 1000-4000 rpm, and the time is 0.5-1 h.

Determination of related substances and content of mirbeoxime: the method under the item of mirbexime tablet in "Compendium of Quality Standards for Veterinary Drugs" (2014 edition), the related substances and content of mirbexime were determined.

The long-acting compound anthelmintic drug liquid preparation of the present invention is mainly used for preventing and treating pet parasitic infection, and the pets include dogs, cats, lizards, guinea pigs, alpacas, horses, rabbits, tortoises and the like.

The long-acting compound anthelmintic medicinal liquid preparation of the present invention can be used for preventing and treating internal and external parasitic diseases, and the effective internal parasites include canine heartworm, gastrointestinal nematode, roundworm, hookworm, whipworm, roundworm and tapeworm; Effective ectoparasites are fleas, lice, and mites.

The long-acting compound anthelmintic medicinal liquid preparation of the present invention is preferably a long-acting injection.

Beneficial effects:

1. The present invention combines anti-nematode drugs, anti-taenia drugs and insect juvenile hormone drugs to expand the anti-insect spectrum. Milbe oxime has a weak effect on ectoparasites. After adding juvenile hormones, it can play a synergistic effect, which improves the killing rate of ectoparasite eggs and larvae.

2. The product of the present invention has a good killing effect on nematodes, tapeworms in vivo and fleas, lice, mites in vitro, etc., achieves excellent in vivo and in vitro effects, and parasitic infection is not easy to recur; Simultaneously through experimental research, The long-acting compound anthelmintic drug liquid preparation of the present invention is stable and safe, and pets can use it with confidence.

3. The compound mirboxime long-acting injection prepared by the present invention is an injection dosage form, which improves the bioavailability of tablets, capsules, and oral dosage forms, and can ensure that in the course of clinical use, the optimal expelling and killing body can be achieved. Effects of internal and external parasites.

4. The compound mirbeoxime long-acting injection prepared by the present invention forms a gel state due to the addition of a macromolecular suspending agent, forms a certain package for the main drug, adds a wetting agent, and forms a phospholipid bimolecule. The coating layer and the dispersion medium are macromolecular oily substances. After the comprehensive preparation is prepared, it has a long-term effect. In the body subcutaneously, the oily gel state is formed, and the body will not have an allogeneic reaction to it. Explain the medicine and form a long-acting mechanism.

5. The compound mirboxime long-acting injection prepared by the present invention has the advantages of low cost, simple operation, good biocompatibility, less irritation and high safety, and promotes and improves the outcome and prognosis of the disease.

Detailed ways

The above content will be further described in detail below through specific implementations in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter to the following examples. All technologies implemented based on the content of the present invention belong to the scope.

Embodiment 1 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition and dosage of the long-acting compound deworming drug liquid preparation:

Raw material name party 1 Milbeoxime 5g albendazole 50g Pyriproxyfen 30g Aluminum monostearate 10g Aluminum distearate 10g Tween 80 5g Lecithin 5g Alpha-Tocopherol 1g Ethyl oleate + N,N-dimethylformamide (1:1) Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Prepared by high temperature method: take 700 mL of ethyl oleate+N,N-dimethylformamide (1:1), and at 130 °C, transfer ethyl oleate+N,N-dimethylformamide (1 : 1) add aluminum monostearate and aluminum distearate, maintain for 1h, and make aluminum monostearate and aluminum distearate gel completely; add α-tocopherol, dissolve and stir evenly and then cool down to Below 40℃, add Tween 80, lecithin, milbe oxime (particle size D90≤5μm), albendazole (particle size D90≤5μm), pyriproxyfen (particle size D90≤5μm); high pressure homogenization (pressure is 20000psi) ) for 1 hour, take the mixture cooled to room temperature, and dilute to the mark with a small amount of ethyl oleate + N,N-dimethylformamide (1:1).

Embodiment 2 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

Raw material name Formulation Milbeoxime 10g Fenbendazole 100g Dioxycarb 50g Aluminum monostearate 20g Tween 80 6g Lecithin 6g p-Hydroxy-tert-butylanisole 3g Soybean oil + N,N-dimethylformamide (1:1) Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Prepared by high temperature method: take 700mL of soybean oil+N,N-dimethylformamide (1:1), put soybean oil+N,N-dimethylformamide (1:1) into soybean oil+N,N-dimethylformamide (1:1) at 130°C Add aluminum monostearate and keep it for 1 hour to make the aluminum monostearate gel completely; add p-hydroxytert-butyl anisole, dissolve and stir evenly, quickly cool to below 40°C, add Tween 80, lecithin, mirin Beoxime (particle size D90≤5μm), fenbendazole (particle size D90≤5μm), dioxycarb (particle size D90≤5μm); high pressure homogenization (pressure 20000psi) for 1h, take the mixture cooled to room temperature, add a small amount of Soybean oil + N,N-dimethylformamide (1:1) is adjusted to the mark; the semi-finished product is tested and repackaged after passing the test.

Embodiment 3 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

Raw material name Formulation Milbeoxime 8g combendazole 70g Methoprene 40g Aluminum distearate 10g Glyceryl Stearate 10g Span 40 5g Hydroxylated lecithin 5g Alpha-tocopherol + di-tert-butyl-p-cresol (BHT) (1:1) 2g Ethyl oleate Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Preparation by high temperature method: take 700 mL of ethyl oleate, add aluminum distearate and glyceryl stearate to ethyl oleate at 130°C, and maintain for 1 h to make aluminum distearate, stearic acid After the glycerides are completely gelled; add α-tocopherol + di-tert-butyl-p-cresol (BHT) (1:1), dissolve and stir evenly, cool down quickly to below 40°C, add Span 40, hydroxylated lecithin, Milbeoxime (particle size D90≤5μm), conbendazole (particle size D90≤5μm), methoprene (particle size D90≤5μm); high pressure homogenization (pressure 20000psi) for 0.5h, take the mixture cooled to room temperature, Dilute the volume to the mark with a small amount of ethyl oleate; after the semi-finished product has passed the inspection, it is divided into packages.

Embodiment 4 A kind of long-acting compound anthelmintic medicine liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Preparation by low-temperature method: take 700 mL of propylene glycol, add microcrystalline wax and hydroxypropyl methylcellulose to propylene glycol at 80 ° C, maintain for 1 hour, make the microcrystalline wax and hydroxypropyl methyl cellulose completely gelatinized, then cool To below 40 ℃, add Tween 80, lecithin, di-tert-butyl-p-cresol + p-hydroxy-tert-butyl anisole (1:1), milbe oxime (particle size D90≤5μm), nitorbiamine (particle size D90≤5μm), pyridone (particle size D90≤5μm); high-speed shearing (rotation speed 3000rpm) for 1h, take the mixture cooled to room temperature, and use a small amount of propylene glycol to make up the volume to the mark; semi-finished products are divided into packaging after passing the inspection, namely have to.

Embodiment 5 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

Raw material name Formulation Milbeoxime 7g Mebendazole 90g pyridone 50g Xanthan Gum 20g yellow wax 15g Tween 80 5g Lecithin 3g Alpha-Tocopherol 1g Ethyl lactate Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Preparation by low temperature method: take 700 mL of ethyl lactate, add microcrystalline wax and hydroxypropyl methyl cellulose to ethyl lactate at 80°C, and maintain for 1 h to make the microcrystalline wax and hydroxypropyl methyl cellulose completely glue. After melting, cool to below 40℃, add Tween 80, lecithin, α-tocopherol, milbe oxime (particle size D90≤5μm), nitorbamine (particle size D90≤5μm), pyridone (particle size D90≤5μm) 5 μm); high-speed shearing (rotation speed is 3000 rpm) for 1 h, take the mixture cooled to room temperature, and use a small amount of ethyl lactate to make up to the mark; after the semi-finished product is qualified, it is divided into packaging, that is, it is obtained.

Embodiment 6 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

Raw material name Formulation Milbeoxime 6g Ofendazole 70g Methoprene 40g gelatin 20g Microcrystalline Wax 15g Tween 80 5g Soy lecithin 3g Di-tert-butyl-p-cresol 1g Glycerol monooleate + isopropyl myristate (1:1) Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Prepared by a low temperature method: take 700 mL of glycerol monooleate + isopropyl myristate (1:1), put glycerol monooleate + isopropyl myristate (1:1) at 80 °C Add gelatin and microcrystalline wax, keep for 1h, after gelatin and microcrystalline wax are completely gelatinized, cool to below 40 ℃, add Tween 80, soybean lecithin, di-tert-butyl-p-cresol, milbe oxime (particle size D90≤ 5μm), orfendazole (particle size D90≤5μm), methoprene (particle size D90≤5μm); high-speed shearing (rotation speed is 4000rpm) for 0.5h, take the mixture cooled to room temperature, use a small amount of glycerol monooleate Ester + isopropyl myristate (1:1) and make up to the mark; the semi-finished product is tested and packaged after passing the test.

Embodiment 7 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

Raw material name Formulation Milbeoxime 6g Triclobendazole 60g Dioxycarb 30g Hydrogenated Castor Oil 20g Xanthan Gum 15g Span 40 8g Lecithin 3g Alpha-Tocopherol + p-Hydroxy-tert-butylanisole (1:1) 1g Formaldehyde acetal Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Preparation by low-temperature method: take 700 mL of formaldehyde acetal, add gelatin and microcrystalline wax to formaldehyde acetal at 80 °C, maintain for 1 h, make gelatin and microcrystalline wax completely gelatinized, cool to below 40 °C, add Hydrogenated Castor Oil, Span 40, α-Tocopherol + p-Hydroxy-tert-butylanisole (1:1), Milbeoxime (Particle Size D90≤5μm), Triclobendazole (Particle Size D90≤5μm), Dioxygen Granules (particle size D90≤5μm); high-speed shearing (rotation speed is 4000rpm) for 0.5h, take the mixture cooled to room temperature, and use a small amount of formaldehyde acetal to make up to the mark; semi-finished products are tested and packaged after passing the test.

Embodiment 8 A kind of long-acting compound anthelmintic medicinal liquid preparation and preparation method thereof

The composition of the long-acting compound deworming drug liquid preparation:

Raw material name Formulation Milbeoxime 8g bubendazole 80g Pyriproxyfen 40g yellow wax 20g Carboxypropyl methyl cellulose 15g Span 40 8g Hydroxylated lecithin 3g Di-tert-butyl-p-cresol 1g Propylene Glycol + Isopropyl Myristate (1:1) Dilute to 1000mL

The preparation method of long-acting compound anthelmintic medicine liquid preparation:

Preparation by low-temperature method: take 700 mL of propylene glycol + isopropyl myristate (1:1), add yellow wax and carboxypropyl methyl fiber to propylene glycol + isopropyl myristate (1:1) at 80 °C After the yellow wax and carboxypropyl methylcellulose are completely gelatinized, they are cooled to below 40°C, and Span 40, hydroxylated lecithin, di-tert-butyl-p-cresol, milbe oxime (particle size D90≤ 5μm), bubendazole (particle size D90≤5μm), pyriproxyfen (particle size D90≤5μm); high-speed shearing (rotation speed is 4000rpm) for 0.5h, take the mixture cooled to room temperature, use a small amount of propylene glycol + myristic acid Dilute the volume of isopropyl ester (1:1) to the mark; after the semi-finished product has passed the inspection, it is divided into packages.

Example 9 In vitro performance evaluation of mirboxime compound long-acting injection

Milbeoxime compound long-acting injection was subjected to in vitro performance evaluation, including the determination of properties, particle size, 3h sedimentation volume ratio, redispersibility, acupuncture, related substances and content. The measurement results are shown in Table 1-2.

Table 1 In vitro performance evaluation of mirboxime compound long-acting injection

project traits granularity sedimentation volume ratio Redispersibility Needle-free Example 1 pale yellow suspension D90≤5μm 0.96 ** +++ Example 2 pale yellow suspension D90≤5μm 0.98 *** +++ Example 3 pale yellow suspension D90≤5μm 0.98 **** +++ Example 4 pale yellow suspension D90≤5μm 0.99 * +++

Note: * represents the redispersibility, the more the number of *, the better the redispersibility, the + represents the needle penetration, the more + the better the needle penetration.

Table 2 Milbeoxime compound long-acting injection content and related substance results

As can be seen from Table 1 and Table 2, the properties such as the Milbeoxime compound long-acting injection of Examples 1-4 are all good in properties, particle size, sedimentation volume ratio, redispersibility and acupuncture, and related substances are also in compliance with the regulations.

Example 10 Evaluation of the curative effect of Milbeoxime compound long-acting injection in treating parasites

In this experiment, animal clinical experiments were carried out on the long-acting compound anthelmintic drug liquid preparation obtained in Example 1 to test its curative effect. The experimental dogs were found to be infected with a large number of intestinal parasites (such as Trichostrongylus, hookworm, whipworm, roundworm, tapeworm, etc.) by laboratory fecal floatation method and direct smear method.

120 dogs diagnosed with severe intestinal parasitic diseases were randomly divided into 6 groups, the experimental group 1 was the blank control group, and the experimental group 2 was the commercially available Milbeoxime tablet (2.5mg/tablet, Hisun), Experimental groups 3-6 are the products of Example 1, Example 3, Example 7, and Comparative Example 1 (Example 1 with no milbe oxime, and the dosage of other components is unchanged) according to a single dose of milbe oxime. 2.5 mg per kilogram of body weight was administered, and Comparative Example 1 was administered according to the dosage of Example 1, and on the 0th, 5th, 30th, 90th and 150th days after administration, the effects of each group of drugs on nematodes, tapeworms, Average detection rate of ectoparasites.

Table 3 Statistics on the detection rate of nematodes in dogs

group Day 0 Day 5 Day 30 Day 90 Day 150 Blank control group 95.00% 95.00% 100.00% 90.00% 95.00% Commercially available positive group 95.00% 0.00% 0.00% 30.00% 50.00% Example 1 100.00% 0.00% 0.00% 0.00% 0.00% Example 3 100.00% 0.00% 0.00% 0.00% 0.00% Example 7 95.00% 0.00% 0.00% 0.00% 0.00%

Table 4 Statistics on the detection rate of tapeworms in dogs

group Day 0 Day 5 Day 30 Day 90 Day 150 Blank control group 100.00% 100.00% 95.00% 95.00% 100.00% Commercially available positive group 100.00% 100.00% 100.00% 95.00% 100.00% Example 1 100.00% 0.00% 0.00% 0.00% 0.00% Example 3 95.00% 0.00% 0.00% 0.00% 0.00% Example 7 95.00% 0.00% 0.00% 0.00% 0.00%

Table 5 Statistics on the detection rate of ectoparasites in dogs

group Day 0 Day 5 Day 30 Day 90 Day 150 Blank control group 100.00% 100.00% 100.00% 95.00% 100.00% Commercially available positive group 100.00% 0.00% 0.00% 45.00% 60.00% Example 1 100.00% 0.00% 0.00% 0.00% 0.00% Example 3 95.00% 0.00% 0.00% 0.00% 0.00% Example 7 100.00% 0.00% 0.00% 0.00% 0.00% Comparative Example 1 100.00% 5.00% 10.00% 20.00% 45.00%

As can be seen from Table 3-5, the embodiment of the present invention 1 has obvious insecticidal effect to nematodes, tapeworms, and ectoparasites in dogs, and the detection rates are all lower than the blank control group and the commercially available positive group, and the effect For a long time, there is still a good deworming effect at 150 days. It is confirmed that the combined use of mirbexime, benzimidazole drugs and juvenile hormone insecticides has significantly better anti-parasitic effect than the single commercially available mirbexime preparation. It was confirmed by comparative experiments that in the absence of mirbeoxime, the antibody ectoparasite effect of the product of Comparative Example 1 was significantly poorer than that of Example 1, indicating that mirbeoxime has the ability of antibody ectoparasites to juvenile hormone drugs. The synergistic effect increases the killing rate of ectoparasite eggs and larvae.

The test results show that the long-acting compound anthelmintic medicinal liquid preparation prepared in the embodiment of the present invention has a good effect of repelling and killing parasites in dogs within 150 days.

Embodiment 11 Safety test of mirboxime compound long-acting injection

40 Kunming mice of about 20 g were selected and randomly divided into 4 groups with 10 mice in each group, half male and female. The 1st group is the control group, intramuscular injection of 0.5m1 normal saline; the 2nd-4th group is the test group, the long-acting compound anthelmintic drug liquid of Example 1 of the present invention of different doses (high dose, medium dose and low dose) is selected for use Preparation preparation, because the dosage of commercially available positive control pharmaceutical preparation milbeoxime for dogs is 2.5mg-1.0mg/10kg, so the safety test high-dose group, middle-dose group and low-dose group of the present invention are injected intramuscularly with 5.0 mL, 3.0mL, and 1.0mL were used only once, followed by continuous observation for 3-5 months, during which the eating, drinking, behavioral changes and death of the mice were recorded. After the experiment, 3 mice in each group were randomly selected for Dissect, observe the pathological changes of organs, and record.

Results: The mice in the control group and experimental groups 2-4 did not die during the test period. They ate and drank normally, and had no obvious abnormal behavior. There were no abnormal lesions in the stomach and intestines, and there was no significant difference with the control group. The results show that the long-acting compound anthelmintic drug liquid preparation prepared by the present invention is safe to use.

Claims (10)

1. A long-acting compound anthelmintic liquid preparation is characterized in that the effective components in the liquid preparation are milbemycin oxime, benzimidazole drugs and juvenile hormone drugs; the liquid preparation comprises the following components in percentage by mass: 0.5-1% of milbemycin oxime, 5-10% of benzimidazoles, 3-5% of juvenile hormone, 0.1-5% of macromolecular suspending agent, 0.1-5% of wetting agent, 0.01-1% of antioxidant and the balance of dispersing medium.

2. The long-acting compound insect repellent liquid preparation according to claim 1, wherein the liquid preparation comprises the following components in percentage by mass: 0.5-1% of milbemycin oxime, 5-10% of benzimidazoles, 3-5% of juvenile hormone, 2-4% of a polymer suspending agent, 1-2% of a wetting agent, 0.1-0.3% of an antioxidant and the balance of a dispersing medium.

3. The long-acting compound liquid anthelmintic formulation according to claim 1 or 2, wherein the benzimidazole is one of albendazole, mebendazole, fenbendazole, oxfendazole, fenbendazole, triclabendazole, and nitobimine.

4. The long-acting compound liquid anthelmintic formulation according to claim 1 or 2, wherein the juvenile hormone-like drug is one of methoprene, pyriproxyfen, pyridaben and fenoxycarb.

5. The long-acting compound liquid anthelmintic formulation according to claim 1 or 2, wherein the polymeric suspending agent is selected from one or more of hydroxypropyl methylcellulose, xanthan gum, gelatin, aluminum monostearate, aluminum distearate, hydrogenated castor oil, microcrystalline wax, beeswax, and glyceryl stearate.

6. The long-acting compound liquid anthelmintic formulation according to claim 1 or 2, wherein the wetting agent is one or more selected from lecithin, soybean lecithin, hydroxylated lecithin, tween 80, span 40 and span 60.

7. The long-acting compound liquid anthelmintic formulation according to claim 1 or 2, wherein the antioxidant is selected from one or more of α -tocopherol, p-hydroxy-t-butyl anisole, and di-t-butyl-p-cresol; the dispersion medium is one or more selected from ethyl lactate, propylene glycol, soybean oil, ethyl oleate, N-dimethylformamide, isopropyl myristate, formal glycerol and glycerol monooleate.

8. A method for preparing a long-acting compound anthelmintic liquid formulation according to any one of claims 1 to 7, comprising the steps of:

(1) weighing the raw material components according to the formula amount, and treating the dispersion medium at the high temperature of 100-180 ℃ for 0.5-2 h;

(2) the preparation method adopts a low-temperature method: taking a dispersion medium accounting for 50-70% of the total volume of the injection, adding a high-molecular suspending agent into the dispersion medium at 60-100 ℃, and maintaining for 0.5-1 h to ensure that the high-molecular suspending agent is completely gelatinized; cooling to below 40 deg.C, adding wetting agent, antioxidant, milbeoxime, benzimidazole medicine, and juvenile hormone medicine, and high-speed shearing;

or the like, or, alternatively,

the preparation method comprises the following steps: taking a dispersion medium accounting for 50-70% of the total volume of the injection, adding a high-molecular suspending agent into the dispersion medium at 100-140 ℃, and maintaining for 0.5-1 h to ensure that the high-molecular suspending agent is completely gelatinized; adding antioxidant, dissolving, stirring, rapidly cooling to below 40 deg.C, adding wetting agent, milbemycin oxime, benzimidazole medicine, and juvenile hormone medicine, and homogenizing under high pressure;

(3) taking the mixture cooled to room temperature in the step (2), and fixing the volume to the scale by using a small amount of dispersion medium; and (5) detecting the semi-finished product, and subpackaging to obtain the finished product.

9. The method according to claim 8, wherein the high-pressure homogenization in step (2) is carried out at a pressure of 20000 to 26000psi for 0.5 to 1 hour; the high-speed shearing speed is 1000-4000 rpm, and the time is 0.5-1 h.

10. The long-acting compound anthelmintic liquid preparation according to any one of claims 1 to 9, wherein the liquid preparation is long-acting injection and is used for preparing a medicinal injection for preventing and treating parasitic diseases inside and outside a pet.