Pet deworming drops, preparation method and application thereof

Abstract

The application discloses a pet deworming drop, a preparation method and application thereof, and belongs to the field of veterinary drug preparations.The pet deworming drop is prepared from the following raw materials in percentage by weight: dinotefuran 5-30%, methoprene 1-15%, praziquantel 1-15%, an antioxidant 0.05-5%, a composite transdermal agent 0.1-6%, and the rest is a composite solvent.The pet deworming drop can significantly enhance the anti-parasite ability of dinotefuran, the addition of methoprene can inhibit the development of larvae and worm eggs, and prolong the drug effect.The addition of praziquantel can expel internal flukes and tapeworms, expand the clinical anti-parasite spectrum, and achieve the effect of expelling parasites both internally and externally.The preparation has the advantages of rapid transdermal penetration, reduced drug use frequency, simple preparation method, high safety and the like, and has good social and ecological benefits.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug preparations, specifically relating to a pet deworming drops, its preparation method, and its application. Background Technology

[0002] Fipronil, also known as furazolidone (CAS No. 165252-70-0), is a third-generation neonicotinoid insecticide developed by Mitsui Chemicals in 1993 and is currently one of the world's major rice paddy insecticides. Fipronil is the only neonicotinoid insecticide that does not contain chlorine atoms or aromatic rings. Its structural characteristic is that a tetrahydrofuran group replaces the chloropyridinyl or chlorothiazolyl group of neonicotinoids, and it does not contain halogens. Unlike traditional neonicotinoid insecticides, it has higher insecticidal activity, greater systemic and penetrating activity, and a broad insecticidal spectrum. Initially registered for rice, its application has expanded in recent years, and it can be used on rice, vegetables, fruit trees, and flowers. Furthermore, fipronil is very safe for mammals, non-irritating to cats and dogs, and safe for human contact. Currently, there are no registered products in China for use as veterinary drugs containing fipronil, but it is already in use in the European Union: Vectra 3D spot-on solution, whose main ingredients are fipronil, pyriproxyfen, and dichlorvos, is used to treat fleas, ticks, and other external parasites in dogs. Vectra Felis spot-on solution, whose main ingredients are fipronil and pyriproxyfen, is used to treat fleas and other parasites in cats.

[0003] Meprofen, also known as tebufenozide (CAS No. 40596-69-8), is an insect growth regulator and juvenile hormone analog discovered in the 1970s. It is primarily used for flea and tick control in pets and is also effective against a variety of insects in the Lepidoptera, Diptera, Coleoptera, and Homoptera orders. It can control mosquitoes, flies, and other sanitary pests, as well as pests that infest tobacco leaves during storage, such as the tobacco moth. Currently, it is registered for use in veterinary medicine in China, for example, under the brand name Frontline Compound Fipronil Drops, produced by Merial in France. Its main components are fipronil and meprofenozide, used to kill adult fleas, flea eggs, and larvae on the skin of dogs and cats.

[0004] Praziquantel, also known as cyclopyridine isoquinone, CAS number 55268-74-1, chemical name: 2-cyclohexylcarbonyl-1,3,4,6,7,11-hexahydro-2-pyrazino(2,1-A)isoquinoline-4-one, molecular formula: C19H24N2O2, relative molecular weight: 312.18, is a broad-spectrum antiparasitic drug. It is used for the treatment and prevention of schistosomiasis, cysticercosis, paragonimiasis, echinococcosis, fascioliasis, echinococcosis, and helminth infections. In China, praziquantel is mainly available in solid forms such as tablets, powders, and premixes for the treatment of schistosomiasis, tapeworm infection, and cysticercosis in animals.

[0005] Of the three medications mentioned above, the dinotefuran drops only target external parasites such as fleas, the metoprofen drops only target parasite eggs, and the praziquantel drops only target internal parasites such as schistosomes and tapeworms. Each of these drops has its limitations when used alone, failing to achieve a simultaneous internal and external treatment effect, thus affecting pet owners' choices. Furthermore, these drops suffer from poor product stability, poor transdermal absorption, and short duration of action. Summary of the Invention

[0006] Therefore, it is necessary to address the shortcomings of traditional deworming drops, such as limited efficacy, inability to achieve simultaneous in vivo and in vitro deworming, poor product stability, poor transdermal effect, and short duration of action, by providing a pet deworming drop, its preparation method, and its application.

[0007] The first aspect of this application provides a pet deworming drops, which, by weight percentage, comprises the following components: 5%-30% fipronil, 1%-15% methoxyprotein, 1%-15% praziquantel, 0.1%-6% composite transdermal agent, 0.05%-5% antioxidant, and the balance being a composite solvent.

[0008] The composite transdermal agent is composed of azone, polyvinylpyrrolidone K17, and propylene glycol; the weight ratio of azone, polyvinylpyrrolidone K17, and propylene glycol is 1:(1-5):(5-10).

[0009] The antioxidant mentioned is 2,6-di-tert-butyl-p-cresol (BHT).

[0010] The composite solvent is composed of N-methylpyrrolidone, isosorbide dimethyl ether, and dimethyl sulfoxide; the weight ratio of N-methylpyrrolidone, isosorbide dimethyl ether, and dimethyl sulfoxide is 1:(0.2-2):(2-10).

[0011] Furthermore, by weight percentage, the pet deworming drops comprise the following components: 10%-30% fipronil, 7%-12% methoxyprotein, 7%-12% praziquantel, 1%-4% composite transdermal agent, 0.1%-1% antioxidant, and the balance being a composite solvent.

[0012] The weight ratio of azone, polyvinylpyrrolidone K17, and propylene glycol in the composite transdermal agent is 1:(2-4):(5-8).

[0013] The weight ratio of N-methylpyrrolidone, isosorbide dimethyl ether, and dimethyl sulfoxide in the composite solvent is 1:(0.5-2):(5-10).

[0014] Furthermore, by weight percentage, the pet deworming drops comprise the following components: 30% fipronil, 10% methoxyprone, 7.5% praziquantel, 4% complex transdermal agent, 0.2% antioxidant, and the balance being a complex solvent.

[0015] The weight ratio of azone, polyvinylpyrrolidone K17, and propylene glycol in the composite transdermal agent is 1:2:5.

[0016] The weight ratio of N-methylpyrrolidone, isosorbide dimethyl ether, and dimethyl sulfoxide in the composite solvent is 1:1:10.

[0017] The second aspect of this application provides a method for preparing a pet deworming drop, the method comprising:

[0018] 1) Mix and dissolve dimethyl sulfoxide, isosorbide dimethyl ether, and N-methylpyrrolidone;

[0019] 2) Add azone, polyvinylpyrrolidone K17, and propylene glycol to the solution obtained in step 1), and continue stirring to dissolve;

[0020] 3) Add fipronil, metoprofen, and praziquantel to the solution obtained in step 2), and continue stirring until the materials are completely dissolved;

[0021] 4) Add the antioxidant BHT to the solution obtained in step 3) and stir for 20 minutes to obtain a mixed solution;

[0022] 5) Filter the mixed solution obtained in step 4) to obtain pet deworming drops.

[0023] The third aspect of this application provides the use of the aforementioned pet deworming drops in the prevention or treatment of feline parasite infections.

[0024] Furthermore, the cat parasite mentioned is an ear mite.

[0025] The present invention has the following beneficial effects:

[0026] 1. This invention creatively combines fipronil, metoprofen, and praziquantel to form a pet deworming drop. This not only significantly enhances the antiparasitic ability of fipronil, but the addition of metoprofen inhibits the development of larvae and eggs, prolonging the efficacy. The addition of praziquantel can expel internal trematodes and tapeworms, broadening the clinical antiparasitic spectrum. Therefore, this invention's drops have both in vivo and in vitro deworming effects, reducing the frequency of veterinary drug use.

[0027] 2. The composite transdermal agent selected in this invention uses azone, polyvinylpyrrolidone K17, and propylene glycol as transdermal agents. The combined action of these transdermal agents results in rapid transdermal penetration and good efficacy.

[0028] 3. The composite solvent selected in this invention is a combination of dimethyl sulfoxide, N-methylpyrrolidone, and isosorbide dimethyl ether, which dissolves the active ingredient rapidly, has good solubility, is not prone to precipitation at low temperatures, and improves the low-temperature storage stability of the active ingredient in the drops.

[0029] 4. The preparation method of the pet deworming drops of the present invention has the advantages of simple preparation method, high safety, high efficiency, low production energy consumption and good deworming effect, and has good social and ecological benefits. Detailed Implementation

[0030] The present invention will be further described below with reference to specific embodiments, but the invention is not limited to these specific embodiments. Those skilled in the art should recognize that the present invention covers all alternatives, improvements, and equivalents that may be included within the scope of the claims. 1. Specific Implementation Examples

[0032] This invention provides a pet flea and tick treatment, the preparation method of which is as follows:

[0033] 1) Mix and dissolve dimethyl sulfoxide, isosorbide dimethyl ether, and N-methylpyrrolidone.

[0034] 2) Add azone, polyvinylpyrrolidone K17, and propylene glycol to the solution obtained in step 1), and continue stirring to dissolve.

[0035] 3) Add fipronil, metoprofen, and praziquantel to the solution obtained in step 2) and continue stirring until the materials are completely dissolved.

[0036] 4) Add the antioxidant BHT to the solution obtained in step 3) and stir for 20 minutes to obtain a mixed solution.

[0037] 5) Filter the mixed solution obtained in step 4) to obtain pet deworming drops.

[0038] The amount of each component added in Examples 1-3 is shown in Table 1.

[0039] Table 1 shows the amount of each component added in Examples 1-3.

[0040]

[0041] To further illustrate the beneficial effects of the present invention, comparative examples are set up using only the pet flea and tick drops of Example 1 as an example. The amount of each component added in Comparative Examples 1-18 is shown in Table 2.

[0042] Table 2 shows the addition amounts of each component in Comparative Examples 1-18.

[0043]

[0044] The difference between Comparative Example 18 and Example 1 lies in the different preparation process steps, specifically:

[0045] 1) Mix and dissolve dimethyl sulfoxide, isosorbide dimethyl ether, propylene glycol, and dinotefuran.

[0046] 2) Add azone, polyvinylpyrrolidone K17, and N-methylpyrrolidone to the solution obtained in step 1) and continue stirring to dissolve.

[0047] 3) Add methoxyprotein and praziquantel to the solution obtained in step 2) and continue stirring until the materials are completely dissolved.

[0048] 4) Add the antioxidant BHT to the solution obtained in step 3) and stir for 5 minutes to obtain a mixed solution.

[0049] 5) Then, filter the resulting mixed solution to obtain pet deworming drops.

[0050] 2. Key performance indicators of pet flea and tick drops tested

[0051] 2.1 Physicochemical Index Testing of Pet Flea and tick Drops

[0052] The physicochemical properties of the pet deworming drops in Examples 1-3 and Comparative Examples 1-18 were determined. The cold storage stability test method referred to the low temperature stability test method in GB / T19136-2003, and the high temperature test method referred to the stability test guidelines for raw materials and preparations in Section 9001 of the 2020 edition of the Chinese Veterinary Pharmacopoeia. The samples were placed at 60°C for 10 days, and samples were taken on the 10th day. The tests were conducted according to the requirements of the key stability test items. The specific data are shown in Table 3.

[0053] Table 3 shows the cold storage stability and high temperature test data for each embodiment and comparative example.

[0054]

[0055]

[0056] As shown in Table 3, the present invention selects a reasonable component system, which exhibits good stability under the synergistic effect of the components, and all performance indicators are qualified. Comparative Example 5 shows that due to the absence of the antioxidant BHT, the material changed color after the high-temperature test, and the decomposition rates of praziquantel and methicillin were higher than in other formulations. Comparative Example 14, due to the addition of the antioxidant BHA, had a lower antioxidant effect than BHT, also resulting in color change after the high-temperature test, and the decomposition rates of praziquantel and methicillin also increased. Comparative Example 18, due to the different preparation methods, resulted in unqualified low-temperature stability, color change of the material during the high-temperature test, and increased decomposition rates of praziquantel and methicillin. Comparative Examples 6-10, due to inappropriate ratios of the transdermal agent and solvent, resulted in unqualified low-temperature stability and crystal precipitation.

[0057] 2.2 In vitro transdermal test (permeability test)

[0058] Preparation of ex vivo skin: Select 2-3 month old Bama miniature pigs, euthanize them, remove the hair on the back and ears of the skin with an electric hair removal device or scalpel, peel off the skin, remove subcutaneous fat, tissue and capillaries, select intact skin, wash with physiological saline, immerse in physiological saline, store for later use, and use within one week.

[0059] In vitro transdermal test: The skin of a prepared miniature pig was fixed to the mouth of a test tube, with the inner skin facing the tube. The test tube was filled with N-methylpyrrolidone as the receiving solution, air bubbles were removed, and the receiving solution was brought into close contact with the skin. Then, the pet deworming drops from Example 1 and Comparative Examples 1-18 were applied to the skin surface. The temperature of the receiving solution was maintained at 37±1℃. 3 mL of the receiving solution was collected at 2h, 4h, 6h, 8h, 10h, and 24h after application, and the test tube was simultaneously filled with 3 mL of N-methylpyrrolidone. The permeation concentration per unit area was calculated based on the combined content of fipronil, metoclopramide, and praziquantel. Detailed data are shown in Table 4.

[0060] Table 4 shows the permeate concentration per unit area data for Example 1 and Comparative Examples 1-18.

[0061]

[0062] As can be seen from the data in Table 4, the compound drops prepared in Example 1 of this invention have a significant transdermal effect due to the use of a composite transdermal agent. In contrast, the transdermal effects of combinations of transdermal agents and solvents in Comparative Examples 1-17 (without, alone, or outside the specified proportions) are significantly less pronounced than in Example 1, indicating that the components selected in this invention are reasonable and result in a good transdermal effect.

[0063] 3. Parasite Killing Efficacy Test

[0064] At an animal market, 190 cats aged 12 months or older, weighing between 2.5 kg and 7.5 kg, were randomly selected. The cats' bodies and ears were cleaned to kill parasites. The cats were randomly divided into 19 groups of 10 each. Group 1 was Example 1, and groups 2-19 were Comparative Examples 1-18. Twenty-five ear mites were injected into the ears of each cat. Three days after infection, the fur on the back of the cats' necks was parted, and 1 mL of the 19 samples were applied sequentially to the skin of each group of cats. After the application, the cats were separated into different cages and allowed to resume normal eating and living conditions.

[0065] The infection status of cats in each group was observed on days 0, 14, and 28 after drug administration, and the infection results were statistically analyzed. Judgment criteria: If the number of ear mites in the field of view (40x magnification) exceeded 25 in each cat during the observation period, the drug was considered ineffective. If the number of ear mites in the field of view was less than 25, the drug was considered effective. If no ear mites were found in the field of view, the cat was considered cured. Specific data are shown in Table 5.

[0066] Table 5 shows the infection results of Example 1 and Comparative Examples 1-18.

[0067]

[0068] As shown in Table 5, the components of Example 1 of the present invention are reasonable, and the components work synergistically, resulting in good insecticidal effect. The efficacy and cure rate against cat ear mites are both 100%. Comparative Examples 1-18, due to different formulations and processes, have worse effects than Example 1.

[0069] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pet flea and tick treatment, characterized in that: The pet flea and tick drops comprise the following components by weight percentage: Fipronil 30%; Methoxyprone 10%; Praziquantel 7.5%; 4% of the compound transdermal agent; Antioxidant 0.2%; The remainder is a composite solvent; The composite transdermal agent is composed of azone, polyvinylpyrrolidone K17, and propylene glycol in a weight ratio of 1:2:

5. The composite solvent is composed of N-methylpyrrolidone, isosorbide dimethyl ether, and dimethyl sulfoxide in a weight ratio of 1:1:10; The preparation method of the aforementioned pet flea and tick drops includes: 1) Mix and dissolve dimethyl sulfoxide, isosorbide dimethyl ether, and N-methylpyrrolidone; 2) Add azone, polyvinylpyrrolidone K17, and propylene glycol to the solution obtained in step 1), and continue stirring to dissolve; 3) Add fipronil, metoprofen, and praziquantel to the solution obtained in step 2), and continue stirring until the materials are completely dissolved; 4) Add antioxidant to the solution obtained in step 3) and stir for 20 minutes to obtain a mixed solution; 5) Filter the mixed solution obtained in step 4) to obtain pet deworming drops.

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