Antiparasitic compositions and uses thereof

Abstract

The application relates to an anti-parasite composition and application thereof, and the anti-parasite composition comprises the following components in mass percentage (w / v): 6-10% of non-pyrantel, 6-10% of pyrantel, 0.5-2% of moxidectin, 8-12% of methoprene, 0.1-0.3% of an antioxidant, 3-5% of a skin protective agent and the balance of a solvent, wherein the antioxidant is dibutylhydroxytoluene and tea polyphenol. The anti-parasite composition disclosed by the application has a wide parasite expelling spectrum, is mild, stable and long-acting, and can expel internal and external parasites.

Description

Technical Field

[0001] This application relates to the field of veterinary chemical preparations technology, and in particular to an antiparasitic composition and its application. Background Technology

[0002] Parasitic diseases are a significant factor affecting pet health. Some parasitic diseases are zoonotic and can also harm the health of pet owners, making regular deworming necessary. Compared to oral deworming medications, topical deworming drops are significantly less irritating to a pet's digestive system and are easier to use, making them the preferred option for most pet owners.

[0003] Existing topical flea and tick treatments on the market have two main drawbacks. First, their incomplete spectrum of activity means pet owners need to treat their pets both internally and externally, increasing the frequency of administration. Second, most flea and tick medications are fat-soluble, meaning the solvents used in these treatments are primarily organic. These solvents can irritate the skin, especially in sensitive pets, potentially causing redness, swelling, and peeling at the application site. Furthermore, the effectiveness of traditional flea and tick medications typically lasts only a month or less. To ensure the pet's health, regular deworming is necessary, leading to more frequent use of these medications. This not only causes significant skin irritation for pets but is also inconvenient for pet owners. Summary of the Invention

[0004] Therefore, it is necessary to provide an antiparasitic composition and its application to address the above problems. The antiparasitic composition described in this application has a broad spectrum of anthelmintic activity, is mild, stable, and long-lasting, and can simultaneously treat both in vivo and in vitro parasites.

[0005] An antiparasitic composition comprising the following components in weight percentages (w / v): 6%–10% feprerone, 6%–10% praziquantel, 0.5%–2% moxiquidine, 8%–12% methoxyprotein, 0.1%–0.3% antioxidant, 3%–5% skin protectant, and the balance being a solvent, wherein the antioxidant is butylated hydroxytoluene and tea polyphenols.

[0006] In one embodiment, the mass ratio of the butylated hydroxytoluene to the tea polyphenols is 1:1 to 2:1.

[0007] In one embodiment, the mass ratio of the antioxidant to the methoxyprone is (1~3):100.

[0008] In one embodiment, the mass ratio of the antioxidant to the fipronil is (1~3):83.

[0009] In one embodiment, the mass ratio of the antioxidant to the praziquantel is (1~3):83.

[0010] In one embodiment, the mass ratio of the antioxidant to the moxicritin is (1~3):10.

[0011] In one embodiment, the skin protectant is selected from at least one of propylene glycol, glycerol, and urea.

[0012] In one embodiment, the solvent is selected from at least one of benzyl alcohol, ethanol, dimethyl sulfoxide, ethyl acetate, propylene carbonate, diethylene glycol monoethyl ether, and N-methylpyrrolidone.

[0013] An antiparasitic composition as described above is used for internal parasite control in pets.

[0014] An antiparasitic composition as described above is used for external parasite control of pets.

[0015] The antiparasitic composition described in this application uses a specific ratio of fipronil, praziquantel, moxicillin, metoprone, and butylated hydroxytoluene (BHT) antioxidants, tea polyphenol antioxidants, and skin protectants in a synergistic compound. This not only enhances the stability of the antiparasitic composition under complex environmental conditions such as light and high temperature, effectively inhibiting its degradation, thereby prolonging the duration of drug action, reducing the frequency of drug use, and reducing the irritation of the solvent to the skin, but also simultaneously kills a variety of parasites such as mites, fleas, ticks, worms, tapeworms, and canine heartworms. It has a broad spectrum of parasite control, is mild, and has high safety, enabling simultaneous treatment of both internal and external parasites. Detailed Implementation

[0016] To facilitate understanding of this application, it will be described in more detail below. However, it should be understood that this application can be implemented in many different forms and is not limited to the embodiments or examples described herein. Rather, these embodiments or examples are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. The terminology used herein in the specification of this application is for the purpose of describing particular implementations or embodiments only and is not intended to limit the application. The optional range of the term "and / or" as used herein includes any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all related listed items. In this application, when numerical ranges are involved, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, and every value between such minimum and maximum values. Further, when a range refers to an integer, it includes every integer between the minimum and maximum values ​​of the range. Furthermore, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges to which they are incorporated.

[0018] Fipronil, as an insecticide, is mainly used against adult ticks and fleas; methoprene, as an insect growth regulator, often acts on flea eggs and larvae; moxiquidine has good killing effects on internal and external parasites, especially nematodes and arthropods, as well as heartworm larvae; praziquantel has broad-spectrum anti-schistosomiasis and anti-tapeworm activity, and has good activity against various adult and larval tapeworms. When fipronil, methoprene, moxiquidine, and praziquantel are used in combination, fipronil and methoprene kill external parasites, eggs, and larvae through contact, while moxiquidine and praziquantel kill internal trematodes, tapeworms, and heartworms, thus covering common internal and external parasites in pets and providing a broad spectrum of antiparasitic activity.

[0019] However, after long-term and in-depth research, the applicant discovered that directly combining fipronil, methoxyprone, moxiquidine, and praziquantel results in poor stability of the composition due to significant differences in their physicochemical properties. Therefore, this application provides an antiparasitic composition comprising the following components in weight percentages (w / v): 6%–10% fipronil, 6%–10% praziquantel, 0.5%–2% moxiquidine, 8%–12% methoxyprone, 0.1%–0.3% antioxidant, 3%–5% skin protectant, and the balance being solvent, wherein the antioxidant is butylated hydroxytoluene and tea polyphenols.

[0020] This application screens antioxidants, using a combination of butylated hydroxytoluene (BHT) and tea polyphenols as antioxidants. This combination is synergistically formulated with specific proportions of fipronil, praziquantel, moxicillin, metoprone, and skin protectants. This not only enhances the stability of the antiparasitic composition under complex environmental conditions such as light and high temperatures, effectively inhibiting its degradation and thus prolonging the drug's duration of action, reducing the frequency of drug use, and decreasing the skin irritation of the solvent, but also simultaneously kills multiple parasites such as mites, fleas, ticks, worms, tapeworms, and canine heartworms. It has a broad spectrum of parasite control, is mild, and has high safety, enabling simultaneous treatment of both internal and external parasites.

[0021] Among them, tea polyphenols are the main active ingredients in tea. They have biological activities such as scavenging free radicals and antioxidation. They are pure natural antioxidants. Compared with antioxidants such as butylated hydroxyanisole, thiodipropionic acid, and propyl gallate commonly used in traditional drop products, they have higher safety. Furthermore, when combined with butylated hydroxytoluene (BHT) as an antioxidant, it has a significant effect on enhancing the efficacy stability of specific proportions of drug components such as fipronil, praziquantel, moxicillin, and metoprone.

[0022] It is understood that in the antiparasitic composition, the mass percentage of fipronil includes, but is not limited to, any one of 6%, 7%, 8%, 8.3%, 9%, 10%, or any range between any two; the mass percentage of praziquantel includes, but is not limited to, any one of 6%, 7%, 8%, 8.3%, 9%, 10%, or any range between any two; the mass percentage of moxifloxacin includes, but is not limited to, any one of 0.5%, 1%, 1.5%, 2%, or any range between any two; the mass percentage of metoprone includes, but is not limited to, any one of 8%, 9%, 10%, 11%, 12%, or any range between any two; the mass percentage of antioxidants includes, but is not limited to, any one of 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, or any range between any two; and the mass percentage of skin protectant includes, but is not limited to, any one of 3%, 3.5%, 4%, 4.5%, 5%, or any range between any two.

[0023] In one embodiment of this application, the mass ratio of butylated hydroxytoluene to tea polyphenols is preferably 1:1 to 2:1. By adjusting the dosage ratio of butylated hydroxytoluene to tea polyphenols, it is beneficial to further optimize and enhance the efficacy stability of specific proportions of fepronil, praziquantel, moxicillin, and metoprone drug components.

[0024] In one embodiment of this application, the preferred mass ratio of the antioxidant to the methoxyprone is (1~3):100, which helps to inhibit the oxidative degradation of methoxyprone under light exposure, thereby further improving the stability of the antiparasitic composition.

[0025] In one embodiment of this application, the preferred mass ratio of the antioxidant to the fipronil is (1~3):83, which helps to inhibit the oxidative degradation of fipronil under high temperature conditions, thereby further improving the stability of the antiparasitic composition.

[0026] In one embodiment of this application, the preferred mass ratio of the antioxidant to the praziquantel is (1~3):83, which helps to inhibit the oxidative degradation of praziquantel under high temperature conditions, thereby further improving the stability of the antiparasitic composition.

[0027] In one embodiment of this application, the preferred mass ratio of the antioxidant to the moxiquitoline is (1~3):10, which helps to inhibit the oxidative degradation of moxiquitoline under high temperature conditions, thereby further improving the stability of the antiparasitic composition.

[0028] In one embodiment of this application, the preferred mass ratio of the antioxidant to the fipronil, the praziquantel, the moxiquitoline, and the methoxyprone is (1~3):83:83:10:100.

[0029] Further preferably, the antiparasitic composition comprises the following components in weight percentages (w / v): 8.3% fipronil, 8.3% praziquantel, 1% moxiquitoline, 10% methoxyprone, 0.1% to 0.3% antioxidant, 3% to 5% skin protectant, and the balance being solvent, wherein the antioxidant is butylated hydroxytoluene and tea polyphenols in a weight ratio of 1:1 to 2:1.

[0030] In one embodiment of this application, the skin protectant includes, but is not limited to, at least one of propylene glycol, glycerol, and urea, preferably propylene glycol, glycerol, or urea. By using the skin protectant in conjunction with the antiparasitic composition of this application, it is not only beneficial to improve the skin irritation of the antiparasitic composition, but also to synergistically optimize the compatibility and stability of the drug components, which can prolong the duration of drug action, thereby reducing the number of times the drug is used and bringing convenience to pet owners.

[0031] In one embodiment of this application, the solvent includes, but is not limited to, at least one of benzyl alcohol, ethanol, dimethyl sulfoxide (DMSO), ethyl acetate, propylene carbonate, diethylene glycol monoethyl ether, and N-methylpyrrolidone, preferably DMSO or N-methylpyrrolidone.

[0032] The antiparasitic composition provided in this application can be used for both internal and external parasite control in pets. Based on the stable and long-lasting technical advantages of this antiparasitic composition, in practical applications, compared with conventional antiparasitic agents, it requires a smaller dosage while achieving better efficacy. This further reduces the potential irritation of the drug to pets and their owners, thus significantly improving product safety.

[0033] The following specific embodiments will further illustrate the antiparasitic composition and its application. However, those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used without specified manufacturers are all commercially available conventional products.

[0034] All examples and comparative examples were formulated into antiparasitic compositions according to the components and proportions shown in Table 1, in units of mass (g) to volume (mL) percentage, where BHA is butylated hydroxyanisole.

[0035] Table 1

[0036]

[0037] The prepared antiparasitic composition was subjected to skin irritation test, in vivo insecticidal effect test, in vitro insecticidal effect test and stability test.

[0038] Test Example 1: Skin Irritation Test

[0039] Test drugs: antiparasitic compositions obtained in Examples 1, 2, 3, 4, and 5, and antiparasitic compositions obtained in Comparative Example 1, and physiological saline.

[0040] Experimental Methods: Thirty-six New Zealand rabbits, half male and half female, were selected. Twenty-four hours before the experiment, the rabbits' fur was removed without damaging the epidermis, covering an area of ​​approximately 3.0 × 3.0 cm. 0.5 ml of the antiparasitic composition was evenly applied to the hairless skin, and skin reactions were observed under natural light. The right side served as a blank control, with saline solution applied. Four hours after local administration, the treatment site was cleaned with saline solution. Skin condition was observed after cleaning and at 24, 48, and 72 hours post-cleaning for the presence of erythema, edema, etc. Irritation response and intensity were scored according to the Technical Guidelines for Research on Irritation, Allergenicity, and Hemolysis of Chemical Drugs, specifically referring to Tables 2 and 3. The scoring results are shown in Table 4. The average skin irritation response score was calculated as (total erythema formation score + total edema formation score) / total number of animals.

[0041] Table 2

[0042]

[0043] Table 3

[0044]

[0045] Table 4

[0046]

[0047] As shown in Table 4, when Examples 1-5 were applied to laboratory animals, only one animal in Example 4 developed mild erythema within 24 hours, while the others did not develop erythema, eschar, or swelling within 72 hours. In contrast, when Comparative Example 1 was applied to laboratory animals, erythema, eschar, and swelling occurred in most animals within 72 hours. The scoring results indicate that Comparative Example 1 was mildly irritating to laboratory animals, while Examples 1-5 were non-irritating. This demonstrates that the antiparasitic composition provided in this application is mild, non-irritating, and highly safe.

[0048] Experimental Example 2: In vivo insecticidal effect test

[0049] Test drugs: The antiparasitic compositions obtained in Examples 1-5 and the antiparasitic composition obtained in Comparative Example 1 were used.

[0050] Experimental method: The stray cat shelter selected 70 cats that were naturally infected with roundworms and tapeworms through fecal examination. Most of them were mixed infections. The cats were 6 months old to adulthood. They were housed separately for one week to allow the cats to adapt to the environment and become tame before the formal experiment began.

[0051] Seventy cats were divided into seven groups of ten each, based on the principle of distributing the infecting parasite species and numbers as evenly as possible. Group 1 was the control group without medication, Group 2 was the self-made sample group of Example 1, Group 3 was the self-made sample group of Example 2, Group 4 was the self-made sample group of Example 3, Group 5 was the self-made sample group of Example 4, Group 6 was the self-made sample group of Example 5, and Group 7 was the sample group of Comparative Example 1.

[0052] Administer 0.12 mL per kg of body weight. Part the fur on the back of the cat's neck and drip the entire amount of medication from the applicator onto a small spot on the skin.

[0053] Fecal samples were collected from each cat on the day of administration (day 0, before administration) and at 7, 14, 21, 28, 35, 42, 49, 56, and 63 days after administration. The collected fecal samples were mixed evenly, and the number of roundworm and tapeworm eggs was counted separately. The reduction rate of each type of egg was calculated as follows: Egg (body) reduction rate = [Number of eggs (body) before administration - Number of eggs (body) after administration] / Number of eggs (body) before administration × 100%.

[0054] The experimental results are shown in Tables 5 and 6.

[0055] Table 5

[0056]

[0057] As shown in Table 5, Examples 1-5 all achieved a 100% reduction rate of Ascaris eggs 7 days after treatment and maintained an egg reduction rate of over 90% for 56 days. In contrast, Comparative Example 1 achieved a 100% egg reduction rate 7 days after treatment and maintained an egg reduction rate of over 90% for 42 days. Compared to Comparative Example 1, the duration of efficacy in Examples 1-5 was extended by approximately two weeks. This result indicates that the antiparasitic composition provided in this application has a significantly longer duration of efficacy for in vivo insecticidal action.

[0058] Table 6

[0059]

[0060] As shown in Table 6, Examples 1-5 all achieved a tapeworm egg reduction rate of over 95% 7 days after treatment and maintained an egg reduction rate of over 90% for 42 days. In contrast, Comparative Example 1 achieved an egg reduction rate of over 95% 7 days after treatment and maintained an egg reduction rate of over 90% for 35 days. Therefore, compared to Comparative Example 1, the efficacy duration of Examples 1-5 was extended by approximately one week. This result indicates that the antiparasitic composition provided in this application has a significantly improved duration of efficacy for in vivo insecticidal action.

[0061] Experiment Example 3: In vitro insecticidal effect test

[0062] Test drugs: The antiparasitic compositions obtained in Examples 1-5 and the antiparasitic composition obtained in Comparative Example 1 were used.

[0063] Experimental method: The stray cat shelter selected 70 cats that had been naturally infected with fleas, ranging in age from 6 months to adulthood.

[0064] The 70 cats were divided into 7 groups of 10 each, based on the principle of distributing the infection numbers as evenly as possible. Group 1 was the control group without medication, Group 2 was the self-made sample group of Example 1, Group 3 was the self-made sample group of Example 2, Group 4 was the self-made sample group of Example 3, Group 5 was the self-made sample group of Example 4, Group 6 was the self-made sample group of Example 5, and Group 7 was the sample group of Comparative Example 1.

[0065] Administer 0.12 mL per kg of body weight. Part the fur on the back of the cat's neck and drip the entire amount of medication from the applicator onto a small spot on the skin.

[0066] The reduction rate of fleas after medication was recorded for each cat on the day of administration (day 0, before administration) and at 7, 14, 21, 28, 35, 42, 49, 56, 63 and 70 days after administration. The results are shown in Table 7.

[0067] Table 7

[0068]

[0069] As shown in Table 7, Examples 1-5 all achieved a 100% flea reduction rate 7 days after treatment and maintained a reduction rate of over 90% for 70 days. In contrast, Comparative Example 1 achieved a 100% flea reduction rate 7 days after treatment and maintained a reduction rate of over 90% for 56 days. Compared to Comparative Example 1, the efficacy duration of Examples 1-5 was extended by at least two weeks. This result indicates that the antiparasitic composition provided in this application has a significantly improved duration of efficacy for in vitro insecticidal use.

[0070] Test Example 4: Stability Test

[0071] The antiparasitic compositions prepared in Examples 1, 2, 3, 6, 7, 8 and Comparative Examples 2, 3, 4, 5, 6, 7, 8, 9 were placed under high-temperature conditions for 10 days to detect the content of moxicritin, fipronil, praziquantel, and related substances, and to examine the product stability. Specifically, the high-temperature test was conducted by placing an appropriate amount of sample in a constant temperature chamber at 60°C for 10 days, and taking samples for analysis on the 10th day. The results are shown in Tables 8 to 10.

[0072] The antiparasitic compositions prepared in Examples 1, 2, 3, 6, 7, 8 and Comparative Examples 2, 3, 4, 5, 6, 7, 8, 9 were placed under light conditions for 10 days to detect the content of methoxyprone and related substances, and to examine the stability of the products. Specifically, the light test was conducted as follows: an appropriate amount of sample was placed in a transparent glass bottle and placed under a clarity tester (illuminance of 4500 lx ± 500 lx) for 10 days. Samples were taken for analysis on the 10th day, and the results are shown in Table 11.

[0073] Table 8

[0074]

[0075] Table 9

[0076]

[0077] Table 10

[0078]

[0079] Table 11

[0080]

[0081] As shown in Tables 8-10, under high temperature conditions of 60℃, the contents of fipronil, praziquantel, and moxiquidine in Comparative Example 2 (without antioxidant) all decreased, while the contents of fipronil sulfonate, praziquantel impurity B, and moxiquidine impurities E+F and G (the individual unknown impurity before impurity G) all increased. This indicates that the absence of antioxidants affects the stability of fipronil, praziquantel, and moxiquidine at high temperatures. In Examples 1, 2, and 3, the increases in the number of fipronil sulfonate and the individual unknown impurity before moxiquidine impurity G were smaller than those in Comparative Examples 3, 4, 5, 6, 7, 8, and 9, indicating that the antioxidant combination of BHT and tea polyphenols, within a certain range of application, can make the antiparasitic composition more stable at high temperatures.

[0082] As shown in Table 11, under light conditions, the content of methicillin in Comparative Example 2 (without antioxidants) decreased significantly, while the number of methicillin isomers increased significantly, indicating that the absence of antioxidants affects the stability of methicillin under light conditions. The increases in methicillin isomers in Examples 1, 2, and 3 were all lower than those in Comparative Examples 3, 4, 5, 6, 7, 8, and 9, indicating that the combination of BHT and tea polyphenols as antioxidants, within a certain range of application, can make the methicillin in the antiparasitic composition more stable under light.

[0083] Compared with Examples 6 and 7, Examples 1, 2, and 3 showed better high-temperature stability of fipronil, praziquantel, and moxiquidine, and better light stability of methoxyprone, indicating that optimizing the formulation is beneficial to further improve the stability of the antiparasitic composition. Compared with Example 3, Example 8 showed slightly lower high-temperature stability of fipronil, praziquantel, and moxiquidine, and slightly lower light stability of methoxyprone, indicating that optimizing the ratio of BHT to tea polyphenols is also beneficial to further improve the stability of the antiparasitic composition, especially when the mass ratio of BHT to tea polyphenols is 1:1 to 2:1, the stability effect is better.

[0084] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0085] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. An antiparasitic composition, characterized in that, The antiparasitic composition comprises the following components in weight percentages (w / v): 6%–10% feprerone, 6%–10% praziquantel, 0.5%–2% moxiquidine, 8%–12% methoxyprotein, 0.1%–0.3% antioxidant, 3%–5% skin protectant, and the balance being solvent, wherein the antioxidant is butylated hydroxytoluene and tea polyphenols.

2. The antiparasitic composition according to claim 1, characterized in that, The mass ratio of butylated hydroxytoluene to tea polyphenols is 1:1 to 2:

1.

3. The antiparasitic composition according to claim 1 or 2, characterized in that, The mass ratio of the antioxidant to the methoxyprone is (1~3):

100.

4. The antiparasitic composition according to claim 1 or 2, characterized in that, The mass ratio of the antioxidant to the fipronil is (1~3):

83.

5. The antiparasitic composition according to claim 1 or 2, characterized in that, The mass ratio of the antioxidant to the praziquantel is (1~3):

83.

6. The antiparasitic composition according to claim 1 or 2, characterized in that, The mass ratio of the antioxidant to the moxicritin is (1~3):

10.

7. The antiparasitic composition according to claim 1, characterized in that, The skin protectant is selected from at least one of propylene glycol, glycerol, and urea.

8. The antiparasitic composition according to claim 1, characterized in that, The solvent is selected from at least one of benzyl alcohol, ethanol, dimethyl sulfoxide, ethyl acetate, propylene carbonate, diethylene glycol monoethyl ether, and N-methylpyrrolidone.

9. An antiparasitic composition as described in any one of claims 1 to 8 for internal parasite control in pets.

10. An antiparasitic composition according to any one of claims 1 to 8 for external parasite control of pets.

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