Special anti-parasitic chewable tablet for animals and preparation method thereof

Abstract

The invention relates to the technical field of veterinary preparations. The invention provides a special anti-parasitic chewable tablet for animals and a preparation method thereof. The chewable tablet is prepared from the following components in parts by weight: 10.5 to 16 parts of active ingredients, 11.5 to 18.5 parts of glycerol, 15 to 20 parts of gelatin, 8 to 10 parts of maltitol or sorbitol, 6 to 9 parts of microcrystalline cellulose, 10 to 20 parts of adhesive, 0.5 to 1.5 parts of magnesium stearate, 0.1 to 0.5 part of vitamin E and 0.01 to 0.05 part of BHT (butylated hydroxytoluene) or BHA (butylated hydroxytoluene), the active component is one or more of arfamarin, fluralab, selamectin and ivermectin. The invention further relates to a preparation method of the pesticide composition containing the fluralab, the selamectin and the ivermectin. The chewable tablet disclosed by the invention is suitable for efficiently preventing and treating ticks, mites and fleas by animals, and has the characteristics of good palatability and convenience in administration. The blank of combination of a flexible dosage form and efficient parasite expelling in the prior art is filled up, and the composition is suitable for animal feeding and particularly suitable for daily prevention and treatment of companion animals.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of veterinary preparations, in particular to an animal-specific anti-parasitic chewable tablet and a preparation method thereof. BACKGROUND

[0002] External parasites such as ticks, mites and fleas are common pathogens of pets, which not only cause skin inflammation, anemia and other health problems, but also can transmit zoonoses. The current mainstream prevention and control drugs on the market include drops, sprays, oral tablets and collars, among which chemical synthetic drugs (such as fipronil, afoxolaner, etc.) are widely used due to their high efficiency.

[0003] The existing dosage forms on the market have certain limitations. Ordinary tablets have poor palatability, and animals (especially companion animals) have a high refusal rate, which requires forced feeding, leading to difficult operation for the owner and stress for the animal. The drops / sprays have skin irritation, and the drug efficacy is easily reduced due to licking or bathing of the pet. Although the hard chewable tablets improve the palatability, they are not friendly to young, old or animals with fragile teeth due to their high hardness.

[0004] The soft chewable tablet has soft texture, is suitable for pets to chew and swallow, and can improve the voluntary feeding rate by adding a food attractant (such as liver flavor), and realize drug sustained release through auxiliary material optimization, prolong the protection period, and avoid gastrointestinal irritation or oral mucosa damage caused by traditional dosage forms. SUMMARY

[0005] The present application aims to provide an animal-specific anti-parasitic chewable tablet and a preparation method thereof, which develops a soft chewable tablet with high palatability and low stress through an innovative formula and preparation process, fills the gap of the combination of "flexible dosage form + high-efficiency parasite control" in the prior art, and is suitable for animal feeding, especially for daily prevention and control application of companion animals.

[0006] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0007] The present application provides an animal-specific anti-parasitic chewable tablet, which comprises the following components in parts by weight: active ingredient 10.5-16 parts, glycerol 11.5-18.5 parts, gelatin 15-20 parts, maltitol or sorbitol 8-10 parts, microcrystalline cellulose 6-9 parts, binder 10-20 parts, magnesium stearate 0.5-1.5 parts, vitamin E 0.1-0.5 parts, BHT or BHA 0.01-0.05 parts.

[0008] The active ingredient is one or more of afoxolaner, fluralaner, selamectin and ivermectin.

[0009] Preferably, the concentration of afoxolaner in the chewable tablet is 5-15 mg / tablet; the concentration of fluralaner is 10-20 mg / tablet; the concentration of selamectin is 6-24 mg / tablet; and the concentration of ivermectin is 0.1-1 mg / tablet.

[0010] Preferably, the type of the binder is hydroxypropyl methyl cellulose, polyethylene glycol 3350 or polyethylene glycol 400.

[0011] Preferably, the chewable tablet further contains animal raw material powder or essence.

[0012] The type of the animal raw material powder is liver powder or chicken powder; and the type of the essence is beef essence or fish essence.

[0013] When the chewable tablet contains animal raw material powder, the weight fraction of the animal raw material powder is 25-30 parts; and when the chewable tablet contains essence, the weight fraction of the essence is 0.5-2 parts.

[0014] The present application also provides a preparation method of the chewable tablet, comprising the following steps:

[0015] (1) mixing raw materials in proportion to obtain a mixture;

[0016] (2) tabletting the mixture to obtain a tablet;

[0017] (3) drying the tablet to obtain the chewable tablet.

[0018] Preferably, in step (2), a low-temperature soft chewable tablet press is used for tabletting, and the temperature for tabletting is < 30℃.

[0019] Preferably, in step (3), the temperature for drying is 10-28℃, and the water content after drying is ≤ 5%.

[0020] The present application provides an animal-specific anti-parasitic chewable tablet and a preparation method thereof. The chewable tablet comprises the following components in weight fractions: 10.5-16 parts of active ingredients, 11.5-18.5 parts of glycerol, 15-20 parts of gelatin, 8-10 parts of maltitol or sorbitol, 6-9 parts of microcrystalline cellulose, 10-20 parts of a binder, 0.5-1.5 parts of magnesium stearate, 0.1-0.5 parts of vitamin E, and 0.01-0.05 parts of BHT or BHA. The active ingredients are one or more of afoxolaner, fluralaner, selamectin and ivermectin. The chewable tablet of the present application is suitable for efficient prevention and treatment of ticks, mites and fleas in animals, has good palatability and convenient administration, fills the gap of the combination of "flexible dosage form + high-efficiency insect repellent" in the prior art, and is suitable for animal feeding, especially for daily prevention and treatment of companion animals. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 Pathohistological changes of different dose groups of oral fluoro-ranatm chewable tablets. DETAILED DESCRIPTION

[0022] The present application provides an anti-parasite chewable tablet for animals, which comprises the following components by weight: active ingredient 10.5-16 parts, glycerin 11.5-18.5 parts, gelatin 15-20 parts, maltitol or sorbitol 8-10 parts, microcrystalline cellulose 6-9 parts, binder 10-20 parts, magnesium stearate 0.5-1.5 parts, vitamin E 0.1-0.5 parts, BHT or BHA 0.01-0.05 parts.

[0023] The active ingredient is one or more of afoxolaner, fluoro-ranatm, selamectin and ivermectin.

[0024] In the present application, the chewable tablet comprises the following components by weight: active ingredient 12.5-15.5 parts, glycerin 12.5-15 parts, gelatin 17-18 parts, maltitol or sorbitol 9 parts, microcrystalline cellulose 7-8 parts, binder 15 parts, magnesium stearate 1 part, vitamin E 0.3-0.4 parts, BHT or BHA 0.02-0.03 parts.

[0025] In the present application, the concentration of afoxolaner in the chewable tablet is preferably 5-15 mg / tablet, further preferably 10 mg / tablet; the concentration of fluoro-ranatm is preferably 10-20 mg / tablet, further preferably 15 mg / tablet; the concentration of selamectin is preferably 6-24 mg / tablet, further preferably 12-18 mg / tablet; the concentration of ivermectin is preferably 0.1-1 mg / tablet, further preferably 0.5 mg / tablet.

[0026] In the present application, the type of binder is preferably hydroxypropyl methylcellulose, polyethylene glycol 3350 or polyethylene glycol 400.

[0027] In the present application, the chewable tablet preferably further comprises animal raw material powder or essence;

[0028] The type of animal raw material powder is liver powder or chicken powder; the type of essence is beef essence or fish essence;

[0029] When the chewable tablet contains animal raw material powder, the weight fraction of the animal raw material is preferably 25-30 parts, further preferably 27-28 parts; when the chewable tablet contains essence, the weight fraction of the essence is preferably 0.5-2 parts, further preferably 1-1.5 parts.

[0030] The present application further provides a preparation method of the chewable tablet, comprising the following steps:

[0031] (1) mixing raw materials in proportion to obtain a mixture;

[0032] (2) tabletting the mixture to obtain tablets;

[0033] (3) drying the tablets to obtain the chewable tablets.

[0034] In the present application, the temperature for tabletting in step (2) is preferably < 30°C, and more preferably < 25°C.

[0035] In the present application, the temperature for drying in step (3) is preferably 10-28°C, and more preferably 15-20°C, and the water content after drying is preferably ≤ 5%, and more preferably ≤ 4%.

[0036] In the present application, the quality control standards for the product are as follows:

[0037] Hardness: 5-35 N (soft chewable characteristics)

[0038] Palatability test: ≥ 80% voluntary consumption rate of pets (compared with ordinary tablets)

[0039] Stability: ≥ 90% content of main components after 6 months of accelerated test at 40°C / 75% RH.

[0040] In the present application, the indications and usage of the product are as follows:

[0041] Animals: dogs, cats, sheep, pigs

[0042] Target parasites: ticks, fleas, scabies mites, ear mites, etc.

[0043] Administration: direct feeding or mixing with food, once a month (adjusted according to the half-life of the drug).

[0044] The technical solutions provided by the present application will be described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0045] Example 1

[0046] (1) raw materials are weighed in the following proportions by weight:

[0047] Fluralaner 10%, Ivermectin 0.5%, glycerol 15.5%, gelatin 18.0%, maltitol 8.59%, microcrystalline cellulose 6.7%, hydroxypropyl methylcellulose 4.6%, polyethylene glycol 3350 9.8%, magnesium stearate 1%, chicken meal 25.1%, vitamin E 0.2%, BHT 0.01%.

[0048] (2) mixing the active ingredient flucllurane and the matrix ingredient in proportion to obtain a mixture; wherein the gelatin needs to be heated and melted before mixing with other matrix; the mixture is pressed into tablets to form tablets; the tablets are dried at room temperature to obtain the chewable tablets.

[0049] Example 2

[0050] (1) the raw materials are weighed in proportion by weight as follows:

[0051] flucllurane 15.0%, glycerol 11.5%, gelatin 17.0%, maltitol 8.14%, microcrystalline cellulose 8.25%, polyethylene glycol 3350 11.4%, magnesium stearate 1%, pork liver powder 27.4%, vitamin E 0.3%, BHT 0.01%.

[0052] (2) mixing the active ingredient flucllurane and the matrix ingredient in proportion to obtain a mixture; wherein the gelatin needs to be heated and melted before mixing with other matrix; the mixture is pressed into tablets to form tablets; the tablets are dried at room temperature to obtain the chewable tablets.

[0053] Example 3

[0054] (1) the raw materials are weighed in proportion by weight as follows:

[0055] afolaner 12.0%, ivermectin 0.5%, glycerol 18.5%, gelatin 18.0%, maltitol 9.2%, microcrystalline cellulose 8.25%, hydroxypropyl methyl cellulose 3.52%, polyethylene glycol 400 12.4%, magnesium stearate 1%, beef flavor 0.5%, vitamin E 0.2%, BHA 0.01%.

[0056] (2) mixing the active ingredient afolaner, ivermectin and the matrix ingredient in proportion to obtain a mixture; wherein the gelatin needs to be heated and melted before mixing with other matrix; the mixture is pressed into tablets to form tablets; the tablets are dried at room temperature to obtain the chewable tablets.

[0057] Example 4

[0058] (1) the raw materials are weighed in proportion by weight as follows:

[0059] selamectin 15.0%, ivermectin 1%, glycerol 13.5%, gelatin 17.5%, maltitol 9.2%, microcrystalline cellulose 8.25%, hydroxypropyl methyl cellulose 3.52%, polyethylene glycol 400 15.4%, magnesium stearate 1%, beef flavor 2%, vitamin E 0.2%, BHA 0.01%.

[0060] (2) mixing the active ingredient selamectin, ivermectin and the matrix ingredient in proportion to obtain a mixture; wherein the gelatin needs to be heated and melted respectively before mixing with other matrix; the mixture is pressed into tablets to form tablets; the tablets are dried at room temperature to obtain the chewable tablets.

[0061] Test Example 1 Acute toxicity test in mice in vivo

[0062] SPF Kunming mice were used in the test, with a number of 36, half male and half female, and a body weight of 18-22g. The test was divided into 8 groups, and the chewable tablets prepared in Examples 1-4 were respectively administered (the chewable tablets of Examples 1-4 were respectively administered at two doses of 2000mg / kg and 5000mg / kg). After administration, the appearance, signs, diet, water intake, mental state, behavior, and other related changes of the mice were observed, and the death time and number of mice were recorded, and the observation was continued for 7 days. After administration, continuous observation was carried out for the first 3h, and then observation was carried out every 15min within 3h-8h, every 30min within 8h-12h, every 2h after 12h, and every day after 24h until the end of the 7th day.

[0063] After the end of the test, all test mice were sacrificed. Data statistical analysis was carried out by using the Korbor method. In the acute toxicity test of mice orally administered with fluoroelarana, clinical observation after administration found that the mice appeared to be restless for a short time (30min), and had low spirits and uneven back hair, and no death phenomenon was observed in the test group and the healthy control group. After the test group and the control group were sacrificed, histopathological observation was carried out, and it was found that the liver, kidney and spleen of the mice only had slight pathological changes (see Table 1). Figure 1 The calculation showed that the LD50 of mice orally administered with fluoroelarana was >5000mg / kg, and the toxicity classification of fluoroelarana was actually non-toxic, with good safety.

[0064] Test Example 2 Pharmacokinetic test in dogs in vivo

[0065] The healthy dogs were orally administered with the fluoroledana chewable tablets prepared in Example 2 by single dose according to the body weight. The main pharmacokinetic parameters AUC(0-∞) was 28629.45±3017.31 d*ng / mL, AUC(0-t) was 22279.16±2450.15 d*ng / mL, Cmax was 1689.58±124.12 ng / mL, MRT was 31.44±5.95 d, t1 / 2 was 25.40±8.91 d, Tmax was 1.21±0.35 d, CL was 4215.23 mL / d / kg, and Vz was 192246.31 mL / kg by non-compartment model (NCA) analysis in Phoenix64 (8.1.03530) pharmacokinetic analysis software. The fluoroledana chewable tablets showed the characteristics of fast absorption and slow elimination in the dogs. Compared with the control drug, t1 / 2 and AUC(0-∞) had significant difference (P>0.05), the relative bioavailability of the fluoroledana chewable tablets of the present application was 125.20%, and t1 / 2 was prolonged by 6 d. The results showed that the fluoroledana chewable tablets of the present application had the characteristics of good absorption, slow elimination, high efficiency and long-acting in vivo pharmacokinetics.

[0066] Clinical efficacy test on fleas of test example 3

[0067] Before administration, the average number of infected fleas of the test drug group (the fluoroledana chewable tablets prepared in Example 2) and the control drug group (Bayvet) was 26.96 and 29.60 respectively, and the difference in the average number of infected fleas between the two groups was not significant (P>0.05); the average number of flea feces piles of the test drug group and the control drug group was 13.57 and 14.87 respectively, and the difference in the average number of flea feces piles between the two groups was not significant (P>0.05). One day after administration, the average reduction rate of fleas of the test drug group was 99.6%; 15 d, 30 d and 60 d after administration, the average reduction rate of fleas was maintained at 100%; 90 d after administration, the average reduction rate of fleas was 99.7%; one day after administration, the average reduction rate of the number of flea feces piles was 98.6%; 15 d after administration, the average reduction rate of the number of flea feces piles was 99.5%; 30 d-90 d after administration, the average reduction rate of the number of flea feces piles was 100%. One day after administration, the average reduction rate of fleas of the control drug group was 99.5%; 15 d and 30 d after administration, the average reduction rate of fleas was maintained at 100%; 60 d after administration, the average reduction rate of fleas was 99.8%; 90 d after administration, the average reduction rate of fleas was 99.6%; one day after administration, the average reduction rate of the number of flea feces piles was 98.0%; 15 d after administration, the average reduction rate of the number of flea feces piles was 99.0%, and 30 d-90 d after administration, the average reduction rate of the number of flea feces piles was 100%.

[0068] The results show that the fluazuron chewable tablets have a significant killing effect on the fleas (flea feces) of the infected dogs, have a fast effect, the killing effect on the fleas can reach more than 99% on the first day, the killing effect on the flea feces reaches more than 96%, and the drug effect is maintained for 90 days. At the end of the test, the number of fleas (flea feces) is not increased.

[0069] Clinical drug effect test on ticks in test example 4

[0070] Before administration, the average number of ticks infected on the dogs in the test drug group (fluazuron chewable tablets prepared in example 2) and the control drug group (Bayvet) is 19.6 and 17.9 respectively. One day after administration of the test drug group, the average reduction rate of ticks is 99.7%, and the reduction rate of ticks is maintained at 100% 15 days, 30 days and 60 days after administration of the test drug group. 90 days after administration, the average reduction rate of ticks is 99.7%, and the average reduction rate of ticks is maintained at 100% 1 day, 15 days and 30 days after administration of the control drug group. 60 days and 90 days after administration, the average reduction rate of ticks is 99.6%.

[0071] The results show that the fluazuron chewable tablets have a significant killing effect (more than 99%) on the ticks infected on the dogs, have a fast effect, and the drug effect is maintained for 90 days. At the end of the test, the number of ticks is not increased.

[0072] It can be known from the above examples that the present application provides an anti-parasitic chewable tablet special for animals and a preparation method thereof. The chewable tablet comprises the following components in parts by weight: 10.5-16 parts of active ingredients, 11.5-18.5 parts of glycerol, 15-20 parts of gelatin, 8-10 parts of maltitol or sorbitol, 6-9 parts of microcrystalline cellulose, 10-20 parts of a binder, 0.5-1.5 parts of magnesium stearate, 0.1-0.5 parts of vitamin E, 0.01-0.05 parts of BHT or BHA; the active ingredients are one or more of alfoxalan, fluazuron, selamectin and ivermectin. The chewable tablet of the present application is suitable for efficient prevention and treatment of ticks, mites and fleas of animals, has the characteristics of good palatability and convenient administration. The present application fills the blank of the combination of "flexible dosage form + high-efficiency insect repellent" in the prior art, is suitable for animal feeding, and is especially suitable for daily prevention and treatment of companion animals.

[0073] The above only describes the preferred embodiments of the present application, and it should be noted that, for ordinary skilled persons in the technical field, some improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A chewable tablet for animal-specific antiparasitic purposes, characterized in that, The chewable tablet comprises the following components in parts by weight: 10.5–16 parts of active ingredient, 11.5–18.5 parts of glycerin, 15–20 parts of gelatin, 8–10 parts of maltitol or sorbitol, 6–9 parts of microcrystalline cellulose, 10–20 parts of binder, 0.5–1.5 parts of magnesium stearate, 0.1–0.5 parts of vitamin E, and 0.01–0.05 parts of BHT or BHA; The active ingredient is one or more of afolanar, fleraranar, selamectin, and ivermectin.

2. The chewable tablet according to claim 1, characterized in that, The chewable tablets contain afolanar at a concentration of 5–15 mg / tablet; fluranarar at a concentration of 10–20 mg / tablet; selamectin at a concentration of 6–24 mg / tablet; and ivermectin at a concentration of 0.1–1 mg / tablet.

3. The chewable tablet according to claim 1, characterized in that, The adhesive is of the type of hydroxypropyl methylcellulose, polyethylene glycol 3350, or polyethylene glycol 400.

4. The chewable tablet according to any one of claims 1 to 3, characterized in that, The chewable tablets also contain animal raw material powder or flavoring; The animal raw material powder is liver powder or chicken powder; the flavoring is beef flavoring or fish flavoring. When the chewable tablet contains animal raw material powder, the weight percentage of the animal raw material is 25 to 30 parts; when the chewable tablet contains flavoring, the weight percentage of the flavoring is 0.5 to 2 parts.

5. A method for preparing the chewable tablet according to any one of claims 1 to 4, characterized in that, Includes the following steps: (1) Mix the raw materials in a certain proportion to obtain a mixture; (2) Compress the mixture into tablets to obtain tablets; (3) The tablets are dried to obtain the chewable tablets.

6. The method according to claim 5, characterized in that, In step (2), a low-temperature soft chewable tablet press is used for tableting, and the tableting temperature is <30℃.

7. The method according to claim 5, characterized in that, The drying temperature in step (3) is 10-28°C, and the moisture content after drying is ≤5%.

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