Compound febantel tablet and preparation method thereof

Abstract

The invention relates to the technical field of veterinary drugs, in particular to a compound febantel tablet and a preparation method thereof. The dosage form of the compound febantel tablet is a tablet. Comprising 24.5 to 42 parts of a coating material taking febantel and praziquantel as active ingredients, 14 to 16 parts of pyrantel pamoate and 37.1 to 70.5 parts of a pharmaceutical adjuvant. The pharmaceutic adjuvants comprise a filling agent, an internal disintegrating agent, an internal flow aid, a disintegration promoting agent, an adhesive, a lubricating agent, an external disintegrating agent, an external flow aid, a coloring agent and a flavoring agent. The preparation method of the compound febantel tablet comprises the following steps: mixing the coating material, the pyrantel pamoate, the filling agent, the internal disintegrating agent, the internal flow aid, the disintegration promoting agent, the adhesive and the lubricant, granulating, drying, performing screen finishing, adding the external disintegrating agent, the external flow aid, the coloring agent and the flavoring agent, uniformly mixing, and tabletting. The tablet can be rapidly disintegrated, is stable in dissolution, is beneficial to drug release, and has a good taste.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of veterinary medicine, in particular to a compound febantel tablet and a preparation method thereof. BACKGROUND

[0002] Parasitic diseases in livestock and companion animals (such as dogs and cats) are one of the core challenges in the global livestock and pet breeding fields. Parasites persistently parasitize in the body of animals in a hidden way, continuously consume host nutrients and destroy tissues and organs, not only leading to animal growth retardation and production performance decline, but also causing secondary infection or spreading of zoonosis, which seriously threatens public health safety.

[0003] Febantel is an important choice for current anti-parasitic treatment, which is metabolized into active ingredients such as fenbendazole in the body of animals, inhibits the function of nematode microtubulin by targeting, and has a significant killing effect on adult worms, larvae and eggs, and is widely used for the prevention and control of parasites. However, the existing febantel preparations (such as conventional tablets and granules) commonly used in veterinary clinics have the following defects: First, poor disintegration performance: traditional dosage forms rely on natural peristalsis of the gastrointestinal tract or body fluid penetration to complete disintegration, which is slow and incomplete, resulting in slow drug release; Second, low dissolution rate: the active ingredients of the drug are difficult to be fully dissolved from the preparation, and the bioavailability is limited, which requires increasing the dosage or frequency of administration to achieve the therapeutic effect, which not only increases the cost, but also may cause toxicity due to drug accumulation; The above problems directly lead to the problems of slow onset, poor efficacy and easy recurrence of the existing febantel preparations in clinical application, especially in companion animals such as dogs and cats. Therefore, it has become a key requirement to develop a febantel preparation with rapid disintegration, high dissolution and controlled release to improve the effect of parasitic prevention and control. SUMMARY

[0004] The present application aims to solve the problems in the prior art and provides a compound febantel tablet and a preparation method thereof.

[0005] A compound febantel tablet, which is in the form of a tablet; the raw materials thereof include, by mass fraction, 24.5-42 parts of a coating material containing febantel and pyrantel as active ingredients, 14-16 parts of thymol and 37.1-70.5 parts of pharmaceutical excipients.

[0006] Preferably, the mass ratio of febantel to pyrantel is 15-20:2-6.

[0007] Preferably, the mass ratio of febantel to pyrantel to thymol is 15-20:2-6:14-16.

[0008] Preferably, the coating material is prepared by the following steps: adding non-bantel, praziquantel, polyethylene glycol, emulsifier into ethyl acetate, stirring at 40-50℃ for 5-10min to obtain a pre-preparation; adding polyvinyl alcohol into deionized water, heating to 90-95℃ and stirring until completely dissolved, cooling to 70-80℃, adding amino-terminated polyamide and stirring until uniform, adding the pre-preparation dropwise under stirring, cooling to room temperature after dropwise addition, standing for 2-4h, filtering, washing with deionized water, freezing at -11~-20℃ for 1-2h, restoring to room temperature for 10-20min, freezing again at -5~-15℃ for 10-20min, and freeze-drying.

[0009] Preferably, the mass ratio of non-bantel, praziquantel, polyethylene glycol, emulsifier, polyvinyl alcohol, and amino-terminated polyamide is 15-20:2-6:1-3:1-2:5-10:0.5-1.

[0010] Preferably, the molecular weight of polyethylene glycol is 600-800.

[0011] Preferably, the emulsifier is poloxamer 188 or / and Tween-80.

[0012] Preferably, the pharmaceutical excipients include: fillers, internal disintegrants, internal glidants, disintegration promoters, binders, lubricants, external disintegrants, external glidants, colorants, and flavoring agents; the mass ratio of fillers, internal disintegrants, internal glidants, disintegration promoters, binders, lubricants, external disintegrants, external glidants, colorants, and flavoring agents is 30-40:1-5:1-2:1-4:1-5:0.5-1.5:1-3:0.5-1:0.1-1:1-8.

[0013] Preferably, the fillers include: lactose, microcrystalline cellulose; the mass ratio of lactose and microcrystalline cellulose is 15-20:18-20.

[0014] Preferably, the internal disintegrants and external disintegrants are both sodium carboxymethyl starch.

[0015] Preferably, the internal glidants and external glidants are talc or / and colloidal silicon dioxide.

[0016] Preferably, the disintegration promoters include: sodium bicarbonate, citric acid; the mass ratio of sodium bicarbonate and citric acid is 1-2:1-2.

[0017] Preferably, the binder is a polyvinylpyrrolidone aqueous solution with a mass fraction of 8-12%.

[0018] Preferably, the lubricant is magnesium stearate.

[0019] Preferably, the flavoring agent is dog powder.

[0020] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: mixing the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, internal disintegrant, internal flow aid, disintegrant, binder and lubricant, granulating, drying and sieving, adding external disintegrant, external flow aid, colorant and flavoring agent and mixing evenly, and then compressing into tablets.

[0021] Preferably, during the tableting process, the pre-pressure is 3-5 kN and the main pressure is 10-15 kN. Beneficial effects

[0022] This invention uses a compound of non-bantel and praziquantel as the core material, and the surface is coated and cured. This not only enhances the stability of non-bantel and praziquantel, but also facilitates the release of non-bantel and praziquantel due to the diffusion of ethyl acetate in the system to form a large number of through pores. The combination of polyvinyl alcohol and amino-terminated polyamide amine can significantly enhance the stability of the coating material. While ensuring hardness, the tablet has high porosity, which significantly improves the disintegration rate and dissolution rate.

[0023] This invention utilizes a coating material containing nonbantel and praziquantel as active ingredients, combined with pyrantel pamoate for granulation, and rationally controls the ingredient ratio. This not only greatly increases the contact area between the drug and gastrointestinal fluid, but also, with the addition of lactose and microcrystalline cellulose as fillers, exhibits excellent hydrophilicity and high disintegration efficiency. At the same time, it avoids sudden rises and falls in blood drug concentration, reducing liver and kidney toxicity caused by the accumulation of high-concentration drugs, and has significant preventive and therapeutic effects against parasites.

[0024] This invention enables tablets to disintegrate rapidly even in a high-hardness state, with stable dissolution, which facilitates drug release and effectively reduces drug toxicity and side effects. It overcomes the shortcomings of existing non-bantel formulations, while also providing a pleasant taste, increasing compliance in dogs and cats, and improving oral bioavailability. The process is simple, with a short production cycle, significantly improving production efficiency and reducing production costs, making it suitable for industrial-scale production. Attached Figure Description

[0025] Figure 1 This is a comparison chart of the hardness and porosity of the compound nonbantel tablets obtained in Example 5 and Comparative Examples 1-3.

[0026] Figure 2 This is a comparison chart of the disintegration time of the compound nonbantal tablets obtained in Example 5 and Comparative Examples 1-3.

[0027] Figure 3 The cumulative release curves are for the compound nonbantal tablets obtained in Example 5 and Comparative Examples 1-3.

[0028] Figure 4 This is a comparison chart showing the reduction rate of worm eggs and the worm egg negative conversion rate after treating pet dogs naturally infected with worms with the compound nonbantal tablets obtained in Example 5 and Comparative Examples 1-3. Detailed Implementation

[0029] The present invention will be further explained below with reference to specific embodiments.

[0030] The colloidal silica used below was purchased from Xi'an Mouxiang Pharmaceutical Excipients Co., Ltd.

[0031] The dog powder used below is a pet food flavor enhancer, purchased from Aisibifu (Chuzhou) Pet Food Co., Ltd. Example

[0032] A compound nonbantal tablet, the raw materials of which include: 24.5g of coating material with nonbantal and praziquantel as active ingredients, 14g of pyrantel dihydroxynaphthyl thiamethoxam, and 37.1g of pharmaceutical excipients.

[0033] The coating material is prepared using the following steps: 15g of nonbantal, 2g of praziquantel, 1g of polyethylene glycol 600, and 1g of Tween-80 are added to 100g of ethyl acetate and stirred at 40℃ for 5min at a stirring speed of 1000r / min to obtain a pre-formulated material; 5g of polyvinyl alcohol is added to 300g of water, heated to 90℃ and stirred until completely dissolved, then cooled to 70℃, and 0.5g of terminal amino-terminated polyamide amine is added and stirred evenly. The pre-formulated material is then added dropwise while stirring at a stirring speed of 500r / min. After complete addition, the mixture is cooled to room temperature and allowed to stand for 2h, filtered, washed with deionized water, frozen at -11℃ for 1h, restored to room temperature and kept warm for 10min, then frozen again at -5℃ for 10min, and finally freeze-dried.

[0034] The pharmaceutical excipients include: 30g of filler, 2g of sodium carboxymethyl starch, 1.5g of colloidal silica, 1g of disintegrant, 1g of 8% polyvinylpyrrolidone aqueous solution, 0.5g of magnesium stearate, 0.1g of colorant, and 1g of dog powder.

[0035] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 5:6. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1:1.

[0036] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, 1g sodium carboxymethyl starch, 1g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 100r / min for 4min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 1g of sodium carboxymethyl starch, 0.5g of colloidal silica, colorant, and dog powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 3kN, a main pressure of 10kN, and a tableting speed of 100,000 tablets / h. Example

[0037] A compound nonbantal tablet, the raw materials of which include: 42g of coating material with nonbantal and praziquantel as active ingredients, 16g of pyrantel dihydroxynaphthyl thiamethoxam, and 70.5g of pharmaceutical excipients.

[0038] The coating material is prepared using the following steps: 20g of nonbantal, 6g of praziquantel, 3g of polyethylene glycol 800, and 2g of Tween-80 are added to 150g of ethyl acetate and stirred at 50℃ for 10min at a stirring speed of 2000r / min to obtain a pre-formulated material; 10g of polyvinyl alcohol is added to 500g of water, heated to 95℃ and stirred until completely dissolved, then cooled to 80℃, and 1g of terminal amino polyamide amine is added and stirred evenly. The pre-formulated material is then added dropwise while stirring at a stirring speed of 1500r / min. After complete addition, the mixture is cooled to room temperature and allowed to stand for 4h, filtered, washed with deionized water, frozen at -20℃ for 2h, restored to room temperature and kept at that temperature for 20min, then frozen again at -15℃ for 20min, and finally freeze-dried.

[0039] The pharmaceutical excipients include: 40g of filler, 8g of sodium carboxymethyl starch, 3g of colloidal silica, 4g of disintegrant, 5g of 12% polyvinylpyrrolidone aqueous solution, 1.5g of magnesium stearate, 1g of colorant, and 8g of dog powder.

[0040] The filler consists of lactose and microcrystalline cellulose in a 1:1 mass ratio. The disintegrant consists of sodium bicarbonate and citric acid in a 2:1 mass ratio.

[0041] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, 5g sodium carboxymethyl starch, 2g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 200r / min for 10min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 3g sodium carboxymethyl starch, 1g colloidal silica, colorant and dog powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 5kN, a main pressure of 15kN and a tableting speed of 100,000 tablets / h. Example

[0042] A compound nonbantal tablet, the raw materials of which include: 34g of coating material with nonbantal and praziquantel as active ingredients, 14.5g of pyrantel dihydroxynaphthyl thiamethoxam, and 52.2g of pharmaceutical excipients.

[0043] The coating material was prepared using the following steps: 19g of nonbantal, 3g of praziquantel, 2.5g of polyethylene glycol 600, and 1.8g of poloxamer 188 were added to 110g of ethyl acetate and stirred at 48℃ for 7 minutes at a stirring speed of 1800r / min to obtain a pre-formulated material; 7g of polyvinyl alcohol was added to 450g of water, heated to 91℃ and stirred until completely dissolved, then cooled to 77℃, and 0.7g of terminal amino-terminated polyamide amine was added and stirred evenly. The pre-formulated material was then added dropwise while stirring at a stirring speed of 1200r / min. After complete addition, the mixture was cooled to room temperature and allowed to stand for 2.5h, filtered, washed with deionized water, frozen at -17℃ for 80min, restored to room temperature and held for 18min, then frozen again at -8℃ for 18min, and finally freeze-dried.

[0044] The pharmaceutical excipients include: 33g of filler, 3.5g of sodium carboxymethyl starch, 1.7g of colloidal silica, 2g of disintegrant, 4g of a 10% (w / w) aqueous solution of polyvinylpyrrolidone, 0.8g of magnesium stearate, 0.9g of colloidal silica, 0.3g of colorant, and 6g of dog powder.

[0045] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 17:19.5. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1.3:1.8.

[0046] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, 2g sodium carboxymethyl starch, colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 180r / min for 6min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 1.5g of sodium carboxymethyl starch, colloidal silica, colorant, and gluten powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 4.5kN, a main pressure of 11kN, and a tableting speed of 100,000 tablets / h. Example

[0047] A compound nonbantal tablet, the raw materials of which include: 34.6g of coating material with nonbantal and praziquantel as active ingredients, 15.5g of pyrantel dihydroxynaphthyl thiamethoxam, and 54.4g of pharmaceutical excipients.

[0048] The coating material was prepared using the following steps: 17g of nonbantal, 5g of praziquantel, 1.5g of polyethylene glycol 800, and 1.2g of poloxamer 188 were added to 130g of ethyl acetate and stirred at 42℃ for 9 minutes at a stirring speed of 1200r / min to obtain a pre-formulated material; 9g of polyvinyl alcohol was added to 350g of water, heated to 93℃ and stirred until completely dissolved, then cooled to 73℃, and 0.9g of terminal amino-terminated polyamide amine was added and stirred evenly. The pre-formulated material was then added dropwise while stirring at a stirring speed of 800r / min. After complete addition, the mixture was cooled to room temperature and allowed to stand for 3.5h, filtered, washed with deionized water, frozen at -13℃ for 100min, restored to room temperature and held for 12min, then frozen again at -12℃ for 12min, and finally freeze-dried.

[0049] The pharmaceutical excipients include: 37g of filler, 6.5g of sodium carboxymethyl starch, 2g of colloidal silica, 3g of disintegrant, 2g of 10% polyvinylpyrrolidone aqueous solution, 1.2g of magnesium stearate, 0.7g of colorant, and 2g of dog powder.

[0050] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 19:18.5. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1.7:1.2.

[0051] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, 4g sodium carboxymethyl starch, 1.3g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 120r / min for 8min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 2.5g sodium carboxymethyl starch, 0.7g colloidal silica, colorant and gluten powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 3.5kN, a main pressure of 13kN and a tableting speed of 100,000 tablets / h. Example

[0052] A compound nonbantal tablet, the raw materials of which include: 34.3g of coating material with nonbantal and praziquantel as active ingredients, 15g of pyrantel dihydroxynaphthyl thiamethoxam, and 53.3g of pharmaceutical excipients.

[0053] The coating material was prepared using the following steps: 18g of nonbantal, 4g of praziquantel, 2g of polyethylene glycol 600, and 1.5g of poloxamer 188 were added to 120g of ethyl acetate and stirred at 45℃ for 8 minutes at a stirring speed of 1500r / min to obtain a pre-formulated material; 8g of polyvinyl alcohol was added to 400g of water, heated to 92℃ and stirred until completely dissolved, then cooled to 75℃, and 0.8g of terminal amino-terminated polyamide amine was added and stirred evenly. The pre-formulated material was then added dropwise while stirring at a stirring speed of 1000r / min. After complete addition, the mixture was cooled to room temperature and allowed to stand for 3 hours, filtered, washed with deionized water, frozen at -15℃ for 90 minutes, restored to room temperature and held for 15 minutes, then frozen again at -10℃ for 15 minutes, and finally freeze-dried.

[0054] The pharmaceutical excipients include: 35g of filler, 5g of sodium carboxymethyl starch, 2.3g of colloidal silica, 2.5g of disintegrant, 3g of 10% polyvinylpyrrolidone aqueous solution, 1g of magnesium stearate, 0.5g of colorant, and 4g of dog powder.

[0055] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 18:19. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1:1.

[0056] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, 3g sodium carboxymethyl starch, 1.5g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 150r / min for 7min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 2g of sodium carboxymethyl starch, 0.8g of colloidal silica, colorant, and dog powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 4kN, a main pressure of 12kN, and a tableting speed of 100,000 tablets / h.

[0057] Comparative Example 1 A compound nonbantal tablet, the raw materials of which include: 49.3g of coating material with nonbantal, praziquantel and pyrantel dihydroxynaphthyl pyrantel as active ingredients, and 53.3g of pharmaceutical excipients.

[0058] The coating material was prepared using the following steps: 18g of nonbantel, 4g of praziquantel, 15g of pyrantel pamoate, 2g of polyethylene glycol 600, and 1.5g of poloxamer 188 were added to 120g of ethyl acetate and stirred at 45℃ for 8 minutes at a stirring speed of 1500r / min to obtain a pre-formulated material. 8g of polyvinyl alcohol was added to 400g of water, heated to 92℃ and stirred until completely dissolved. The mixture was then cooled to 75℃, and 0.8g of terminal amino-terminated polyamide amine was added and stirred until homogeneous. The pre-formulated material was then added dropwise while stirring at a stirring speed of 1000r / min. After complete addition, the mixture was cooled to room temperature and allowed to stand for 3 hours. It was then filtered, washed with deionized water, frozen at -15℃ for 90 minutes, restored to room temperature and held for 15 minutes, and then frozen again at -10℃ for 15 minutes. Finally, it was freeze-dried.

[0059] The pharmaceutical excipients include: 35g of filler, 5g of sodium carboxymethyl starch, 2.3g of colloidal silica, 2.5g of disintegrant, 3g of 10% polyvinylpyrrolidone aqueous solution, 1g of magnesium stearate, 0.5g of colorant, and 4g of dog powder.

[0060] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 18:19. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1:1.

[0061] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, filler, 3g sodium carboxymethyl starch, 1.5g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 150r / min for 7min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 2g of sodium carboxymethyl starch, 0.8g of colloidal silica, colorant, and dog powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 4kN, a main pressure of 12kN, and a tableting speed of 100,000 tablets / h.

[0062] Comparative Example 2 A compound nonbantel tablet, the raw materials of which include: 16.3g of coating material with praziquantel as active ingredient, 18g of nonbantel, 15g of pyrantel dihydroxynaphthyl thiamethoxam, and 53.3g of pharmaceutical excipients.

[0063] The coating material was prepared using the following steps: 4g praziquantel, 2g polyethylene glycol 600, and 1.5g poloxamer 188 were added to 120g ethyl acetate and stirred at 45℃ for 8 minutes at a stirring speed of 1500r / min to obtain a pre-formulated material; 8g polyvinyl alcohol was added to 400g water, heated to 92℃ and stirred until completely dissolved, then cooled to 75℃, and 0.8g terminal amino-terminated polyamide amine was added and stirred evenly. The pre-formulated material was then added dropwise while stirring at a stirring speed of 1000r / min. After complete addition, the mixture was cooled to room temperature and allowed to stand for 3 hours, filtered, washed with deionized water, frozen at -15℃ for 90 minutes, restored to room temperature and held for 15 minutes, then frozen again at -10℃ for 15 minutes, and finally freeze-dried.

[0064] The pharmaceutical excipients include: 35g of filler, 5g of sodium carboxymethyl starch, 2.3g of colloidal silica, 2.5g of disintegrant, 3g of 10% polyvinylpyrrolidone aqueous solution, 1g of magnesium stearate, 0.5g of colorant, and 4g of dog powder.

[0065] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 18:19. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1:1.

[0066] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, non-bantel, bis(hydroxynaphthyl)thiamethoxam, filler, 3g sodium carboxymethyl starch, 1.5g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 150r / min for 7min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 2g of sodium carboxymethyl starch, 0.8g of colloidal silica, colorant, and dog powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 4kN, a main pressure of 12kN, and a tableting speed of 100,000 tablets / h.

[0067] Comparative Example 3 A compound nonbantal tablet, the raw materials of which include: 34.3g of coating material with nonbantal and praziquantel as active ingredients, 15g of pyrantel dihydroxynaphthyl thiamethoxam, and 53.3g of pharmaceutical excipients.

[0068] The coating material was prepared using the following steps: 18g of nonbantal, 4g of praziquantel, 2g of polyethylene glycol 600, and 1.5g of poloxamer 188 were added to 120g of ethyl acetate and stirred at 45℃ for 8 minutes at a stirring speed of 1500r / min to obtain a pre-formulated material; 8.8g of polyvinyl alcohol was added to 400g of water, heated to 92℃ and stirred until completely dissolved, then cooled to 75℃, and the pre-formulated material was added dropwise while stirring at a stirring speed of 1000r / min. After complete addition, the mixture was cooled to room temperature and allowed to stand for 3 hours, filtered, washed with deionized water, frozen at -15℃ for 90 minutes, restored to room temperature and held for 15 minutes, then frozen again at -10℃ for 15 minutes, and finally freeze-dried.

[0069] The pharmaceutical excipients include: 35g of filler, 5g of sodium carboxymethyl starch, 2.3g of colloidal silica, 2.5g of disintegrant, 3g of 10% polyvinylpyrrolidone aqueous solution, 1g of magnesium stearate, 0.5g of colorant, and 4g of dog powder.

[0070] The filler consists of lactose and microcrystalline cellulose in a mass ratio of 18:19. The disintegrant consists of sodium bicarbonate and citric acid in a mass ratio of 1:1.

[0071] The preparation method of the above-mentioned compound nonbantel tablets includes the following steps: S1. Mix the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, 3g sodium carboxymethyl starch, 1.5g colloidal silica, disintegrating agent, polyvinylpyrrolidone aqueous solution, and magnesium stearate. Stir at 150r / min for 7min, granulate, and discharge to obtain the billet. S2. Dry the raw material, put it into a granulator and clean it through a 1.2mm sieve. Add 2g of sodium carboxymethyl starch, 0.8g of colloidal silica, colorant, and dog powder and mix evenly. Compress the mixture into tablets using a tablet press with a pre-pressure of 4kN, a main pressure of 12kN, and a tableting speed of 100,000 tablets / h.

[0072] The hardness and porosity of the compound nonbantal tablets obtained in Example 5 and Comparative Examples 1-3 were determined and calculated in accordance with the Chinese Pharmacopoeia (2020 edition).

[0073] Porosity ( Porosity Calculated using the following formula: Porosity = (v -∑ w / ρ) / v .

[0074] In the formula, v Indicates the volume of the tablet; w Indicates the weight of the tablet components; ρ This indicates the proportion of the components that make up the tablet.

[0075] like Figure 1As shown, the hardness and porosity of the compound non-bantel tablets obtained in Example 5, Comparative Example 1, and Comparative Example 2 were higher than those in Comparative Example 3 (P < 0.05), but there was no significant difference between them (P > 0.05).

[0076] The disintegration time of the compound nonbantal tablets obtained in Example 5 and Comparative Examples 1-3 was examined according to Appendix of the Chinese Veterinary Pharmacopoeia (2010 Edition, Part I). Figure 2 As shown, the disintegration time of the compound nonbantal tablets obtained in Example 5, Comparative Example 1, and Comparative Example 2 was lower than that of Comparative Example 3 (P < 0.05), but there was no significant difference among them (P > 0.05).

[0077] The release rates of the compound nonbantal tablets obtained in Example 5 and Comparative Examples 1-3 were determined according to Appendix of the Chinese Veterinary Pharmacopoeia (2010 Edition, Part I). Each group of sample tablets was placed in a dissolution vessel, rotated, and the time was recorded. Samples were taken at specific times, and an isothermal and equal-volume dissolution medium was immediately added. The filtrate was filtered through a 0.2 μm microporous membrane, dissolved in chloroform, and diluted to the mark. The content was determined by high-performance liquid chromatography, and the cumulative release rate was calculated.

[0078] like Figure 3 As shown, the release rate of the compound non-bantel tablets obtained in Comparative Example 3 was too slow, while the release rate of the compound non-bantel tablets obtained in Comparative Example 2 was too fast. The release rates of the compound non-bantel tablets obtained in Example 5 and Comparative Example 1 were moderate and superior to those of Comparative Example 2 and Comparative Example 3 (P < 0.05); while there was no significant difference between Example 5 and Comparative Example 1 (P > 0.05).

[0079] Naturally infected dogs (clinically manifested as the excretion of worm eggs or segments in their feces) were used as experimental subjects and randomly divided into 4 groups of 12 dogs each. The dogs were treated with the compound febantal tablets obtained in Example 5 and Comparative Examples 1-3, respectively.

[0080] Each group of fecal samples was first examined for the presence of worm eggs using the saturated saline flotation method. If worm eggs were found, the species were identified. Then, the EPG (egg count per gram of feces) of each type of worm was calculated for each dog using the McMaster method and recorded.

[0081] The dosage was 7.5 mg / kg body weight (calculated as nonbantal) on day 0. Administered once daily, followed by observation. The observation period was 14 days. After starting administration, dogs were observed once daily for any toxic side effects. Observations were made on the dogs' body temperature, respiration, heart rate, visible mucous membrane color, water intake, food intake, urine output, mental state, appetite, activity level, and worm excretion before and after administration. Excreted worms or segments were collected and identified.

[0082] On day 5 after administration, fresh feces were collected from the dogs. The EPG of each worm in each dog was calculated and recorded using the McMaster method. The egg reduction rate and egg negative conversion rate were calculated (taking hookworm and Toxocara as examples).

[0083] No drug-related adverse reactions were observed in any of the groups of dogs. Figure 4 As shown, when dogs were treated with the compound nonbantal tablets obtained in Example 5, the reduction rate of parasite eggs and the negative conversion rate of parasite eggs were the highest on the 5th day, which was better than the other groups (P<0.05).

[0084] The reason for the above results is that this invention uses a combination of nonbantel and praziquantel as the core material, and the surface is coated and cured. This not only enhances the stability of nonbantel and praziquantel, but also, due to the diffusion of ethyl acetate in the system, forms a large number of pores, which is conducive to the release of nonbantel and praziquantel. At the same time, the combination of polyvinyl alcohol and amino-terminated polyamide amine can significantly enhance the stability of the coating material. While ensuring hardness, the tablet has high porosity, which significantly improves the disintegration rate and dissolution rate. This invention utilizes a coating material with nonbantel and praziquantel as active ingredients, combined with bis(hydroxynaphthyl)thiamethoxam for granulation, and rationally controls the component ratio. This not only greatly increases the contact area between the drug and gastrointestinal fluid, but also, with the help of lactose and microcrystalline cellulose as fillers, it has excellent hydrophilic properties and high disintegration effect. At the same time, it can avoid sudden rises and falls in blood drug concentration, reduce hepatotoxicity and nephrotoxicity caused by the accumulation of high concentrations of drugs, and has obvious preventive and therapeutic effects on parasites.

[0085] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A compound non-bantel tablet, characterized in that, Its dosage form is tablets; The raw materials, by weight, include: 24.5-42 parts of coating material with nonbantel and praziquantel as active ingredients, 14-16 parts of pyrantel dihydroxynaphthyl thiamethoxam, and 37.1-70.5 parts of pharmaceutical excipients.

2. The compound nonbantel tablets according to claim 1, characterized in that, The mass ratio of nonbantalil to praziquantel is 15-20:2-6; the mass ratio of nonbantalil, praziquantel, and dihydroxynaphthylpyridinium pyrantel is 15-20:2-6:14-16.

3. The compound nonbantel tablets according to claim 1, characterized in that, The coating material is prepared using the following steps: Add non-bantel, praziquantel, polyethylene glycol, and emulsifier to ethyl acetate and stir at 40-50℃ for 5-10 minutes to obtain a pre-prepared material; add polyvinyl alcohol to deionized water, heat to 90-95℃ and stir until completely dissolved, cool to 70-80℃, add terminal amino-terminated polyamide amine and stir until homogeneous, then add the pre-prepared material dropwise while stirring. After complete addition, allow to stand at room temperature for 2-4 hours, filter, wash with deionized water, freeze at -11~-20℃ for 1-2 hours, restore to room temperature and hold for 10-20 minutes, freeze again at -5~-15℃ for 10-20 minutes, and freeze-dry.

4. The compound non-bantel tablets according to claim 3, characterized in that, The mass ratio of non-bantel, praziquantel, polyethylene glycol, emulsifier, polyvinyl alcohol, and amino-terminated polyamide amine is 15-20:2-6:1-3:1-2:5-10:0.5-1.

5. The compound nonbantel tablets according to claim 3, characterized in that, The molecular weight of polyethylene glycol is 600-800; The emulsifier is poloxamer 188 or / and Tween-80.

6. The compound nonbantel tablets according to claim 1, characterized in that, Pharmaceutical excipients include: The ingredients include fillers, internal disintegrants, internal flow aids, disintegrating agents, adhesives, lubricants, external disintegrants, external flow aids, colorants, and flavoring agents. The mass ratio of fillers, internal disintegrants, internal flow aids, disintegrating agents, adhesives, lubricants, external disintegrants, external flow aids, colorants, and flavoring agents is 30-40:1-5:1-2:1-4:1-5:0.5-1.5:1-3:0.5-1:0.1-1:1-8.

7. The compound nonbantel tablets according to claim 6, characterized in that, The filler includes: Lactose, microcrystalline cellulose; The mass ratio of lactose to microcrystalline cellulose is 15-20:18-20.

8. The compound non-bantel tablets according to claim 6, characterized in that, Both the internal and external disintegrants are sodium carboxymethyl starch; The internal and external flow aids are talc and / or colloidal silica; The disintegrating agents include sodium bicarbonate and citric acid, with a mass ratio of sodium bicarbonate to citric acid of 1-2:1-2.

9. The compound nonbantel tablets according to claim 6, characterized in that, The adhesive is an aqueous solution of polyvinylpyrrolidone with a mass fraction of 8-12%; The lubricant is magnesium stearate; the flavoring agent is dog powder.

10. A method for preparing compound nonbantel tablets as described in any one of claims 6-9, characterized in that, The process includes the following steps: mixing the coating material, bis(hydroxynaphthyl)thiamethoxam, filler, internal disintegrant, internal flow aid, disintegrant, binder, and lubricant; granulating; drying and sieving; adding external disintegrant, external flow aid, colorant, and flavoring agent; mixing evenly; and then tableting.

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