Veterinary levamisole praziquantel hydrochloride chewable tablet and preparation method thereof

Abstract

The invention provides a veterinary levamisole hydrochloride praziquantel chewable tablet and a preparation method thereof, and relates to the technical field of veterinary pharmaceutical compositions, the veterinary levamisole hydrochloride praziquantel chewable tablet comprises the following components by weight: 1-30 parts of levamisole hydrochloride, 1-30 parts of praziquantel, 5-60 parts of an adsorbent, 10-60 parts of a filler, 0.5-20 parts of an adhesive, 1-30 parts of a flavoring agent, and 0.5-20 parts of a lubricant; the coating further comprises a certain amount of coloring agent, antioxidant and water.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary pharmaceutical compositions, and in particular to veterinary levamisole praziquantel hydrochloride chewable tablets and a preparation method thereof. Background Art

[0002] Dogs and cats are good friends of humans, and people have an increasing demand for their breeding. Dogs and cats are also very susceptible to parasites, such as gastrointestinal nematodes, lung nematodes, tapeworms, schistosomiasis, cysticercosis, etc. There are many opportunities for direct or indirect contact between humans and dogs and cats, and they are very susceptible to some zoonotic diseases, such as echinococcosis, which is a zoonosis. Dogs are the final hosts of echinococcosis, and humans are very susceptible to echinococcosis due to direct or indirect contact with dogs infected with echinococcosis. Other canines and felines, including wild animals, such as foxes, wolves, and manuls, may also be infected with zoonotic parasites, and directly or indirectly transmit them to humans, so their prevention and treatment is also very important. Therefore, a compound chewable tablet that is effective or synergistic against major parasites such as nematodes, tapeworms, and flukes, stable, has taste-masking and food-inducing functions, improves drug compliance, and is particularly suitable for canines, cats, and drug-refusing animals to eat is developed.

[0003] In the prior art, praziquantel is a broad-spectrum anti-trematode and tapeworm drug, which has a rapid and obvious damaging effect on the cortex of the worm body, and can also cause tonic contraction of the worm body muscles to produce spastic paralysis. Levamisole hydrochloride is also a broad-spectrum anthelmintic, which has a good effect on roundworms, hookworms, pinworms and strongyloides, but both praziquantel and levamisole hydrochloride have a certain bitterness and odor, making it difficult for canines, cats and other animals to actively eat and chew completely, thereby affecting the absorption of the drug. In addition, when preparing veterinary anthelmintics, most of them are in the form of tablets, which are more convenient to use. However, if the preparation method is not good, the stability of its active ingredients may be greatly reduced over time, which is not conducive to the efficacy of the drug. Summary of the invention

[0004] The object of the present invention is to provide a veterinary levamisole praziquantel hydrochloride chewable tablet and a preparation method thereof, so as to realize the preparation of a composite chewable tablet containing levamisole praziquantel hydrochloride. The prepared chewable tablet has good taste and strong palatability, can be fully chewed by animals, ensures that the drug is fully absorbed, has high bioavailability, and at the same time, the efficacy of the chewable tablet drug is not greatly affected by the passage of time, thereby ensuring the anthelmintic effect.

[0005] The present invention is achieved by the following technical scheme: 1-30 parts of levamisole hydrochloride, 1-30 parts of praziquantel, 5-60 parts of adsorbent, 10-60 parts of filler, 0.5-20 parts of adhesive, 1-30 parts of flavoring agent, and 0.5-20 parts of lubricant;

[0006] Also included are certain amounts of colorants, antioxidants and water.

[0007] In order to better realize the present invention, further, the adsorbent is selected from one or a combination of corn cob, β-cyclodextrin, silica, and sulfonic acid calixarene.

[0008] In order to better realize the present invention, further, the filler is selected from one or a combination of milk powder, cross-linked polyvinylpyrrolidone, polysorbate 80, microcrystalline cellulose, lactose, mannitol, sucrose, fructose, dextrin, flavor, sodium hydroxymethyl starch, chicken liver powder, chicken extract, and beef extract.

[0009] In addition, sulfonic acid calixarene, corn starch, sweeteners, pregelatinized starch, PVP, β-glucan, and silicon dioxide can also be used as fillers.

[0010] In order to better realize the present invention, further, the adhesive is one or a combination of pregelatinized starch, silica gel, hydroxypropyl methylcellulose, povidone, PVP (polyvinyl pyrrolidone) K30, corn starch, and dextrin.

[0011] In order to better realize the present invention, further, the lubricant is selected from magnesium stearate or talc.

[0012] In order to better realize the present invention, further, the flavoring agent is selected from one or a combination of chicken flavor, beef flavor, fish flavor, chicken liver powder, chicken liver flavor, chicken extract, beef extract, milk powder, cream or milk flavor, yeast powder, mannitol, and sucralose sweetener.

[0013] In order to better realize the present invention, further, the colorant is selected from one or a combination of caramel color, red iron oxide, yellow iron oxide, lemon yellow, carmine, sunset red or sunset yellow.

[0014] In order to better realize the present invention, further, it also includes a coating film-forming agent, and the coating film-forming agent is selected from one or a combination of polyethylene glycol 200-6000, PVP, pregelatinized starch, silica gel, and hydroxypropyl methylcellulose.

[0015] In order to better realize the present invention, further, it also includes a coating liquid, which is one or a combination of coating powders such as hydroxypropyl methylcellulose, β-glucan, and polyethylene glycol.

[0016] In order to better realize the present invention, further, the antioxidant is selected from one or a combination of HBA (butylated hydroxyanisole), EDTA-2Na (disodium ethylenediaminetetraacetate), BHT (2,6-di-tert-butyl-4-methylphenol), TBHQ (tert-butylhydroquinone), and vitamin C.

[0017] A method for preparing veterinary levamisole praziquantel hydrochloride chewable tablets comprises the following preparation steps:

[0018] S1 main drug mixture

[0019] Adding levamisole hydrochloride, praziquantel and part of the adsorbent or filler into a mixer in equal amounts to obtain a first mixed powder;

[0020] S2 Ultrafine Grinding

[0021] The first mixed powder is ultrafinely crushed by a jet mill to a D90 of ≤15 μm, thereby increasing the specific surface area and improving the solubility, and the dissolution T50 is ≤10 minutes to obtain a second mixed powder;

[0022] S3 adsorption inclusion

[0023] Add the remaining adsorbent to the second mixed powder, mix for 30 minutes, and after sufficient adsorption and inclusion, check that the adsorption and inclusion effect is satisfactory, to obtain a third mixed powder;

[0024] S4 Remix

[0025] Add the remaining filler, flavoring agent and lubricant to the third mixed powder, mix them evenly, and test the uniformity to obtain a fourth mixed powder;

[0026] S5 soft material

[0027] Add the binder into purified water and soak until transparent, then add part of the flavoring agent and stir evenly, add it into the fourth mixed powder in a linear state, and stir evenly to obtain a soft material;

[0028] S6 Granulation

[0029] The soft material is granulated through a 12-20 mesh sieve, and the moisture content of the granules is controlled to be ≤5.0%;

[0030] S7 Dry

[0031] Put the prepared wet granules into an oven for drying at a temperature of 50-60°C for 20-60 minutes, and control the granule moisture content to ≤3.0%;

[0032] S8 whole grain

[0033] The dried granules are screened through a 12-20 mesh sieve to obtain whole granules;

[0034] S9 Mixed

[0035] Add the obtained whole granules, lubricant, remaining flavoring agent, colorant, and antioxidant into a mixer at a speed of 8-20 rpm, mix for 10-30 minutes, and check the uniformity;

[0036] S10 tableting

[0037] Use a rotary tablet press with a punch diameter of 8-15mm and concave punching. The tablets pressed out have a smooth surface, the tablet weight difference is controlled to be ±5%, the hardness is moderate, the hardness is 40-80N, the disintegration time meets the requirements, the tablet surface is intact when shaken, and the friability is ≤0.9%, which meets the coating conditions, and the tablet core is obtained;

[0038] S11 coating

[0039] Put the tablet core into the coating machine, spray the coating liquid evenly on the surface of the tablet core to form a coating layer, until the coating layer weight increases to 2-8% of the tablet core weight, the inlet air temperature is 40-60°C, the tablet bed temperature is 30-60°C, cool and dry, and you have it.

[0040] The coating solution is prepared by adding coating powders such as hydroxypropyl methylcellulose, β-glucan, polyethylene glycol, a small amount of flavoring agent, etc. into pure water, and continuously stirring until uniform to obtain the coating solution.

[0041] The beneficial effects of the present invention are:

[0042] The present invention cooperates with each other by setting levamisole hydrochloride and praziquantel to work synergistically, wherein praziquantel interferes with the calcium ion channel of the worm, causes muscle spasm and cortical damage of the worm, causes vacuoles to form on the surface of the worm and lyses, and is finally cleared by the host immune system. It has a strong expelling and killing effect on schistosomiasis, tapeworms and trematodes (such as lung flukes, Clonorchis sinensis), and cysticercosis. Praziquantel directly kills the worm, and the residual worm antigens may induce an inflammatory response in the host. Levamisole hydrochloride is not only a broad-spectrum anthelmintic (such as roundworms and hookworms), but also can enhance the host immune response by enhancing T cell activity and activating macrophage function. The synergistic combination of levamisole hydrochloride and praziquantel can achieve the effect of directly killing the worm and enhancing the immune response of animals, and is particularly suitable for hosts with mixed infections or immunosuppression.

[0043] The invention adds adsorbents, fillers, adhesives, flavoring agents and the like to drug components, performs ultrafine grinding, absorption, inclusion and flavoring through airflow, and adopts step-by-step mixing, moisture control and temperature control in the preparation process, so as to prepare a drug that can improve the taste of chewable tablets, shield bitterness and peculiar smell, and has uniform and stable ingredients, moderate hardness and good palatability. For canines, cats and other animals, the feeding rate of the animals can be increased, so that the animals can fully chew the drugs, thereby ensuring the purpose of the animals absorbing the drug efficacy.

[0044] The present invention adopts a step-by-step mixing method in the preparation process, specifically, levamisole hydrochloride, praziquantel and a small amount of adsorbent or filler are premixed in an equal amount, and then mixed with other auxiliary materials in an equal amount after being ultrafinely ground by air flow. Such an operation method is conducive to controlling the density difference and making the drug components uniform and stable. DETAILED DESCRIPTION

[0045] The technical solution of the present invention will be described below in conjunction with examples of the present invention.

[0046] Example 1:

[0047] The components of veterinary levamisole hydrochloride and praziquantel chewable tablets are as follows: levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents selected from β-cyclodextrin 5%, silicon dioxide 10% and corn cob 5%; fillers selected from corn starch 15.48%, microcrystalline cellulose 16%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 10%; binder selected from PVPK30 10%; flavoring agents selected from beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5%; lubricant selected from magnesium stearate 1.5%; colorant selected from red iron oxide 0.5%; antioxidant selected from BHT 0.02%; appropriate amount of water.

[0048] Preparation method of veterinary levamisole hydrochloride praziquantel chewable tablets

[0049] S1 main drug mixture

[0050] Add levamisole hydrochloride, praziquantel, adsorbent, filler, adhesive, flavoring agent, and lubricant into a mixer in equal amounts, and mix for 8-30 minutes at a speed of 20 rpm to obtain a first mixed powder;

[0051] S2 Ultrafine Grinding

[0052] The first mixed powder is ultrafinely crushed by a jet mill to a D90 of ≤15 μm, thereby increasing the specific surface area and improving the dissolution rate (dissolution T50 ≤10 minutes) to obtain a second mixed powder;

[0053] S3 adsorption inclusion

[0054] Add the remaining adsorbent to the second mixed powder, mix for 10-30 minutes, fully adsorb and include, and after checking that the adsorption and inclusion effect is qualified, add sulfonic acid calixarene for inclusion to obtain a third mixed powder;

[0055] S4 Remix

[0056] Add the remaining filler, flavoring agent and lubricant to the third mixed powder, mix them evenly, and detect praziquantel ±7% and levamisole hydrochloride ±5% by HPLC (dual wavelength detection). If the uniformity is qualified, a fourth mixed powder is obtained;

[0057] S5 soft material coating

[0058] Add the binder to purified water and soak until transparent, then add the flavoring agent and stir evenly, add it to the fourth mixed powder in a linear state, and stir evenly to obtain a soft material;

[0059] S6 Granulation

[0060] The soft material is granulated through a 12-20 mesh sieve, and the moisture content of the granules is controlled to be ≤5.0%;

[0061] S7 Dry

[0062] Put the prepared wet granules into an oven for drying at a temperature of 50-60°C for 20-60 minutes, and control the granule moisture content to ≤3.0%;

[0063] S8 whole grain

[0064] The dried granules are screened through a 12-20 mesh sieve to obtain whole granules;

[0065] S9 Mixed

[0066] Add the obtained whole granules, lubricant, remaining flavoring agent, colorant, and antioxidant into a mixer at a speed of 8-20 rpm, mix for 10-30 minutes, and check the uniformity;

[0067] S10 tableting

[0068] Use a rotary tablet press with a punch diameter of 8-15mm and a shallow concave punch. The tablets pressed out have a smooth surface, the tablet weight difference is controlled to be ±5%, the hardness is moderate, the hardness is 40-80N, the disintegration time meets the requirements, the tablet surface is intact when shaken, and the friability is ≤0.9%, which meets the coating conditions, and the tablet core is obtained;

[0069] S11 coating

[0070] Put the tablet core into the coating machine, spray the coating liquid evenly on the surface of the tablet core to form a coating layer, until the coating layer weight increases to 2-8% of the tablet core weight, the inlet air temperature is 40-60°C, the tablet bed temperature is 30-60°C, cool and dry, and you have it.

[0071] The coating liquid is prepared by adding coating powder hydroxypropyl methylcellulose, β-glucan, polyethylene glycol and a small amount of flavoring agent into pure water and continuously stirring until uniform.

[0072] Preparation method is the same as Example 1

[0073] Example 2:

[0074] Levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 20.48%, microcrystalline cellulose 16%, polysorbate 80 0.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 10%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5%; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0075] Preparation method is the same as Example 1

[0076] Example 3:

[0077] Levamisole hydrochloride 2.5%; praziquantel 10%; silicon dioxide 15% is selected as the adsorbent; corn starch 18.48%, microcrystalline cellulose 10%, polysorbate 80 0.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6% are selected as the filler; PVP K30 10% is selected as the binder; beef flavor 7.5%, sucralose 1.5%, chicken liver powder 7.5% is selected as the flavoring agent; magnesium stearate 1.5% is selected as the lubricant; red iron oxide 0.5% is selected as the colorant; BHT 0.02% is selected as the antioxidant; water is appropriate.

[0078] Preparation method is the same as Example 1

[0079] Example 4:

[0080] Levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 15.48%, microcrystalline cellulose 20%, polysorbate 800.5%, cross-linked polyvinylpyrrolidone 15%; binder includes PVP K30 15%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver flavor 1.5%; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0081] Preparation method is the same as Example 1

[0082] Example 5:

[0083] Levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 15.48%, microcrystalline cellulose 16%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 10%; binder includes PVP K30 15%; flavoring agents include beef extract 1.5%, sucralose 1.5%, chicken extract 1.5%; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0084] Preparation method is the same as Example 1

[0085] Example 6:

[0086] Levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 15.48%, microcrystalline cellulose 14.5%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 10%; binder includes PVP K30 15%; flavoring agents include mannitol 1%, fish flavor 1%, beef powder 1%, sucralose 1.5%, chicken extract 1.5%; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0087] Preparation method is the same as Example 1

[0088] Example 7:

[0089] Levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 15.48%, microcrystalline cellulose 20%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 4.5%; binder includes PVP K30 15%; flavoring agents include mannitol 1%, fish flavor 1%, beef powder 1%, sucralose 1.5%, chicken extract 1.5%; lubricant includes magnesium stearate 1.5%; colorant includes yellow iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0090] Preparation method is the same as Example 1

[0091] Example 8:

[0092] Levamisole hydrochloride 2.5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 15.48%, microcrystalline cellulose 20%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 4.5%; binder includes PVP K30 15%; flavoring agents include mannitol 1%, fish flavor 1%, beef powder 1%, sucralose 1.5%, chicken extract 1.5%; lubricant includes magnesium stearate 1.5%; colorant includes sunset red 0.5%; antioxidant includes TBHQ 0.02%; water in appropriate amount.

[0093] Preparation method is the same as Example 1

[0094] Example 9:

[0095] Levamisole hydrochloride 1%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 23.48%, microcrystalline cellulose 18.5%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5; lubricant includes magnesium stearate 1.5%; colorant includes sunset red 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0096] Preparation method is the same as Example 1

[0097] Example 10:

[0098] Levamisole hydrochloride 10%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 14.48%, microcrystalline cellulose 18.5%, polysorbate 800.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0099] Preparation method is the same as Example 1

[0100] Example 11:

[0101] Levamisole hydrochloride 5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 20.48%, microcrystalline cellulose 16.5%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water in appropriate amount.

[0102] Preparation method is the same as Example 1

[0103] Example 12:

[0104] Levamisole Hydrochloride 5%; Praziquantel 10%; The adsorbent is selected from β-cyclodextrin 5% and silicon dioxide 10%; The filler is selected from corn starch 20.48%, microcrystalline cellulose 16.5%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6%; The binder is selected from PVP K30 10%; The flavoring agent is selected from beef essence 1.5%, sucralose 1.5%, chicken liver powder 1.5; The lubricant is selected from magnesium stearate 1.5%; The coloring agent is selected from red iron oxide 0.5%; The antioxidant is selected from BHT 0.02%; Appropriate amount of water.

[0105] The preparation method is the same as that of Example 1

[0106] Example 13:

[0107] Levamisole Hydrochloride 5%; Praziquantel 10%; The adsorbent is selected from β-cyclodextrin 5% and silicon dioxide 10%; The filler is selected from corn starch 20.48%, microcrystalline cellulose 16.5%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6%; The binder is selected from PVP K30 10%; The flavoring agent is selected from beef essence 1.5%, sucralose 1.5%, chicken liver powder 1.5; The lubricant is selected from magnesium stearate 1.5%; The coloring agent is selected from red iron oxide 0.5%; The antioxidant is selected from BHT 0.02%; Appropriate amount of water.

[0108] The preparation method is the same as that of Example 1

[0109] Example 14:

[0110] Levamisole Hydrochloride 5%; Praziquantel 10%; The adsorbent is selected from β-cyclodextrin 5% and silicon dioxide 10%; The filler is selected from corn starch 20.48%, microcrystalline cellulose 16.5%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 6%; The binder is selected from PVP K30 10%; The flavoring agent is selected from beef essence 1.5%, sucralose 1.5%, chicken liver powder 1.5; The lubricant is selected from magnesium stearate 1.5%; The coloring agent is selected from red iron oxide 0.5%; The antioxidant is selected from BHT 0.02%; Appropriate amount of water.

[0111] The preparation method is the same as that of Example 1

[0112] Example 15:

[0113] Levamisole hydrochloride 5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 20.48%, microcrystalline cellulose 15%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 7.5%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water is appropriate.

[0114] Preparation method is the same as Example 1

[0115] Example 16:

[0116] Levamisole hydrochloride 5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 20.48%, microcrystalline cellulose 15%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 7.5%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water is appropriate.

[0117] Preparation method is the same as Example 1

[0118] Example 17:

[0119] Levamisole hydrochloride 5%; praziquantel 10%; adsorbents include β-cyclodextrin 5% and silicon dioxide 10%; fillers include corn starch 20.48%, microcrystalline cellulose 15%, polysorbate 80 1.5%, sulfonic acid calixarene 5%, cross-linked polyvinylpyrrolidone 7.5%; binder includes PVP K30 10%; flavoring agents include beef flavor 1.5%, sucralose 1.5%, chicken liver powder 1.5; lubricant includes magnesium stearate 1.5%; colorant includes red iron oxide 0.5%; antioxidant includes BHT 0.02%; water is appropriate.

[0120] Preparation method is the same as Example 1

[0121] Examples

[0122] 1. High temperature test: The chewable tablets obtained in Examples 1-17 were placed in a stability test chamber at 60°C for 5 and 10 days before sampling and testing. The results are as follows:

[0123] Example 1-5 High temperature test results:

[0124]

[0125]

[0126] High-temperature test results of Examples 6 - 10

[0127]

[0128] High-temperature test results of Examples 11 - 14

[0129]

[0130]

[0131] High-temperature test results of Examples 15 - 17

[0132]

[0133]

[0134] 2. High-humidity test: The test samples were placed in a stability test chamber and sampled and tested after being placed for 5 days and 10 days at 25°C and a relative humidity of 90 ± 5%. The results are as follows:

[0135] High-humidity test results of Examples 1 - 5:

[0136]

[0137] High-humidity test results of Examples 6 - 10:

[0138]

[0139]

[0140] High-humidity test results of Examples 11 - 14:

[0141]

[0142] High-humidity test results of Examples 15 - 17:

[0143]

[0144]

[0145] 3. High-intensity light irradiation test: The test samples were placed in a stability test chamber and sampled and tested after being placed for 5 days and 10 days under the condition of 4500 lx ± 500 lx. The results are as follows:

[0146] High-intensity light irradiation test results of Examples 1 - 5

[0147]

[0148]

[0149] Strong light irradiation test results of Examples 6-10

[0150]

[0151] Strong light irradiation test results of Examples 11-14

[0152]

[0153]

[0154] Strong light exposure test results of Examples 15-17

[0155]

[0156] 4. Accelerated test: The test sample is placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples are taken at the end of the first, second, third and sixth months of the test. The test results are as follows:

[0157] Accelerated test results of Examples 1-5

[0158]

[0159] Accelerated test results of Examples 6-10

[0160]

[0161]

[0162] Accelerated test results of Examples 11-14

[0163]

[0164]

[0165] Accelerated test results of Examples 15-17

[0166]

[0167]

[0168] 5. Long-term stability test: The test sample is placed at a temperature of 25±2℃ and a relative humidity of 60±10% for 36 months. Samples are taken at the end of the 3rd, 6th, 9th, 12th, 18th, 24th and 36th months during the test. The sampling test results are as follows:

[0169] Long-term stability test results of Examples 1-5

[0170]

[0171]

[0172] Long-term stability test results of Examples 6-10

[0173]

[0174]

[0175] Long-term stability test results of Examples 11-14

[0176]

[0177]

[0178] Long-term stability test results of Examples 15-17

[0179]

[0180]

[0181]

[0182] The experimental results of Examples 1-5 are as follows:

[0183] The results of the test samples under high temperature, high humidity, strong light irradiation and accelerated test showed that the content of levamisole hydrochloride and praziquantel showed a downward trend, the total impurities increased, and the hardness was stable; long-term observation showed that the content was stable with little change and the hardness was stable. The preparation process of the veterinary levamisole hydrochloride and praziquantel chewable tablets of the present invention is stable and reliable.

[0184] Among them, Example 1, Example 2, and Example 3 respectively selected 2, 3, and 1 adsorbent, and the product contents thereof were qualified, uniform and stable, and the differences in quality etc. were very small.

[0185] Compared with Example 1 and Example 2, Example 3 greatly increases the amount of flavoring agent used, and the product content is qualified, with little difference, and the quality is uniform and stable.

[0186] Compared with Example 1, Example 2 and Example 3, Example 4 changes the chicken extract in the flavoring agent to chicken essence, so that all essences are used, and the sweetener remains unchanged. The product content is qualified, the difference is not large, and the quality is uniform and stable.

[0187] Compared with Example 1, Example 2 and Example 3, Example 5 changes the beef flavor in the flavoring agent to beef extract in Example 4, thereby using all extracts, and the sweetener remains unchanged. The product content is qualified, the difference is not large, and the quality is uniform and stable.

[0188] The experimental results of Examples 6-10 are as follows:

[0189] The results of high temperature, high humidity, strong light irradiation and accelerated tests show that the content of levamisole hydrochloride and praziquantel is on a downward trend, the total impurities increase, and the hardness is stable; long-term observation shows that the content is stable with little change and the hardness is stable. The preparation process of the veterinary levamisole hydrochloride and praziquantel chewable tablets of the present invention is stable and reliable.

[0190] Example 6 adds flavoring agents such as milk, mannitol, and fish flavoring, thereby making the flavoring agent more diverse. The product content is qualified, the difference is not large, and the quality is uniform and stable.

[0191] Example 7 and Example 8 used different antioxidants and colorants, and the product contents were qualified, with little difference, and the quality was uniform and stable.

[0192] In Example 9 and Example 10, different contents of main drug raw materials were used and auxiliary materials were adjusted appropriately. The contents of the products were qualified, with little difference and uniform and stable quality.

[0193] The experimental results of Examples 11-14 are as follows:

[0194] The results of high temperature, high humidity, strong light irradiation and accelerated tests show that the content of levamisole hydrochloride and praziquantel is on a downward trend, the total impurities increase, and the hardness is stable; long-term observation shows that the content is stable with little change and the hardness is stable. The preparation process of the veterinary levamisole hydrochloride and praziquantel chewable tablets of the present invention is stable and reliable.

[0195] In Example 11, Example 12, Example 13, and Example 14, different requirements (D60≤15μm, D30≤15μm, D10≤15μm, D90≤30μm) are adopted for airflow pulverization of the main drug raw materials. The product content is qualified, the deviation is large, and the quality is stable. However, the ultrafine control adopted in the present invention is D90≤15μm, and its deviation is smaller and more reasonable.

[0196] The experimental results of Examples 15-17 are as follows:

[0197] The results of high temperature, high humidity, strong light irradiation and accelerated tests show that the content of levamisole hydrochloride and praziquantel is on a downward trend, the total impurities increase, and the hardness is stable; long-term observation shows that the content is stable with little change and the hardness is stable. The preparation process of the veterinary levamisole hydrochloride and praziquantel chewable tablets of the present invention is stable and reliable.

[0198] Example 15, Example 16, and Example 17 use different coating materials for coating, and the results are not much different. The product content is qualified, the deviation is small, and it is uniform and stable.

[0199] Animal Experimentation:

[0200] The veterinary levamisole praziquantel hydrochloride chewable tablets produced by the present invention can achieve a self-feeding rate of 90.2-96.9% for cats and dogs, wherein the lowest rate for coating without flavoring agent is about 91%; the chewing completion rate is 90-95%, wherein the flavoring agent, especially the sweetener, is added before ultrafine and adsorption inclusion, and the effect is better.

[0201] The above is only a specific example of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A veterinary levamisole praziquantel hydrochloride chewable tablet, characterized in that: It includes the following components, by weight: 1-30 parts of levamisole hydrochloride, 1-30 parts of praziquantel, 5-60 parts of adsorbent, 10-60 parts of filler, 0.5-20 parts of binder, 1-30 parts of flavoring agent, 0.5-20 parts of lubricant; Also included are certain amounts of colorants, antioxidants and water.

2. The veterinary levamisole praziquantel hydrochloride chewable tablet according to claim 1, characterized in that: The adsorbent is one or a combination of corn cob, beta-cyclodextrin, silicon dioxide, and sulfonic acid calixarene.

3. The veterinary levamisole praziquantel hydrochloride chewable tablet according to claim 2, characterized in that: The filler is one or a combination of milk powder, cross-linked polyvinylpyrrolidone, polysorbate 80, microcrystalline cellulose, lactose, mannitol, sucrose, fructose, dextrin, essence, sodium hydroxymethyl starch, chicken liver powder, chicken extract, and beef extract.

4. The veterinary levamisole praziquantel hydrochloride chewable tablet according to claim 3, characterized in that: The adhesive is one or a combination of pregelatinized starch, silica gel, hydroxypropyl methylcellulose, povidone, PVP, corn starch, and dextrin.

5. The veterinary levamisole praziquantel hydrochloride chewable tablets according to claim 4, characterized in that: The lubricant is magnesium stearate or talc.

6. The veterinary levamisole praziquantel hydrochloride chewable tablets according to any one of claims 1 to 5, characterized in that: The flavoring agent is one or a combination of chicken flavor, beef flavor, fish flavor, chicken liver powder, chicken liver flavor, chicken extract, beef extract, milk powder, cream or milk flavor, yeast powder, mannitol, and sucralose sweetener.

7. The veterinary levamisole praziquantel hydrochloride chewable tablets according to claim 6, characterized in that: The colorant is one or a combination of caramel color, red iron oxide, yellow iron oxide, lemon yellow, carmine, sunset red or sunset yellow.

8. The veterinary levamisole praziquantel hydrochloride chewable tablet according to claim 7, characterized in that: The antioxidant is one or a combination of HBA, EDTA-2Na, BHT, TBHQ and vitamin C.

9. The method for preparing the veterinary levamisole praziquantel hydrochloride chewable tablets according to claim 8, characterized in that: S1 main drug mixture Adding levamisole hydrochloride, praziquantel and an adsorbent or a filler into a mixer in equal amounts to obtain a first mixed powder; S2 Ultrafine Grinding The first mixed powder is ultrafinely crushed by a jet mill to a D90 of ≤15 μm, thereby increasing the specific surface area and improving the solubility, and the dissolution T50 is ≤10 minutes to obtain a second mixed powder; S3 adsorption inclusion Add the remaining adsorbent to the second mixed powder, mix, fully adsorb and encapsulate, and after checking that the adsorption and encapsulation effect is qualified, obtain the third mixed powder; S4 Remix Add the remaining filler, flavoring agent and lubricant to the third mixed powder, mix them evenly, and test the uniformity to obtain a fourth mixed powder; S5 soft material Add the binder into purified water and soak until transparent, then add the flavoring agent and stir evenly, add it into the fourth mixed powder in a linear state, and stir evenly to obtain a soft material; S6 Granulation The soft material is granulated through a 12-20 mesh sieve, and the moisture content of the granules is controlled to be ≤5.0%; S7 Dry Put the prepared wet granules into an oven for drying at a temperature of 50-60°C for 20-60 minutes, and control the granule moisture content to ≤3.0%; S8 whole grain The dried granules are sieved through a 12-20 mesh sieve to obtain whole granules; S9 Mixed Add the obtained whole granules, lubricant, remaining flavoring agent, colorant, and antioxidant into a mixer at a speed of 8-20 rpm, mix for 10-30 minutes, and check the uniformity; S10 tableting The tablets pressed by the rotary tablet press have a smooth surface, the tablet weight difference is controlled to be ±5%, and the hardness is 40-80N to obtain the tablet core; S11 coating Put the tablet core into the coating machine, spray the coating liquid evenly on the surface of the tablet core to form a coating layer, cool and dry.

10. A veterinary levamisole praziquantel hydrochloride chewable tablet prepared by the preparation method according to claim 9.

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