A kind of Milbemycin oxime praziquantel flavored tablet and preparation method thereof

Abstract

The present invention relates to a milbemycin praziquantel flavored tablet and a preparation method thereof. The milbemycin praziquantel flavored tablet of the present invention is composed of a tablet core and a drug-free coating layer coated on the surface of the tablet core, the coating layer can be one or more layers, and the coating layer contains at least one appetite attractant or flavor corrector; the tablet core is composed of micropills, a flow aid, and a lubricant; the preparation process of the milbemycin praziquantel flavored tablet of the present invention is drug-containing powder→micropills→tablet core→coating layer→flavored tablet, the preparation process is simple, the main drug and the auxiliary agent can be evenly mixed together, so that the auxiliary agent can play a better role, improve the stability of the drug, improve the taste of the drug, and is suitable for industrial production, and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of pet medicines, and in particular to a milbemycin praziquantel flavored tablet and a preparation method thereof. Background Art

[0002] China's pet industry is developing rapidly. The number of people keeping pets is increasing, and there are more and more pets. Most of the pets are cats and dogs. Pet cats and dogs are very susceptible to parasites, such as nematodes, worms, flukes, etc., and most parasites can be transmitted to humans. Therefore, pet anti-parasites are very important. Currently, parasite prevention and treatment drugs on the market include tablets and topical liquids, mainly oral tablets. Most drugs have a certain peculiar smell and bitterness, and pets have very sensitive senses of smell and taste. Therefore, the oral tablets for pets currently on the market have the problem of difficulty in administration. The reason is that most tablets do not contain attractants, or if attractants are added, and because many pets will chew the drugs in their mouths and crush the tablets, the effect of covering up the peculiar smell and bitterness of the drugs cannot be achieved.

[0003] Milbemycin oxime is a macrolide anti-endoparasite drug. It is an oxime derivative of milbemycin A3 and A4, of which A4 accounts for more than 80%. It mainly paralyzes and dies the worm by enhancing the release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the worm. Specifically, it mainly acts as an agonist of GABA neurotransmitters in nerve cells, and can also bind to glutamate-gated Cl- channels in nerve and muscle cells of invertebrates. In both cases, it blocks the transmission of nerve signals of the parasite, and eventually the worm becomes paralyzed, causing the muscles to lose their ability to contract, stop eating, and cause the worm to die. It is commonly used to prevent heartworm disease and control whipworm disease in dogs caused by roundworms and hookworms. Praziquantel is a synthetic isoquinoline pyridine derivative that is effective against most trematodes in humans and animals, has a good anthelmintic effect on all adult tapeworms of livestock and companion animals, and also has a good effect on tapeworm larvae. Milbemycin oxime praziquantel flavored tablets are a broad-spectrum antiparasitic drug that has a good expelling and killing effect on internal and external parasites, especially nematodes and arthropods. It can be used to treat multiple infections caused by juvenile and adult nematodes and tapeworms, and can be used to prevent and treat nematode-induced canine heartworm disease.

[0004] Since the two APIs of milbemycin and praziquantel have bitter taste, pets often refuse to eat or spit out the food during clinical administration. Forced administration of the drug may cause scratches or bites by the pets, which makes clinical administration inconvenient or the dosage inaccurate, thus reducing the therapeutic effect. Therefore, it is particularly important to develop a new milbemycin praziquantel tablet with good taste. Summary of the invention

[0005] Based on the above reasons, in order to solve the shortcomings of the prior art, the present invention provides a milbemycin praziquantel flavored tablet for pets for treating and preventing internal and external parasites. It can not only solve the problem of pet parasites, but also overcome the difficulty of administering commercially available preparations, increase the pet's willingness to eat independently, avoid vomiting, and facilitate pet owners to administer the medicine.

[0006] The present invention also provides a method for preparing the above-mentioned Milbemycin oxime praziquantel flavored tablets for pets. The preparation process is drug-containing powder→pellets→tablet core→coating layer→flavored tablets. The preparation process is simple and suitable for large-scale production.

[0007] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme. The milbemycin praziquantel flavored tablet of the present invention is composed of a tablet core and a drug-free coating layer coated on the surface of the tablet core, the coating layer can be one or more layers, and the coating layer contains at least one flavor corrective (also known as an appetite attractant); the tablet core is composed of micropellets, a glidant, and a lubricant; wherein the weight percentage of the micropellets, the glidant, and the lubricant in the tablet core is

[0008] Pellets 95.0%-98.0%

[0009] Glidant 1.0%-2.5%

[0010] Lubricant 1.0%-2.5%.

[0011] Preferably, the glidant is calcium silicate, colloidal silicon dioxide or a combination of one or more of silicon dioxide.

[0012] Preferably, the lubricant is a combination of one or more of magnesium stearate, talc or glyceryl behenate.

[0013] Preferably, the particle size of the micropill is between 200 and 400 microns.

[0014] The pellets are composed of milbemycin, praziquantel, a filler, a disintegrant, and a binder, wherein the weight percentages of milbemycin, praziquantel, a filler, a disintegrant, and a binder are

[0015]

[0016]

[0017] The milbemycin used in the present invention is a complex of milbemycin A3 and milbemycin A4, which, calculated as anhydrous, contains milbemycin (A3+A4) of not less than 95%; and, measured by the method under the content determination item, milbemycin A4 is not less than 80% of the sum of milbemycin A3 and milbemycin A4.

[0018] Preferably, the filler is a combination of one or more of microcrystalline cellulose, maltodextrin, lactose monohydrate, sucrose, starch or dextrin.

[0019] Preferably, the disintegrant is a combination of one or more of dry starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone or cross-linked sodium carboxymethyl cellulose. The use of a disintegrant can disintegrate and break the pellets after the drug comes into contact with water, increase the surface area of ​​the drug in contact with the dissolution medium, and help improve the solubility of the drug.

[0020] Preferably, the binder is a combination of one or more of povidone, sodium carboxymethyl cellulose or hydroxypropyl methyl cellulose.

[0021] The method for preparing the milbemycin praziquantel flavored tablets of the present invention is pellet compression. In order to ensure the fluidity of the pellets and to ensure that the pellets are not crushed during tablet compression, we need to control the particle size of the pellets. The particle size of the pellets is controlled between 200 and 400 microns.

[0022] A milbemycin oxime praziquantel flavored tablet, which consists of a tablet core and a coating layer, wherein the coating layer accounts for 2.0%-8.0% of the tablet core weight, preferably 3.0%-5.0%.

[0023] The coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percentage of the colorant, the flavoring agent and the film-forming agent is

[0024] Flavoring agent 10%-30%

[0025] Colorant 1.0%-10%

[0026] Film former 60%-90%.

[0027] Furthermore, the coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percentage of the colorant, the flavoring agent and the film-forming agent is

[0028] Flavoring agent 10%-30%

[0029] Colorant 1.0%-10%

[0030] Film former 60%-89%.

[0031] Preferably, the flavoring agent is a combination of one or more of chicken liver powder, beef essence, beef extract or Ledaxiang. The flavoring agent can increase the palatability of the drug and facilitate drug administration.

[0032] Preferably, the colorant is sunset yellow, sunset red, red iron oxide or a combination of one or more of yellow iron oxide. The colorant can help distinguish drugs of different specifications to prevent wrong administration, and can also make the product more recognizable and enhance the brand image.

[0033] Preferably, the film-forming agent is a combination of one or more of talc, polyethylene glycol 6000, and hydroxypropyl methylcellulose. The film-forming agent can eliminate dust, make the appearance smoother, and isolate the tablet core from air, moisture, and light, thereby improving the stability of the drug and helping to ensure the efficacy of the drug.

[0034] The present invention also provides a method for preparing milbemycin oxime praziquantel flavored tablets for pets, which comprises the following steps:

[0035] 1) passing the prescribed amount of milbemycin oxime, praziquantel, filler and disintegrant through a 50-mesh sieve and placing them in a fluidized bed, and mixing the drugs and excipients uniformly under the action of a hot air flow at 40° C. to 50° C. at the bottom of the fluidized bed to obtain a mixture;

[0036] 2) spraying a prescribed amount of adhesive solution into the mixture in step 1), the powder absorbed by the solution begins to bond into small particles, and as the adhesive solution is continuously added, the small particles slowly aggregate to form coarse micropellets;

[0037] 3) The coarse pellets obtained in step 2) are further dried in a fluidized bed at 40° C.-50° C., and sieved twice, the mesh sizes of the two sieves being 400 μm and 200 μm, respectively, to obtain pellets with a particle size of 200-400 μm;

[0038] 4) adding a prescribed amount of a glidant and a lubricant to the pellets obtained in step 3), mixing them evenly, and tableting to obtain the tablet core;

[0039] 5) Slowly add the prescribed amount of coating powder into purified water and stir continuously until uniform to obtain a coating solution;

[0040] 6) placing the tablet core obtained in step 4) into a coating machine, and spraying the coating solution in step 5) evenly on the surface of the milbemycin oxime praziquantel tablet core to form a coating layer; until the tablet weight increases by 2.0%-8.0%, to obtain milbemycin oxime praziquantel flavored tablets.

[0041] The coating powder described in the present invention refers to the solid component that does not contain water in the coating liquid prescription.

[0042] Micropellets refer to spherical entities composed of drug powder and excipients, generally with a diameter of less than 2.5mm. Micropellets are a multi-unit dose dispersion type, that is, one dose is often composed of multiple dispersed units, usually a dose is composed of dozens to hundreds of small pellets. Micropellets are currently commonly used in sustained-release or rapid-release preparations for humans. Considering the current difficulties in clinical administration of pet tablets, the present invention applies micropellet technology to Milbemycin praziquantel flavored tablets for the first time as a taste-masking technology, so that when pets bite tablets, they can effectively delay the release of odor and bitterness in the oral cavity of the drug, thereby solving the problem of vomiting in pets.

[0043] In order to solve the problem of pets chewing tablets, the present invention prepares the drug into micro-pellets, and then compresses the micro-pellets into tablets, and the tablet core is coated and taste-masked again. In this way, whether the pet swallows the tablet directly or bites the tablet to take it, it can have a good taste-masking effect, and the pet's autonomous intake rate is increased; at the same time, the milbemycin oxime praziquantel flavored tablet of the present invention has an isolation and moisture-proof effect through the film-forming agent in the coating layer, which strengthens the protection of the product, does not affect the dissolution and efficacy of the drug, can also mask the taste, increase the pet's active intake rate, and solve the problem of difficulty in administering medicine to the pet.

[0044] The preparation method of the milbemycin praziquantel flavored tablets of the present invention has a simple process, can evenly mix the main drug and the auxiliary agent, so that the auxiliary agent can play a better role, improve the stability of the drug, improve the taste of the drug, is suitable for industrial production, and has broad application prospects. DETAILED DESCRIPTION

[0045] The present invention is described in detail below in conjunction with the embodiments. It must be pointed out that the following embodiments are only used to illustrate the present invention but not to limit the present invention.

[0046] Milbemycin oxime (A3+A4=97.5%; A4 / (A3+A4)=83.3%) used in the present invention was purchased from Zhejiang Hisun Pharmaceutical Co., Ltd.; praziquantel was purchased from Hisun Pharmaceutical Nantong Co., Ltd.; iron oxide red and sunset yellow were purchased from Shanghai Yipin Pigment Co., Ltd.; polyethylene glycol 6000 was purchased from Shanghai Maihong Biotechnology Co., Ltd.; chicken liver powder was purchased from Qingdao Longhai Food Co., Ltd.; sucrose was purchased from Nanning Sugar Co., Ltd.; cross-linked polyvinyl pyrrolidone was purchased from Huangshan Bangsen New Materials Co., Ltd.; povidone and colloidal silicon dioxide were purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.; lactose monohydrate was purchased from German Meggle Group; magnesium stearate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, talc, and dextrin were purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; beef extract was purchased from PF, Inc.; and cross-linked sodium carboxymethyl cellulose was purchased from DuPont.

[0047] The coating machine involved in the present invention is a Xiaolun high-efficiency coating machine, model BG-100. The coating parameters are a rotation speed of 10 rpm, an air inlet temperature of 60°C, a bed temperature of 40°C, until the tablets gain 2.0%-8.0%.

[0048] The fluidized bed involved in the present invention is a multifunctional granulation and pilling fluidized bed, model DPL-II. The fluidized bed fan frequency is 20hz, the air inlet temperature is 55℃, the drying temperature is 45℃, the material temperature is controlled at 35℃, and the turntable speed is 400rpm.

[0049] Example 1

[0050] Tablet prescription:

[0051] Table 1

[0052]

[0053]

[0054] Coating liquid prescription:

[0055] Table 2

[0056]

[0057] Note: Purified water will be dried during the coating preparation process, and the amount of purified water will not be calculated in the coating prescription.

[0058] Preparation method:

[0059] 1) Passing a prescribed amount of milbemycin oxime, praziquantel, sucrose as a filler, and sodium croscarmellose as a disintegrant through a 50-mesh sieve, placing the mixture in a fluidized bed, and mixing the drugs and excipients uniformly under the action of a hot air flow at 45° C. at the bottom of the fluidized bed to obtain a mixture;

[0060] 2) Spraying a prescribed amount of a 15% aqueous solution of a binder, povidone, into the mixture in step 1), the powders absorbing the solution begin to bond into small particles, and as the aqueous solution of the binder povidone is continuously added, the small particles slowly aggregate to form coarse micropellets;

[0061] 3) The coarse pellets obtained in step 2) are further dried in a fluidized bed at 45° C. and sieved twice, with the mesh sizes of 400 μm and 200 μm, respectively, to obtain pellets with a particle size of 200-400 μm;

[0062] 4) adding a prescribed amount of a glidant, colloidal silicon dioxide, and a lubricant, magnesium stearate to the pellets obtained in step 3), mixing them evenly, and tableting to obtain the tablet core;

[0063] 5) Slowly add the prescribed amount of coating powder into purified water and stir continuously until uniform to obtain a coating solution;

[0064] 6) The tablet core obtained in step 4) is placed in a coating machine, and the coating solution in step 5) is evenly sprayed on the surface of the milbemycin oxime praziquantel tablet core to form a coating layer, and milbemycin oxime praziquantel tablets with different coating ratios are prepared, as shown in Table 3 below.

[0065] Coating weight gain ratio:

[0066] Table 3

[0067] Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Sample 7 Chip 1% 2% 3% 5% 8% 10%

[0068] Note: Coating weight gain percentage refers to the ratio of the weight gain of the tablet core after coating to the tablet core weight.

[0069] Example 2

[0070] Tablet prescription:

[0071] Table 4

[0072]

[0073] Coating liquid prescription:

[0074] Table 5

[0075]

[0076]

[0077] The preparation method is the same as that of Example 1, wherein the weight gain of the coating treatment accounts for 3%.

[0078] Note: Purified water will be dried during the coating preparation process, and the amount of purified water will not be calculated in the coating prescription.

[0079] Example 3

[0080] Tablet prescription:

[0081] Table 6

[0082]

[0083] Coating liquid prescription:

[0084] Table 7

[0085]

[0086]

[0087] Note: Purified water will be dried during the coating preparation process, and the amount of purified water will not be calculated in the coating prescription.

[0088] The preparation method is the same as that of Example 1, wherein the weight gain of the coating treatment is 3%.

[0089] Example 4

[0090] Tablet prescription:

[0091] Table 8

[0092]

[0093] Coating liquid prescription:

[0094] Table 9

[0095]

[0096] Note: Purified water will be dried during the coating preparation process, and the amount of purified water will not be calculated in the coating prescription.

[0097] The preparation method is the same as that of Example 1, wherein the weight gain of the coating treatment is 3%.

[0098] Test 1:

[0099] Before being absorbed, the drug in the solid preparation must be disintegrated and dissolved and then converted into a solution to be absorbed. Therefore, an in vitro dissolution experiment is performed to simulate the process of drug dissolution and release in the pet's body. Take seven samples in Example 1 for dissolution testing. The limit requirement is that the dissolution within 30 minutes is not less than 80% of the labeled amount. The dissolution medium is a 37°C aqueous solution of 0.4% SDS, the rotation speed is 100rpm, and 5ml is sampled at 30min, filtered, and the filtrate is taken as the test solution to determine the dissolution of milbemycin and praziquantel. The test results are shown in Table 10.

[0100] Table 10

[0101] serial number Dissolution of Milbemycin Oxime (%) Dissolution rate of praziquantel (%) Sample 1 (chip) 99.9 91.6 Sample 2 (1%) 99.8 91.5 Sample 3 (2%) 99.2 90.1 Sample 4 (3%) 98.5 89.5 Sample 5 (5%) 97.5 89.1 Sample 6 (8%) 95.6 85.4 Sample 7 (10%) 72.5 73.4

[0102] The data in Table 10 above show that sample 7 (accounting for 10%) failed the test, and the dissolution of the drug slowed down, affecting the release of the drug in the pet's body, thereby reducing the efficacy of the product. Therefore, the weight proportion of the coating layer for the tablet core should not exceed 8%.

[0103] Test 2:

[0104] Seven samples of the Milbemycin oxime praziquantel flavored tablets for pets prepared in Example 1 were used to conduct a comparative test on the active feeding of pet cats using a conventional tablet (Milbemycin oxime praziquantel tablets without pellet tableting technology). The test site was the stray pet shelter in Hangzhou.

[0105] Among them, the specific formula and preparation method of the common process tablets are as follows:

[0106] Tablet prescription:

[0107] Table 11

[0108]

[0109] Coating liquid prescription:

[0110] Table 12

[0111]

[0112] Note: The dosage of raw materials and auxiliary materials in the prescription of ordinary process tablets is the same as that in Example 1, and the coating weight gain accounts for 3%.

[0113] Preparation method:

[0114] 1) Passing a prescribed amount of milbemycin oxime, praziquantel, sucrose as a filler, and sodium croscarmellose as a disintegrant through a 50-mesh sieve, placing the mixture in a wet granulator, and mixing the mixture uniformly to obtain a mixture;

[0115] 2) adding a prescribed amount of a 15% aqueous solution of a binder, povidone, to the mixture in step 1), and simultaneously starting a shearing machine for granulation to obtain wet granules;

[0116] 3) transferring the wet granules in step 2) to an oven for drying at a temperature of 45° C., and sieving the granules with a 24-mesh sieve to obtain dry granules;

[0117] 4) putting the dry granules obtained in step 3) into a mixer, adding the prescribed amount of glidant colloidal silicon dioxide and lubricant magnesium stearate, mixing evenly, and tableting to obtain tablet cores;

[0118] 5) Slowly add the prescribed amount of coating powder into purified water and stir continuously until uniform to obtain a coating solution;

[0119] 6) placing the tablet core obtained in step 4) into a coating machine, and spraying the coating solution in step 5) evenly on the surface of the milbemycin oxime praziquantel tablet core to form a coating layer, thereby obtaining milbemycin oxime praziquantel tablets prepared by conventional process.

[0120] Test method: 160 pet cats were randomly selected and divided into 8 groups, with 20 cats in each group, numbered A, B, C, D, E, F, G and H. Two tests were conducted: 1. Seven samples in Example 1 and samples of ordinary process tablets were fed to the pets respectively, and the active feeding rate of each group of pets was calculated; 2. The seven samples in Example 1 and samples of ordinary process tablets were fed into the oral cavity of the pets, and the amount of uneaten and spit out by each group of pets was calculated. The test results are shown in Table 13.

[0121] Table 13

[0122]

[0123] The results in Table 13 above show that the active feeding rate of the pets of the milbemycin praziquantel flavored tablets prepared after coating of the present invention is significantly improved, much higher than the core sample, and the milbemycin praziquantel flavored tablets of the present invention can solve the problem of pet medication. The active feeding rate of sample 3 reaches 80%, so the weight proportion of the coating layer as the core should not be less than 2%.

[0124] The vomiting number is the number of drugs that are fed into the pet's mouth but vomited out by the pet without taking it. From the vomiting rate results (Table 13), the vomiting rate of Milbemycin oxime praziquantel flavored tablets using micropellet tableting technology is greatly reduced, which can effectively solve the vomiting phenomenon of pets.

[0125] Milbemycin oxime praziquantel flavored tablets for pets must not only meet quality requirements and not affect the efficacy of the drug, but also increase the active feeding rate of pets, reduce the vomiting rate of pets, and solve the problem of difficult drug administration. The results of test one and test two show that Milbemycin oxime praziquantel flavored tablets use micropellet tableting technology and tablet core coating treatment, which can significantly increase the active feeding rate of pets and reduce the vomiting rate of pets.

[0126] Test three:

[0127] The samples prepared in Examples 1 to 4 were taken to test the flowability, tablet appearance, friability and disintegration time of the micropill.

[0128] The test index of pellet fluidity is: angle of repose <40°;

[0129] The inspection index of the surface appearance is: the surface is smooth when observed with naked eyes;

[0130] The test index of friability is: the weight loss shall not exceed 0.8%, and no broken, cracked or crushed pieces shall be detected;

[0131] The test index of disintegration time is: disintegration time shall not exceed 15 minutes. The test results are shown in Table 14.

[0132] Table 14

[0133]

[0134] It can be seen from the data in Table 14 above that the milbemycin praziquantel flavored tablets provided by the present invention are prepared by a method for tabletting with pellets and coating treatment, and the prepared tablets have beautiful tablet appearance, good particle fluidity, strong wear resistance, and fast disintegration; by optimizing the prescription and process, the stability of the drug in the production process is guaranteed and the product quality is improved.

[0135] Test 4:

[0136] The absorption rate of drugs in the body is often determined by the speed of dissolution. If the dissolution rate is too fast, obvious adverse reactions may occur, and the time to maintain the drug effect will also be shortened. If the dissolution rate is too slow, the drug cannot be absorbed and the blood concentration of the therapeutic effect cannot be reached. Therefore, the dissolution rate of the drug should be controlled. Take the samples prepared in Example 1-Example 4 for dissolution detection, and the limit requirement is that the dissolution within 30 minutes is not less than 80% of the labeled amount. The dissolution medium is a 37°C aqueous solution of 0.4% SDS, the rotation speed is 100rpm, and 5ml is sampled at 30min, filtered, and the subsequent filtrate is taken as the test solution to determine the dissolution of milbemycin oxime and praziquantel. The dissolution results are shown in Tables 15 and 16.

[0137] Table 15 Dissolution of Milbemycin

[0138] time 30(min) Sample 4 of Example 1 98.5％ Example 2 96.2％ Example 3 93.1％ Example 4 93.9％

[0139] Table 16 Dissolution of praziquantel

[0140] time 30(min) Example 1 (Sample 4) 89.5％ Example 2 94.1％ Example 3 96.1％ Example 4 96.9％

[0141] From the above dissolution data, it can be seen that the samples prepared in Examples 1 to 4 all dissolved more than 80% within 30 minutes, and all met the quality standard requirements.

[0142] Test Five:

[0143] The products produced by the preparation method of the present invention were tested for influencing factors. Sample 4 of Example 1 was placed under high temperature 60°C and 40°C, high humidity RH75% and RH92.5% and strong light 4500Lx±500Lx, respectively. Samples were taken on 5 days and 10 days, tested, and compared with those on 0 day, as shown in the following Tables 17-19.

[0144] The inspection of relevant substances complies with the relevant provisions under tablets in Appendix 5 of the "Chinese Pharmacopoeia of Veterinary Medicine", and the content is determined in accordance with the high performance liquid chromatography method in Appendix 36 of the "Chinese Pharmacopoeia of Veterinary Medicine".

[0145] Related substances: Praziquantel impurities A, B, and C shall not exceed 0.5% on average, Milbemycin impurity D shall not exceed 1.5%, other impurities shall not exceed 1.0%, and total impurities shall not exceed 6.0%;

[0146] Content: Milbemycin oxime and praziquantel contents are 90.0%-110.0% of the labeled amount;

[0147] Dissolution: The limit requirement is that no less than 80% of the labeled amount is dissolved within 30 minutes.

[0148] Table 17 High temperature test results

[0149]

[0150] Table 18 Lighting test results

[0151]

[0152] Table 19 High humidity test results

[0153]

[0154]

[0155] According to the analysis of the influencing factor data in Tables 17-19 above, the prescription provided by the present invention and the product prepared according to the preparation method of the present invention have good stability under high temperature, high humidity and light conditions.

[0156] Test six:

[0157] The product produced by the preparation method of the present invention was used for clinical trials to observe the clinical effect of milbemycin praziquantel flavored tablets (sample 4 in Example 1) on parasites in cats, and the adverse reactions that may occur during the medication were also observed.

[0158] Experimental animals: domestic cats, aged from 1.5 months to adulthood. After being transported to the laboratory, the cats were kept in separate cages for 7 to 10 days to adapt to the environment and become tame, and the spirit and appetite of the cats were observed. At the same time, the feces just discharged by the cats were collected one by one, and the worm eggs were checked by saturated salt water flotation method and water washing sedimentation method respectively. Among them, cats with at least one positive test for the eggs of Toxocara felis, Capillaria, hookworm, Clonorchis sinensis, Echinostoma, Pharyngostoma, Taenia solium, and Dipylidium, and with good spirits and appetite, were used for the experiment.

[0159] Trial Groups:

[0160] The animals were randomly divided into 3 groups, namely:

[0161] Group I: Milbemycin oxime praziquantel flavored tablets low-dose group, Milbemycin oxime 1 mg / kg + praziquantel 2.5 mg / kg;

[0162] Group II: Milbemycin oxime praziquantel flavored tablets medium dose group, Milbemycin 2 mg / kg + praziquantel 5 mg / kg;

[0163] Group III: high-dose group of Milbemycin oxime praziquantel flavored tablets, Milbemycin 4 mg / kg + Praziquantel 10 mg / kg.

[0164] There were 35 cats in each group. The types of eggs infected by cats in each group were similar, as shown in Table 20:

[0165] Table 20 Types of worms and number of cats infected in each experimental group

[0166]

[0167] Dosage regimen:

[0168] The medium-dose group of Milbemycin oxime praziquantel flavored tablets was orally administered once. The dosing regimen of the low-dose group and the high-dose group was similar to that of the medium-dose group, but the dose was halved or doubled.

[0169] Clinical observation:

[0170] After administration, the cats were observed once in the morning and once in the afternoon for the following items: mental state, appetite, activity, and deworming status of the cats; the deworming bodies or segments were collected for worm species identification to understand the deworming status and deworming peak.

[0171] Fecal egg count:

[0172] Fresh feces of cats infected with Capillaria were collected 1 day before administration and on the 7th and 14th days after administration, and the number of Capillaria eggs per gram was calculated using the McMaster method.

[0173] Parasitological necropsy:

[0174] On the 15th day after administration, all the test cats were euthanized. Then, according to the complete parasitological autopsy method, the parasites in the digestive tract, liver, trachea, lungs, and bladder of each cat were collected, the species were identified, and the number of parasites was counted according to the species.

[0175] Effect evaluation:

[0176] According to the change of the number of worm eggs in feces, the clinical efficacy test results of each animal are evaluated according to the following standards:

[0177] ① Cure: The reduction rate of worm eggs in feces is ≥90%, and the physical signs of the test animals return to normal.

[0178] ②Effective: The reduction rate of worm eggs in feces is ≥60%, and the animal's physical signs have improved but have not completely returned to normal.

[0179] ③ Ineffective: The reduction rate of worm eggs in feces is less than 60%, and the animal's condition is not significantly relieved, and clinical manifestations such as diarrhea and vomiting still exist.

[0180] The clinical observation results are shown in Table 21-27:

[0181] During the entire test period, the spirit, appetite and defecation of all the test cats were normal. The earliest time for cats to excrete worms after administration was 1 hour after administration and the latest was 6 days after administration, but the peak of worm excretion was 48 to 72 hours after administration. The worms that can be examined in the feces with the naked eye are mainly cat toxocara and tapeworm.

[0182] Insect repellent efficiency:

[0183] Based on the number of various worms found in the cat's body, the anthelmintic rate of various worms in each tested drug dosage group and drug control group was calculated according to the following formula.

[0184]

[0185] According to the changes in the Capillaria eggs in cat feces at different times before and after administration, the reduction rate of Capillaria eggs and the rate of negative conversion of eggs in each test drug dosage group and the drug control group were calculated according to the following formula.

[0186]

[0187]

[0188] SPSS software was used to perform descriptive statistics on the mean EPG before and after administration of each group and the egg reduction rate between groups at different periods, and Duncan's new multiple range method was used for multiple comparisons of the means between groups (P<0.05).

[0189] Table 21 Antiparasitic efficiency against Clonorchis sinensis

[0190]

[0191] Table 22: Antiparasitic efficiency against spiny-mouthed and pharyngeal-mouthed flukes

[0192]

[0193] Table 23 The anthelmintic efficiency of Spirochaete monteri

[0194]

[0195]

[0196] Table 24 Anthelmintic efficiency against Dipylidium

[0197]

[0198] Table 25 Anthelmintic efficiency against Toxocara cati

[0199]

[0200] Table 26 Deworming efficiency against hookworms

[0201]

[0202] Table 27: Antiparasitic efficiency against capillaries

[0203]

[0204]

[0205] Note: Different letters a and b in the upper right corner of the same line indicate significant differences between the values ​​(P<0.05).

[0206] The above test results show that the milbemycin praziquantel flavored tablets produced by the prescription and preparation method of the present invention have good anthelmintic effects on cats infected with Toxocara catus, capillaria, hookworms, Clonorchis sinensis, Echinostoma spp., Pharyngeal flukes, Spirochete monteri and Dipylidia. It is recommended that the dosage for Toxocara catus, hookworms, Echinostoma spp., Pharyngeal flukes and Dipylidia monteri should be a medium dose, administered orally once; the dosage for Capillaria spp. should be a high dose, administered orally once; the dosage for Spirochete monteri should be a high dose, which needs to be repeated for two consecutive days, once a day.

[0207] Adverse reaction observation:

[0208] After administration of the drug to the cats in each test group, the mental state, appetite and activity of the cats before and after administration were compared, and no abnormal reactions related to the administration were found.

Claims

1. A Milbemycin oxime praziquantel flavored tablet, characterized in that: The milbemycin praziquantel flavored tablets are composed of a tablet core and a drug-free coating layer coated on the surface of the tablet core, wherein the coating layer is one or more layers, and the coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percentages of the colorant, the flavoring agent and the film-forming agent are 10%-30% of the flavoring agent, 1.0%-10% of the coloring agent, and 60%-89% of the film-forming agent, and the coating layer contains at least one flavoring agent; the tablet core is composed of micropills, a glidant, and a lubricant, wherein the weight percentages of the micropills, the glidant, and the lubricant in the tablet core are 95.0%-98.0% of the micropills, 1.0%-2.5% of the glidant, and 1.0%-2.5% of the lubricant; the particle size of the micropills is between 200 and 400 microns; The milbemycin praziquantel flavored tablets are obtained by a preparation method comprising the following steps: 1) passing the prescribed amount of milbemycin oxime, praziquantel, filler and disintegrant through a 50-mesh sieve and placing them in a fluidized bed, and mixing the drugs and excipients uniformly under the action of a hot air flow at 40° C. to 50° C. at the bottom of the fluidized bed to obtain a mixture; 2) spraying a prescribed amount of adhesive solution into the mixture in step 1), the powder absorbed by the solution begins to bond into small particles, and as the adhesive solution is continuously added, the small particles slowly aggregate to form coarse micropellets; 3) the coarse pellets obtained in step 2) are further dried in a fluidized bed at 40° C.-50° C., and sieved twice, the mesh sizes of the two sieves being 400 μm and 200 μm, respectively, to obtain pellets; 4) adding a prescribed amount of a glidant and a lubricant to the pellets obtained in step 3), mixing them evenly, and tableting to obtain the tablet core; 5) slowly adding the prescribed amount of coating powder into purified water and stirring continuously until uniform to obtain a coating solution; the coating powder contains a colorant, a flavoring agent and a film-forming agent; 6) placing the tablet core obtained in step 4) into a coating machine, and spraying the coating solution in step 5) evenly on the surface of the milbemycin oxime praziquantel tablet core to form a coating layer; until the tablet weight increases by 2.0%-8.0%, to obtain milbemycin oxime praziquantel flavored tablets.

2. The Milbemycin oxime praziquantel flavored tablet according to claim 1, characterized in that: The glidant is a combination of one or more of calcium silicate and colloidal silicon dioxide; the lubricant is a combination of one or more of magnesium stearate, talc or glyceryl behenate.

3. The Milbemycin oxime praziquantel flavored tablet according to claim 1, characterized in that: The glidant is a combination of one or more of calcium silicate and silicon dioxide; the lubricant is a combination of one or more of magnesium stearate, talc or glyceryl behenate.

4. The Milbemycin oxime praziquantel flavored tablet according to claim 1, 2 or 3, characterized in that: The pellets are composed of milbemycin, praziquantel, a filler, a disintegrant, and a binder, wherein the weight percentage of milbemycin, praziquantel, a filler, a disintegrant, and a binder is 5. The Milbemycin oxime praziquantel flavored tablet according to claim 4, characterized in that: The filler is a combination of one or more of microcrystalline cellulose, maltodextrin, lactose monohydrate, sucrose or starch; the disintegrant is a combination of one or more of dry starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone or cross-linked sodium carboxymethyl cellulose; the binder is a combination of one or more of povidone, sodium carboxymethyl cellulose or hydroxypropyl methylcellulose.

6. The Milbemycin oxime praziquantel flavored tablet according to claim 4, characterized in that: The filler is a combination of one or more of microcrystalline cellulose, lactose monohydrate, sucrose, starch or dextrin; the disintegrant is a combination of one or more of dry starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone or cross-linked sodium carboxymethyl cellulose; the binder is a combination of one or more of povidone, sodium carboxymethyl cellulose or hydroxypropyl methylcellulose.

7. The Milbemycin oxime praziquantel flavored tablet according to claim 1, characterized in that: The coating layer accounts for 2.0% to 8.0% of the weight of the tablet core.

8. The Milbemycin oxime praziquantel flavored tablet according to claim 7, characterized in that: The coating layer accounts for 3.0%-5.0% of the weight of the tablet core.

9. The Milbemycin oxime praziquantel flavored tablet according to claim 1, characterized in that: The flavor corrector is a combination of one or more of chicken liver powder, beef essence, beef extract or Leda fragrance; the colorant is a combination of one or more of sunset yellow, sunset red, red iron oxide or yellow iron oxide; the film-forming agent is a combination of one or more of talc, polyethylene glycol 6000 and hydroxypropyl methylcellulose.

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