WO2022033553A1 - Milbemycin oxime and praziquantel flavor tablets and preparation method therefor - Google Patents

Milbemycin oxime and praziquantel flavor tablets and preparation method therefor Download PDF

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Publication number
WO2022033553A1
WO2022033553A1 PCT/CN2021/112293 CN2021112293W WO2022033553A1 WO 2022033553 A1 WO2022033553 A1 WO 2022033553A1 CN 2021112293 W CN2021112293 W CN 2021112293W WO 2022033553 A1 WO2022033553 A1 WO 2022033553A1
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Prior art keywords
praziquantel
tablet
flavored
mirboxime
coating
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PCT/CN2021/112293
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French (fr)
Chinese (zh)
Inventor
王盈峰
谢等龙
冀伟
陈国庆
罗成江
王以跃
李亚
朱齐凤
徐红波
张华英
梁瑾
张燕
周艳
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浙江海正动物保健品有限公司
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Priority to CN202180055837.4A priority Critical patent/CN116249517A/en
Priority to AU2021323853A priority patent/AU2021323853A1/en
Publication of WO2022033553A1 publication Critical patent/WO2022033553A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/288—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • the invention relates to the technical field of pet medicines, and in particular, the invention relates to a milbe oxime praziquantel flavored tablet and a preparation method thereof.
  • Milbeoxime is a macrolide antibody internal and external parasite drug, and is an oxime derivative of milbemycin A3 and A4, of which A4 accounts for more than 80%.
  • GABA inhibitory neurotransmitter gamma-aminobutyric acid
  • the parasite paralyzes and dies. Specifically, it acts primarily as an agonist of the GABA neurotransmitter in nerve cells, and also binds to glutamate-gated Cl- channels in nerve and muscle cells of invertebrates. In both cases, it blocks the parasite's nerve signaling, eventually paralyzing the parasite, causing the muscles to lose the ability to contract, stop feeding, and cause the parasite to die.
  • Praziquantel is a synthetic isoquinoline pyridine derivative that is effective against most trematodes in humans and animals, and is very effective against all adult tapeworms in livestock and companion animals, as well as against tapeworm larvae. Good results.
  • Milbeoxime praziquantel flavored tablet is a broad-spectrum antiparasitic drug, which has a good 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 heartworm disease in dogs.
  • the present invention provides a pet milbe oxime praziquantel flavored tablet for the treatment and prevention of internal and external parasites, which can not only solve the problem of pet parasites, but also overcome the problems in the market. It is difficult and defective to sell preparations for administration, increase the pet's willingness to feed independently, avoid the phenomenon of vomiting, and facilitate the administration of pet owners.
  • the present invention also provides a preparation method of the above-mentioned mirboxime praziquantel flavored tablet for pets.
  • the preparation process of the process is drug-containing powder ⁇ pellet ⁇ tablet core ⁇ coating layer ⁇ flavored tablet. mass production.
  • the mirboxime 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 is Contains at least one flavoring agent (also known as an appetizer); the tablet core is composed of pellets, glidants, and lubricants; wherein, the pellets, glidants, and lubricants in the tablet core are The weight percentage is
  • the glidant is calcium silicate, colloidal silicon dioxide or a combination of one or more of silicon dioxide.
  • the lubricant is a combination of one or more of magnesium stearate, talc or glyceryl behenate.
  • the particle size of the pellets is between 200 and 400 microns.
  • the pellet is composed of mirbeoxime, praziquantel, filler, disintegrant, and binder, and the weight percentage of the mirboxime, praziquantel, filler, disintegrant, and binder is
  • the milbe oxime used in the present invention is a compound of milbe oxime A3 and milbe oxime A4, and calculated on the basis of anhydrous, the content of milbe oxime (A3+A4) shall not be less than 95%; it is determined by the method under the content determination item , Mirbe oxime A4 shall not be less than 80% of the sum of Mirbe oxime A3 and Mirbe oxime A4.
  • the filler is a combination of one or more of microcrystalline cellulose, maltodextrin, 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 use of disintegrants can disintegrate and break the pellets after the drug contacts with water, increase the surface area of the drug in contact with the dissolution medium, and is beneficial to improve the dissolution rate of the drug.
  • the binder is a combination of one or more of povidone, sodium carboxymethyl cellulose or hydroxypropyl methyl cellulose.
  • the preparation method of the mirboxime praziquantel flavored tablet of the present invention is pellet compression.
  • the particle size of the pellet we control the particle size of pellets to be between 200 and 400 microns.
  • a mirbeoxime praziquantel flavor tablet is composed of a tablet core and a coating layer, and the coating layer accounts for 2.0%-8.0% of the weight of the tablet core, preferably 3.0%-5.0%.
  • the coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percentages of the coloring agent, the flavoring agent and the film-forming agent are:
  • the coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percent of the coloring agent, the flavoring agent and the film-forming agent is
  • the flavoring agent is a combination of one or more of chicken liver powder, beef essence, beef extract or Ledaxiang, and the flavoring agent can increase the palatability of the drug and help give Medicine.
  • the coloring agent is a combination of one or more of sunset yellow, sunset red, iron oxide red or iron oxide yellow, and the coloring agent can help to distinguish medicines of different specifications and prevent wrong administration, It can also make the product more recognizable and enhance the brand image.
  • 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, has a smoother appearance, and can also It can isolate the core from air, moisture, and light, and improve the stability of the drug, thereby helping to ensure the curative effect of the drug.
  • the present invention also provides a preparation method of mirboxime praziquantel flavored tablets for pets, which comprises the following steps:
  • step 2) Spray the adhesive solution of the recipe amount into the mixture in step 1), the powder that has absorbed the solution begins to bond into small particles, and with the continuous addition of the adhesive solution, the small particles slowly aggregate to form coarse pellets ;
  • step 3 Continue to dry the coarse pellets obtained in step 2) in a fluidized bed at 40°C-50°C, and perform two sievings.
  • the apertures of the sieves of the two sievings are 400 microns and 200 microns in turn to obtain a particle size.
  • step 3 in the pellet obtained in step 3), add the glidant and lubricant of recipe quantity, mix well, press tablet, and obtain described tablet core;
  • step 6) Put the tablet core obtained in step 4) into a coating machine, and spray the coating solution in step 5) evenly on the surface of the mirbexime praziquantel tablet core to form a coating layer; until the tablet weight gain is 2.0 %-8.0% to obtain mirbeoxime praziquantel flavored tablets.
  • the coating powder in the present invention refers to the solid component that does not contain water in the coating liquid formulation.
  • Pellet refers to a spherical entity composed of drug powder and excipients, generally less than 2.5mm in diameter. Pellets are a multi-unit dosage dispersive dosage form, that is, a dosage is often composed of multiple dispersed units, usually a dosage consists of dozens of to several hundred pellets. At present, pellets are commonly used in human sustained and controlled-release preparations or immediate-release preparations. Considering the current difficulties in clinical administration of pet tablets, the present invention applies the pellet technology to the mirbexime praziquantel flavored tablet product for the first time as a taste mask. The use of technology enables pets to effectively delay the release of peculiar smell and bitter taste in the mouth when pets bite the tablets, thereby solving the problem of pet vomiting.
  • the medicine in order to solve the problem of pet chewing tablets, the medicine is made into pellets, and then the pellets are compressed, and the tablet core is coated again to mask the taste.
  • the film-forming agent in the layer has the effect of isolation and moisture-proof, which strengthens the protection of the product, does not affect the dissolution and efficacy of the drug, and can also cover up the taste, increase the active feeding rate of pets, and solve the problem of difficult drug administration for pets.
  • the preparation method of the mirbéxime praziquantel flavor tablet of the present invention has the advantages of simple process, and can evenly mix the main drug and the auxiliary agent together, so that the auxiliary agent can play a better role, improve the stability of the drug, and improve the stability of the drug. It is suitable for industrial production and has broad application prospects.
  • the coating machine involved in the present invention is a Xiaolun high-efficiency coating machine, and the model is BG-100.
  • the coating parameters are the rotating speed of 10 rpm, the inlet air temperature of 60° C., and the bed temperature of 40° C., until the tablet weight increases by 2.0% to 8.0%.
  • the fluidized bed involved in the present invention is a multifunctional granulating and pelletizing fluidized bed, and the model is DPL-II.
  • the frequency of the fluidized bed fan is 20hz
  • the air inlet temperature is 55°C
  • the drying temperature is 45°C
  • the material temperature is controlled at 35°C
  • the turntable speed is 400rpm.
  • Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
  • step 2) In the mixture in step 1), spray the adhesive 15% aqueous solution of povidone of the recipe quantity, and the powder that has absorbed the solution begins to bond into small particles, and with the continuous addition of the aqueous solution of povidone of the adhesive, small The particles slowly aggregate to form coarse pellets;
  • step 2) Continue to dry the coarse pellets obtained in step 2) at 45° C. in a fluidized bed, and perform 2 sieving, and the apertures of the sieves are successively 400 microns and 200 microns, and obtain a particle size of 200-400 microns. the pellets;
  • step 3 in the pellet obtained in step 3), add the glidant colloidal silicon dioxide and lubricant magnesium stearate of recipe quantity, mix homogeneously, compress to obtain described tablet core;
  • step 6) Put the tablet core obtained in step 4) into a coating machine, and spray the coating solution in step 5) evenly on the surface of the mirbeoxime praziquantel tablet core to form a coating layer and prepare different coatings.
  • Proportion of mirboxime praziquantel tablets as shown in Table 3 below.
  • the proportion of coating weight gain refers to the ratio of the weight of the tablet core after coating treatment to the weight of the tablet core.
  • the preparation method is the same as that of Example 1, wherein the weight gain ratio of coating treatment is 3%.
  • Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
  • Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
  • the preparation method is the same as that of Example 1, wherein, the weight gain of the coating treatment is 3%.
  • Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
  • the preparation method is the same as that of Example 1, wherein, the weight gain of the coating treatment is 3%.
  • Example 1 Before being absorbed, the drug in the solid preparation must be disintegrated and dissolved and then converted into a solution before it can be absorbed. Therefore, an in vitro dissolution experiment was carried out to simulate the process of dissolution and release of the drug in the pet. Seven samples in Example 1 were taken for dissolution testing. The limit is required to dissolve no less than 80% of the declared amount within 30 minutes.
  • the dissolution medium was 0.4% SDS in 37°C aqueous solution, the rotation speed was 100 rpm, 5 ml was sampled in 30 minutes, filtered, and the subsequent filtrate was taken as the test solution to measure the dissolution of mirbeoxime and praziquantel. The test results are shown in Table 10.
  • Example 1 Take 7 parts of pet milbe oxime praziquantel flavored tablets samples and common process tablets (milbe oxime praziquantel tablets without pellet compression technology) prepared in Example 1 to carry out active feeding of pet cats
  • the test site was a stray pet shelter in Hangzhou.
  • the dosage of raw and auxiliary materials in the prescription of the common technology tablet is the same as that of Example 1, and the weight gain of the coating is 3%.
  • step 2) in the mixture in step 1), add the adhesive 15% aqueous solution of povidone of recipe quantity, open shearing machine simultaneously and carry out granulation, obtain wet granules;
  • step 2) transfer the wet granules in step 2) to an oven for drying, the drying temperature is 45° C., the granules are sieved, and the sieve mesh is 24 meshes to obtain dry granules;
  • step 4) the dry particles obtained in step 3) are put into mixer, the glidant colloidal silicon dioxide and lubricant magnesium stearate of recipe quantity are added, mix homogeneously, and press tablet to obtain tablet core;
  • step 6) Put the tablet core obtained in step 4) into a coating machine, and evenly spray the coating solution in step 5) on the surface of the Mirbe oxime praziquantel tablet core to form a coating layer to obtain common technology Mirbe Oxime Praziquantel Tablets.
  • Test method 160 pet cats were randomly selected and divided into 8 groups, 20 cats in each group, numbered A, B, C, D, E, F, G and H, and two tests will be carried out: 1.
  • Feeding Example 1 respectively 7 samples in the sample and the samples of the common process sheet, calculate the active feed intake rate of each group of pets; 2, 7 parts of the samples in the embodiment 1 and the samples of the common process sheet are fed into the pet's oral cavity, calculate the pet's unhealthy rate of each group of pets. Take the amount of spit, and the test results are shown in Table 13.
  • the number of regurgitations is the number of drugs that are fed into the pet's mouth without the pet spitting out. Judging from the results of the anti-emesis rate (Table 13), the anti-emesis rate of the Milbeoxime praziquantel-flavored tablet that adopted the pellet compression technology process was greatly reduced, and the pet's emesis phenomenon could be well solved.
  • Milbeoxime praziquantel flavored tablets for pets should not only meet the quality requirements without affecting the efficacy of the drug, but also improve the pet's active feed intake rate, reduce the pet's regurgitation rate, and solve the difficult problem of drug administration.
  • the results of test 1 and test 2 show that the mirbeoxime praziquantel flavored tablet adopts the technology of pellet compression, and the tablet core coating treatment can significantly improve the active feeding rate of pets and reduce the regurgitation rate of pets.
  • the samples prepared in Examples 1 to 4 were taken to test the fluidity, surface appearance, friability and disintegration time of pellets.
  • the testing index of pellet fluidity is: angle of repose ⁇ 40°;
  • the detection index of one-sided appearance is: naked eye observation, one-sided smooth;
  • the detection index of friability is: the weight loss shall not exceed 0.8%, and the broken, cracked and crushed pieces shall not be detected at all times;
  • the detection index of the disintegration time is: the disintegration time shall not exceed 15 minutes, and the detection result is shown in Table 14.
  • the mirbene oxime praziquantel flavored tablet provided by the present invention is prepared by pellet compression and coating treatment, and the obtained tablet has a beautiful appearance, good particle fluidity, and wear resistance. It has strong properties and fast disintegration; through the optimization of the prescription and process, the stability of the drug in the production process is guaranteed, and the product quality is improved.
  • 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 cannot achieve therapeutic effects. concentration, and therefore, the dissolution rate of the drug should be controlled.
  • the limit requirement is that the dissolution is not less than 80% of the declared amount within 30 minutes.
  • the dissolution medium was 0.4% SDS in a 37° C.
  • Example 1 98.5%
  • Example 2 96.2%
  • Example 3 93.1%
  • Example 4 93.9%
  • Example 1 (sample four) 89.5%
  • Example 2 94.1%
  • Example 3 96.1%
  • Example 4 96.9%
  • the products produced by the preparation method of the present invention are tested for influencing factors, and the samples four of Example 1 are placed under the conditions of high temperature 60°C and 40°C, high humidity RH75% and RH92.5%, and strong light 4500Lx ⁇ 500Lx, respectively. 5 days, 10 days sampling, testing, and compared with 0 days, see Table 17-19 below.
  • Impurities A, B and C of praziquantel should not exceed 0.5% on average, impurity D of mirbeoxime should not exceed 1.5%, other impurities should not exceed 1.0%, and total impurities should not exceed 6.0%;
  • Milbeoxime and Praziquantel are both 90.0%-110.0% of the labelled amount
  • Dissolution The limit is required to dissolve no less than 80% of the declared amount within 30 minutes.
  • the formulation 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.
  • the products produced by the preparation method of the present invention are used to carry out clinical trials to observe the clinical effect of mirboxime praziquantel flavored tablets (sample four in Example 1) on parasites in cats, and to observe possible adverse reactions during their administration. .
  • Test animals domestic cats, aged 1.5 months to adults. After the cats were transported to the laboratory, they were reared in separate cages for 7-10 days, so that the cats could adapt to the environment and tame, and the spirit and appetite of the cats were observed. At the same time, the feces just excreted by the cats were collected one by one, and the worm eggs were examined by the saturated saline flotation method and the water washing sedimentation method respectively.
  • At least one of the eggs of Toxocara felis, Capillary nematodes, hookworms, Clonorchis sinensis, Acanthostomatosus, Pharyngosomiasis, Taenia trichomoniasis, and Taenia polyporus eggs are positive, and cats with good spirit and appetite are used for test.
  • mice were divided into 3 groups, namely:
  • Group I Milbeoxime praziquantel flavored tablet low-dose group, milbeoxime 1 mg/kg + praziquantel 2.5 mg/kg;
  • Group II Milbeoxime praziquantel flavored tablet middle-dose group, milbeoxime 2mg/kg + praziquantel 5mg/kg;
  • Group III Milbeoxime praziquantel flavor tablet high-dose group, mirbeoxime 4 mg/kg + praziquantel 10 mg/kg.
  • the middle-dose group of mirbeoxime praziquantel flavored tablets was orally administered once.
  • the dosing regimens of the low-dose and high-dose groups were similar to those of the mid-dose group, but the doses were halved or doubled.
  • the fresh feces of cats infected with Capillary nematodes were collected on the 1st day before administration and on the 7th and 14th days after administration, respectively, and the number of C. feces eggs was calculated by McMaster's method.
  • the spirit, appetite and defecation of all test cats were normal throughout the test period.
  • the time for cats to excrete parasites after administration was 1h after administration at the earliest and 6th day after administration at the latest, but the peak of expelling parasites was 48-72 hours after administration.
  • the worms that can be detected in feces with the naked eye are mainly Toxocara feline and tapeworms.
  • the deworming rate of various helminths in each tested drug dose group and drug control group was calculated according to the following formula.
  • the reduction rate of capillary nematode eggs and the negative rate of eggs in each tested drug dose group and drug control group were calculated according to the following formulas.
  • SPSS software was used for descriptive statistics of the mean number of EPG before and after administration in each group and the reduction rate of worm eggs in different periods between groups, and Duncan's new multiple range method was used to conduct multiple comparisons between groups (P ⁇ 0.05).
  • the mirbeoxime praziquantel flavored tablet produced by the prescription and preparation method of the present invention is effective against Toxocara felis, Capillary nematode, Hookworm, Clonorchis sinensis, Acanthostomia, Pharyngosomiasis infected by cats. , Monteggia serrata and Taenia polypora have good deworming effect. It is recommended that the clinical dosage for Toxocara feline, hookworm, Acanthostomatosus, Pharyngeal fluke and Tapeworm is a medium dose, once orally; for Capillary nematode, a high dose, once orally ; The dosage of M. mongolica tapeworm is high dose, and it needs to be repeated for two days, once a day.

Abstract

The present invention relates to a milbemycin oxime and praziquantel flavor tablet and a preparation method therefor. The milbemycin oxime and praziquantel flavor tablet of the present invention consists of a tablet core and a drug-free coating layer coated on the surface of the tablet core. One or more coating layers can be present. The coating layer contains at least one phagostimulant or corrigent. The tablet core consists of a pellet, a glidant, and a lubricant. The preparation process of the milbemycin oxime and praziquantel flavor tablet of the present invention comprises drug-containing powder→micropellet→tablet core→coating layer→flavor tablet. The preparation process is simple, and can uniformly mix a main drug and assistants together, so that the assistants can better function, the stability of the drug is improved, the taste of the drug is improved, and the flavor tablet is suitable for industrial production, and has wide application prospects.

Description

一种米尔贝肟吡喹酮风味片及其制备方法A kind of mirbei oxime praziquantel flavor tablet and preparation method thereof 技术领域technical field
本发明涉及宠物药品技术领域，具体而言，本发明涉及一种米尔贝肟吡喹酮风味片及其制备方法。The invention relates to the technical field of pet medicines, and in particular, the invention relates to a milbe oxime praziquantel flavored tablet and a preparation method thereof.
背景技术Background technique
中国宠物行业在快速发展，饲养宠物的人不断增加，宠物也是越来越多，其中宠物大多以猫和犬为主。而宠物猫和犬非常容易感染寄生虫，如线虫、绕虫、吸虫等，且多数寄生虫能传染给人，因此，宠物抗寄生虫非常重要。目前市场上防治寄生虫药物有片剂和外用液体，以口服片剂为主。而大多数药物有一定异味和苦味，宠物的嗅觉和味觉非常的敏感，因此，目前市售的宠物用口服片剂都存在给药困难的问题，原因在于大多数片剂都未加入诱食剂，或有加入诱食剂，又因为许多宠物会将药物在口中咀嚼，咬碎了药片，达不到掩盖药物异味和苦味的效果。China's pet industry is developing rapidly. The number of people who keep 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, roundworms, flukes, etc., and most parasites can be transmitted to humans. Therefore, pet anti-parasites are very important. At present, there are tablets and liquids for the prevention and control of parasites on the market, mainly oral tablets. However, most medicines have a certain peculiar smell and bitter taste, and pets are very sensitive to smell and taste. Therefore, the current commercial oral tablets for pets are difficult to administer because most of the tablets do not add food attractants. , or adding food attractants, and because many pets will chew the medicine in their mouths and crush the tablets, it cannot achieve the effect of masking the odor and bitterness of the medicine.
米尔贝肟为大环内酯类抗体内外寄生虫药物，是米尔贝霉素A3和A4的肟衍生物，其中A4占比超过80％。主要通过增强虫体的抑制性神经递质γ‐氨基丁酸(GABA)的释放使虫体麻痹死亡。具体地，主要作为神经细胞中GABA神经递质的激动剂，并且还可与无脊椎动物的神经和肌肉细胞中的谷氨酸门控Cl–通道结合。在这两种情况下，它都会阻断寄生虫的神经信号传递，最终虫体瘫痪麻痹，使肌肉失去收缩能力，停止进食，而导致虫体死亡。通常用于预防恶丝虫病，控制蛔虫、钩虫引发犬的鞭虫病。吡喹酮是一种合成的异喹啉吡啶衍生物，对人和动物的大多数吸虫都有效果，对家畜和伴侣动物的所有绦虫成虫均有很好的驱虫效果，对绦虫幼虫也有很好的效果。米尔贝肟吡喹酮风味片是一种广谱抗寄生虫药，对体内、体外寄生虫特别是线虫和节肢动物有良好的驱杀作用。可用于治疗幼年和成年线虫以及绦虫引起的多重感染，并可以用于预防治疗线虫诱导的犬心丝虫疾病。Milbeoxime is a macrolide antibody internal and external parasite drug, and is an oxime derivative of milbemycin A3 and A4, of which A4 accounts for more than 80%. Mainly by enhancing the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), the parasite paralyzes and dies. Specifically, it acts primarily as an agonist of the GABA neurotransmitter in nerve cells, and also binds to glutamate-gated Cl- channels in nerve and muscle cells of invertebrates. In both cases, it blocks the parasite's nerve signaling, eventually paralyzing the parasite, causing the muscles to lose the ability to contract, stop feeding, and cause the parasite to die. Usually used to prevent heartworm disease, control roundworm, hookworm caused by whipworm in dogs. Praziquantel is a synthetic isoquinoline pyridine derivative that is effective against most trematodes in humans and animals, and is very effective against all adult tapeworms in livestock and companion animals, as well as against tapeworm larvae. Good results. Milbeoxime praziquantel flavored tablet is a broad-spectrum antiparasitic drug, which has a good 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 heartworm disease in dogs.
由于米尔贝肟和吡喹酮两种原料药有苦味，因此在临床给药过程中，宠物常常出现拒食或者食用后吐出的现象，强制给药又会有被宠物抓伤或咬伤的风险， 造成临床给药不方便或者剂量不准确，降低了治疗效果。因此研究一种新的口感优质的米尔贝肟吡喹酮片剂尤为重要。Due to the bitter taste of mirbeoxime and praziquantel, during clinical administration, pets often refuse to eat or spit out after eating, and forced administration may cause the risk of being scratched or bitten by pets. The clinical administration is inconvenient or the dose is inaccurate, and the therapeutic effect is reduced. Therefore, it is very important to study a new mirboxime praziquantel tablet with good taste.
发明内容SUMMARY OF THE INVENTION
基于以上原因，为解决现有技术的不足，本发明提供了一种治疗与预防体内外寄生虫的宠物用米尔贝肟吡喹酮风味片，不仅能解决宠物寄生虫的问题，还克服了市售制剂给药困难缺陷，增加宠物自主采食意愿，避免出现反吐现象，方便了宠物主人给药。Based on the above reasons, in order to solve the deficiencies of the prior art, the present invention provides a pet milbe oxime praziquantel flavored tablet for the treatment and prevention of internal and external parasites, which can not only solve the problem of pet parasites, but also overcome the problems in the market. It is difficult and defective to sell preparations for administration, increase the pet's willingness to feed independently, avoid the phenomenon of vomiting, and facilitate the administration of pet owners.
本发明同时还提供了上述宠物用米尔贝肟吡喹酮风味片的制备方法，该工艺制备过程为含药粉末→微丸→片芯→包衣层→风味片，其制备工艺简单，适用于大规模生产。At the same time, the present invention also provides a preparation method of the above-mentioned mirboxime praziquantel flavored tablet for pets. The preparation process of the process is drug-containing powder → pellet → tablet core → coating layer → flavored tablet. mass production.
为了实现本发明的目的，本发明采用以下技术方案。本发明的米尔贝肟吡喹酮风味片由片芯和包覆在片芯表面的不含药的包衣层组成，所述包衣层可以是一层或多层，所述包衣层中含有至少一种矫味剂(也可称为诱食剂)；所述片芯由微丸、助流剂、润滑剂组成；其中，所述片芯中微丸、助流剂、润滑剂的重量百分比为In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions. The mirboxime 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 is Contains at least one flavoring agent (also known as an appetizer); the tablet core is composed of pellets, glidants, and lubricants; wherein, the pellets, glidants, and lubricants in the tablet core are The weight percentage is
微丸              95.0％—98.0％Pellets 95.0%—98.0%
助流剂            1.0％—2.5％Glidant 1.0%—2.5%
润滑剂            1.0％—2.5％。Lubricant 1.0%-2.5%.
作为优选，所述助流剂为硅酸钙、胶体二氧化硅或二氧化硅中的一种或多种的组合。Preferably, the glidant is calcium silicate, colloidal silicon dioxide or a combination of one or more of silicon dioxide.
作为优选，所述润滑剂为硬脂酸镁、滑石粉或山嵛酸甘油酯中的一种或多种的组合。Preferably, the lubricant is a combination of one or more of magnesium stearate, talc or glyceryl behenate.
作为优选，所述微丸的粒径大小在200～400微米之间。Preferably, the particle size of the pellets is between 200 and 400 microns.
其中，所述微丸由米尔贝肟、吡喹酮、填充剂、崩解剂、黏合剂组成，其中所述米尔贝肟、吡喹酮、填充剂、崩解剂、黏合剂的重量百分比为Wherein, the pellet is composed of mirbeoxime, praziquantel, filler, disintegrant, and binder, and the weight percentage of the mirboxime, praziquantel, filler, disintegrant, and binder is
Figure PCTCN2021112293-appb-000001
Figure PCTCN2021112293-appb-000001
Figure PCTCN2021112293-appb-000002
Figure PCTCN2021112293-appb-000002
本发明所用的米尔贝肟为米尔贝肟A3和米尔贝肟A4的复合物，按无水物计算，含米尔贝肟(A3+A4)不得少于95％；按照含量测定项下的方法测定，米尔贝肟A4不得少于米尔贝肟A3与米尔贝肟A4之和的80％。The milbe oxime used in the present invention is a compound of milbe oxime A3 and milbe oxime A4, and calculated on the basis of anhydrous, the content of milbe oxime (A3+A4) shall not be less than 95%; it is determined by the method under the content determination item , Mirbe oxime A4 shall not be less than 80% of the sum of Mirbe oxime A3 and Mirbe oxime A4.
作为优选，所述填充剂为微晶纤维素、麦芽糊精、单水乳糖、蔗糖、淀粉或糊精中的一种或多种的组合。Preferably, the filler is a combination of one or more of microcrystalline cellulose, maltodextrin, lactose monohydrate, sucrose, starch or dextrin.
作为优选，所述崩解剂为干淀粉、羧甲基淀粉钠、交联聚乙烯吡咯烷酮或交联羧甲基纤维素钠中的一种或多种的组合。使用崩解剂可以使药物在与水接触后瓦解微丸并使之破碎，增大药物与溶出介质接触的表面积，有利于提高药物的溶出度。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 disintegrants can disintegrate and break the pellets after the drug contacts with water, increase the surface area of the drug in contact with the dissolution medium, and is beneficial to improve the dissolution rate of the drug.
作为优选，所述黏合剂为聚维酮、羧甲基纤维素钠或羟丙基甲基纤维素中的一种或多种的组合。Preferably, the binder is a combination of one or more of povidone, sodium carboxymethyl cellulose or hydroxypropyl methyl cellulose.
本发明所述的米尔贝肟吡喹酮风味片制备方法为微丸压片，为了保证微丸的流动性，同时为了确保压片时不会将微丸压碎，我们需要控制微丸粒径大小，我们将微丸制备的粒径大小控制在200～400微米之间。The preparation method of the mirboxime praziquantel flavored tablet of the present invention is pellet compression. In order to ensure the fluidity of the pellet, and at the same time to ensure that the pellet will not be crushed during tableting, we need to control the particle size of the pellet. We control the particle size of pellets to be between 200 and 400 microns.
一种米尔贝肟吡喹酮风味片，其由片芯和包衣层组成，所述包衣层占片芯重量的2.0％—8.0％，优选为3.0％—5.0％。A mirbeoxime praziquantel flavor tablet is composed of a tablet core and a coating layer, and the coating layer accounts for 2.0%-8.0% of the weight of the tablet core, preferably 3.0%-5.0%.
所述包衣层含有着色剂、矫味剂和成膜剂，其中着色剂、矫味剂和成膜剂的重量百分比为The coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percentages of the coloring agent, the flavoring agent and the film-forming agent are:
矫味剂            10％—30％Flavoring agent 10%—30%
着色剂            1.0％—10％Colorant 1.0%—10%
成膜剂            60％—90％。Film former 60%-90%.
进一步地，所述包衣层含有着色剂、矫味剂和成膜剂，其中着色剂、矫味剂和成膜剂的重量百分比为Further, the coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight percent of the coloring agent, the flavoring agent and the film-forming agent is
矫味剂            10％—30％Flavoring agent 10%—30%
着色剂            1.0％—10％Colorant 1.0%—10%
成膜剂            60％—89％。Film former 60%-89%.
作为优选，所述的矫味剂为鸡肝粉、牛肉香精、牛肉提取物或乐达香中的一种或多种的组合，所述矫味剂可以增加药物的适口性，有助于给药。Preferably, the flavoring agent is a combination of one or more of chicken liver powder, beef essence, beef extract or Ledaxiang, and the flavoring agent can increase the palatability of the drug and help give Medicine.
作为优选，所述的着色剂为日落黄、日落红、氧化铁红或氧化铁黄中的一种或多种的组合，所述着色剂能有助于区分不同规格的药物，防止错服，还能使产品更具识别性，提升品牌形象。Preferably, the coloring agent is a combination of one or more of sunset yellow, sunset red, iron oxide red or iron oxide yellow, and the coloring agent can help to distinguish medicines of different specifications and prevent wrong administration, It can also make the product more recognizable and enhance the brand image.
作为优选，所述的成膜剂为滑石粉、聚乙二醇6000、羟丙基甲基纤维素中的一种或多种的组合，所述成膜剂能消除粉尘，外表更加光洁，还能让片芯隔离空气、水分、光线，改善药物的稳定性，从而有助于保证药品的疗效。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, has a smoother appearance, and can also It can isolate the core from air, moisture, and light, and improve the stability of the drug, thereby helping to ensure the curative effect of the drug.
本发明还提供一种宠物用米尔贝肟吡喹酮风味片的制备方法，其包括如下步骤：The present invention also provides a preparation method of mirboxime praziquantel flavored tablets for pets, which comprises the following steps:
1)将处方量的米尔贝肟、吡喹酮、填充剂、崩解剂过50目筛处理，放入流化床中，药物和辅料在流化床下部40℃‐50℃热空气流的作用下，混合均匀，得到混合物；1) Pass the 50 mesh sieve of mirbeoxime, praziquantel, filler and disintegrant in the prescribed amount and put them into the fluidized bed. Under the action, mix uniformly to obtain a mixture;
2)向步骤1)中的混合物中喷入处方量的黏合剂溶液，吸收了溶液的粉末开始粘结成小颗粒，随着粘合剂溶液的不断加入，小颗粒慢慢聚合形成粗微丸；2) Spray the adhesive solution of the recipe amount into the mixture in step 1), the powder that has absorbed the solution begins to bond into small particles, and with the continuous addition of the adhesive solution, the small particles slowly aggregate to form coarse pellets ;
3)将步骤2)中得到的粗微丸继续在流化床40℃‐50℃烘干，进行两次过筛，两次过筛的筛网孔径依次为400微米和200微米，得到粒径大小200‐400微米的微丸；3) Continue to dry the coarse pellets obtained in step 2) in a fluidized bed at 40°C-50°C, and perform two sievings. The apertures of the sieves of the two sievings are 400 microns and 200 microns in turn to obtain a particle size. Pellets of size 200-400 microns;
4)在步骤3)得到的微丸中加入处方量的助流剂和润滑剂，混合均匀，压片，得所述的片芯；4) in the pellet obtained in step 3), add the glidant and lubricant of recipe quantity, mix well, press tablet, and obtain described tablet core;
5)将处方量的包衣粉缓慢加入纯化水中，并不断搅拌至均一，得到包衣液；5) slowly adding the coating powder of the recipe amount into the purified water, and stirring continuously until uniform, to obtain a coating liquid;
6)将步骤4)中得到的片芯放入包衣机中，将步骤5)中的包衣液均匀喷洒在米尔贝肟吡喹酮片芯表面，形成包衣层；直至片增重2.0％‐8.0％，得到米尔贝肟吡喹酮风味片。6) Put the tablet core obtained in step 4) into a coating machine, and spray the coating solution in step 5) evenly on the surface of the mirbexime praziquantel tablet core to form a coating layer; until the tablet weight gain is 2.0 %-8.0% to obtain mirbeoxime praziquantel flavored tablets.
本发明所述的包衣粉是指包衣液处方中不含水的固体组分。The coating powder in the present invention refers to the solid component that does not contain water in the coating liquid formulation.
微丸是指药物粉末和辅料构成的圆球状实体，一般直径小于2.5mm，微丸剂是一种多单元剂量分散型剂型，即一个剂量往往由多个分散的单元组成，通常一个剂量由几十至几百个小丸组成。目前微丸常用于人用缓控释制剂或速释制剂，考虑目前宠物片剂临床给药的难题，本发明首次将微丸技术应用在米尔贝肟吡喹酮风味片产品上，作为掩味技术使用，使宠物在咬碎药片时，能有效的延缓药物在口腔中释放出异味和苦味，从而解决宠物出现反吐现象的问题。Pellet refers to a spherical entity composed of drug powder and excipients, generally less than 2.5mm in diameter. Pellets are a multi-unit dosage dispersive dosage form, that is, a dosage is often composed of multiple dispersed units, usually a dosage consists of dozens of to several hundred pellets. At present, pellets are commonly used in human sustained and controlled-release preparations or immediate-release preparations. Considering the current difficulties in clinical administration of pet tablets, the present invention applies the pellet technology to the mirbexime praziquantel flavored tablet product for the first time as a taste mask. The use of technology enables pets to effectively delay the release of peculiar smell and bitter taste in the mouth when pets bite the tablets, thereby solving the problem of pet vomiting.
本发明为了解决宠物咀嚼药片的难题，将药物制成微丸，再将微丸进行压片，片芯再一次包衣掩味处理。这样宠物无论是直接吞服或是咬破药片服用，都能很好的起到掩味效果，增加了宠物自主服用的采食率；同时本发明的米尔贝肟吡喹酮风味片通过包衣层中的成膜剂起到隔离防潮效果，加强了产品的防护，同时不影响药物溶出和疗效，还能掩盖味道，增加宠物主动采食率，解决宠物给药困难的问题。In the present invention, in order to solve the problem of pet chewing tablets, the medicine is made into pellets, and then the pellets are compressed, and the tablet core is coated again to mask the taste. In this way, whether the pet is swallowed directly or taken by biting the tablet, it can have a good taste-masking effect, which increases the feed intake rate of the pet independently; The film-forming agent in the layer has the effect of isolation and moisture-proof, which strengthens the protection of the product, does not affect the dissolution and efficacy of the drug, and can also cover up the taste, increase the active feeding rate of pets, and solve the problem of difficult drug administration for pets.
本发明米尔贝肟吡喹酮风味片的制备方法，其工艺简单，能够将主药和助剂均匀地混合在一起，使得助剂能够更好地发挥作用，提高药物的稳定性，改善药物的口感，并适合产业化产生，具有广阔的应用前景。The preparation method of the mirbéxime praziquantel flavor tablet of the present invention has the advantages of simple process, and can evenly mix the main drug and the auxiliary agent together, so that the auxiliary agent can play a better role, improve the stability of the drug, and improve the stability of the drug. It is suitable for industrial production and has broad application prospects.
具体实施方式detailed description
以下结合实施例对本发明进行详细说明，必须指出，以下实施例只用于说明本发明，而不构成对本发明的限制。The present invention will be described in detail below with reference to the examples. It must be pointed out that the following examples are only used to illustrate the present invention, but not to limit the present invention.
本发明所用的米尔贝肟(A3+A4＝97.5％；A4/(A3+A4)＝83.3％)购买于浙江海正药业股份有限公司；吡喹酮购买于海正药业南通有限公司；氧化铁红、日落黄购买于上海一品颜料有限公司；聚乙二醇6000购买于上海迈弘生物科技有限公司；鸡肝粉购买于青岛陇海食品有限公司；蔗糖购买于南宁糖业股份有限公司；交联聚乙烯吡咯烷酮购买于黄山邦森新材料有限公司；聚维酮、胶体二氧化硅购买于湖州展望药业有限公司；单水乳糖购买于德国美剂乐集团；硬脂酸镁、羧甲基纤维素钠、羟丙基甲基纤维素、滑石粉、糊精购买于安徽山河药用辅料股份有限公司；牛肉提取物购买于PF，Inc.；交联羧甲基纤维素钠购买于DuPont公司。Milbeoxime (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.; Oxidation Iron 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 polyvinylpyrrolidone 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 Meggle Group, Germany; magnesium stearate, carboxymethyl Sodium cellulose, hydroxypropyl methylcellulose, talc, and dextrin were purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; beef extract was purchased from PF, Inc.; croscarmellose sodium was purchased from DuPont company.
本发明所涉及的包衣机为小伦高效包衣机，型号为BG‐100。包衣参数为转速10rpm，进风温度为60℃，床体温度为40℃，直至片增重2.0％—8.0％。The coating machine involved in the present invention is a Xiaolun high-efficiency coating machine, and the model is BG-100. The coating parameters are the rotating speed of 10 rpm, the inlet air temperature of 60° C., and the bed temperature of 40° C., until the tablet weight increases by 2.0% to 8.0%.
本发明所涉及的流化床为多功能制粒制丸流化床，型号为DPL‐Ⅱ。流化床风机频率为20hz，进风温度为55℃，烘干温度为45℃，物料温度控制为35℃，转盘速度为400rpm。The fluidized bed involved in the present invention is a multifunctional granulating and pelletizing fluidized bed, and the model is DPL-II. The frequency of the fluidized bed fan is 20hz, the air inlet temperature is 55°C, the drying temperature is 45°C, the material temperature is controlled at 35°C, and the turntable speed is 400rpm.
实施例1Example 1
片芯处方：Tablet prescription:
表1Table 1
Figure PCTCN2021112293-appb-000003
Figure PCTCN2021112293-appb-000003
Figure PCTCN2021112293-appb-000004
Figure PCTCN2021112293-appb-000004
包衣液处方：Coating liquid prescription:
表2Table 2
Figure PCTCN2021112293-appb-000005
Figure PCTCN2021112293-appb-000005
注：纯化水在包衣的制备过程中将会被烘干，包衣的处方中将不计算纯化水用量。Note: Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
制备方法：Preparation:
1)将处方量的米尔贝肟、吡喹酮与填充剂蔗糖、崩解剂交联羧甲基纤维素钠过50目筛处理，放入流化床中，药物和辅料在流化床下部45℃热空气流的作用下，混合均匀，得到混合物；1) Milbeoxime of recipe quantity, praziquantel and filler sucrose, disintegrating agent croscarmellose sodium are passed through 50 mesh sieves, put into fluidized bed, and medicine and adjuvant are in the lower part of fluidized bed Under the action of hot air flow at 45°C, the mixture is uniformly mixed to obtain a mixture;
2)向步骤1)中的混合物中喷入处方量的黏合剂15％聚维酮水溶液，吸收了溶液的粉末开始粘结成小颗粒，随着粘合剂聚维酮水溶液的不断加入，小颗粒慢慢聚合形成粗微丸；2) In the mixture in step 1), spray the adhesive 15% aqueous solution of povidone of the recipe quantity, and the powder that has absorbed the solution begins to bond into small particles, and with the continuous addition of the aqueous solution of povidone of the adhesive, small The particles slowly aggregate to form coarse pellets;
3)将步骤2)中的得到的粗微丸继续在流化床45℃烘干，进行2次过筛， 筛网的孔径依次为400微米和200微米，得到粒径大小在200‐400微米的微丸；3) Continue to dry the coarse pellets obtained in step 2) at 45° C. in a fluidized bed, and perform 2 sieving, and the apertures of the sieves are successively 400 microns and 200 microns, and obtain a particle size of 200-400 microns. the pellets;
4)在步骤3)得到的微丸中加入处方量的助流剂胶体二氧化硅和润滑剂硬脂酸镁，混合均匀，压片，得所述的片芯；4) in the pellet obtained in step 3), add the glidant colloidal silicon dioxide and lubricant magnesium stearate of recipe quantity, mix homogeneously, compress to obtain described tablet core;
5)将处方量的包衣粉缓慢加入纯化水中，并不断搅拌至均一，得到包衣液；5) slowly adding the coating powder of the recipe amount into the purified water, and stirring continuously until uniform, to obtain a coating liquid;
6)将步骤4)中得到的片芯放入包衣机中，将步骤5)中的包衣液均匀喷洒在米尔贝肟吡喹酮片芯表面，形成包衣层，制备成不同包衣比例的米尔贝肟吡喹酮片，具体如下表3。6) Put the tablet core obtained in step 4) into a coating machine, and spray the coating solution in step 5) evenly on the surface of the mirbeoxime praziquantel tablet core to form a coating layer and prepare different coatings. Proportion of mirboxime praziquantel tablets, as shown in Table 3 below.
包衣增重占比：Coating weight gain percentage:
表3table 3
样品一sample one 样品二Sample two 样品三Sample three 样品四Sample four 样品五Sample five 样品六Sample six 样品七Sample Seven
片芯Chip 占比1％1% 占比2％2% 占比3％3% 占比5％5% 占比8％8% 占比10％10%
注：包衣增重占比是指片芯经过包衣处理后增加的重量与片芯重量的比例。Note: The proportion of coating weight gain refers to the ratio of the weight of the tablet core after coating treatment to the weight of the tablet core.
实施例2Example 2
片芯处方：Tablet prescription:
表4Table 4
Figure PCTCN2021112293-appb-000006
Figure PCTCN2021112293-appb-000006
包衣液处方：Coating liquid prescription:
表5table 5
Figure PCTCN2021112293-appb-000007
Figure PCTCN2021112293-appb-000007
Figure PCTCN2021112293-appb-000008
Figure PCTCN2021112293-appb-000008
制备方法同实施例1，其中包衣处理增重占比为3％。The preparation method is the same as that of Example 1, wherein the weight gain ratio of coating treatment is 3%.
注：纯化水在包衣的制备过程中将会被烘干，包衣的处方中将不计算纯化水用量。Note: Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
实施例3Example 3
片芯处方：Tablet prescription:
表6Table 6
Figure PCTCN2021112293-appb-000009
Figure PCTCN2021112293-appb-000009
包衣液处方：Coating liquid prescription:
表7Table 7
Figure PCTCN2021112293-appb-000010
Figure PCTCN2021112293-appb-000010
Figure PCTCN2021112293-appb-000011
Figure PCTCN2021112293-appb-000011
注：纯化水在包衣的制备过程中将会被烘干，包衣的处方中将不计算纯化水用量。Note: Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
制备方法同实施例1，其中，包衣处理增重为3％。The preparation method is the same as that of Example 1, wherein, the weight gain of the coating treatment is 3%.
实施例4Example 4
片芯处方：Tablet prescription:
表8Table 8
Figure PCTCN2021112293-appb-000012
Figure PCTCN2021112293-appb-000012
包衣液处方：Coating liquid prescription:
表9Table 9
Figure PCTCN2021112293-appb-000013
Figure PCTCN2021112293-appb-000013
注：纯化水在包衣的制备过程中将会被烘干，包衣的处方中将不计算纯化水用量。Note: Purified water will be dried during the preparation of the coating, and the amount of purified water will not be calculated in the coating formulation.
制备方法同实施例1，其中，包衣处理增重为3％。The preparation method is the same as that of Example 1, wherein, the weight gain of the coating treatment is 3%.
测试一：Test one:
固体制剂中的药物在被吸收前，必须经过崩解和溶解然后转为溶液才能被吸收，因此进行体外溶出实验，模拟药物在宠物体内溶解释放的过程。取实施例1中的七份样品进行溶出检测。限度要求为30分钟内溶出不低于标示量的80％。溶出介质为0.4％SDS的37℃水溶液，转速100rpm，于30min取样5ml，过滤，取续滤液作为供试品溶液，测定米尔贝肟和吡喹酮溶出。检测结果见表10。Before being absorbed, the drug in the solid preparation must be disintegrated and dissolved and then converted into a solution before it can be absorbed. Therefore, an in vitro dissolution experiment was carried out to simulate the process of dissolution and release of the drug in the pet. Seven samples in Example 1 were taken for dissolution testing. The limit is required to dissolve no less than 80% of the declared amount within 30 minutes. The dissolution medium was 0.4% SDS in 37°C aqueous solution, the rotation speed was 100 rpm, 5 ml was sampled in 30 minutes, filtered, and the subsequent filtrate was taken as the test solution to measure the dissolution of mirbeoxime and praziquantel. The test results are shown in Table 10.
表10Table 10
编号serial number 米尔贝肟的溶出度(％)Dissolution of Milbeoxime (%) 吡喹酮的溶出度(％)Dissolution of Praziquantel (%)
样品一(片芯)Sample 1 (chip) 99.999.9 91.691.6
样品二(占比1％)Sample 2 (accounting for 1%) 99.899.8 91.591.5
样品三(占比2％)Sample 3 (accounting for 2%) 99.299.2 90.190.1
样品四(占比3％)Sample four (accounting for 3%) 98.598.5 89.589.5
样品五(占比5％)Sample Five (5%) 97.597.5 89.189.1
样品六(占比8％)Sample Six (8%) 95.695.6 85.485.4
样品七(占比10％)Sample Seven (10%) 72.572.5 73.473.4
由上表10数据显示，样品七(占比10％)检测不合格，药物的溶出减慢，影响药物在宠物体内释放，从而降低了产品的疗效。因此，包衣层为片芯的重量占比不要超过8％。The data in Table 10 above shows that sample 7 (10% of the sample) was unqualified, and the dissolution of the drug was slowed down, which affected the release of the drug in the pet, thereby reducing the efficacy of the product. Therefore, the weight of the coating layer for the tablet core should not exceed 8%.
测试二：Test two:
取实施例1中所制得的7份宠物用米尔贝肟吡喹酮风味片样品与普通工艺片(未采用微丸压片技术工艺的米尔贝肟吡喹酮片)进行宠物猫主动采食对比试验，试验场地为杭州市流浪宠物***。Take 7 parts of pet milbe oxime praziquantel flavored tablets samples and common process tablets (milbe oxime praziquantel tablets without pellet compression technology) prepared in Example 1 to carry out active feeding of pet cats For the comparison test, the test site was a stray pet shelter in Hangzhou.
其中，普通工艺片的具体配方及制备方法如下：Wherein, the concrete formula and preparation method of common technology sheet are as follows:
片芯处方：Tablet prescription:
表11Table 11
Figure PCTCN2021112293-appb-000014
Figure PCTCN2021112293-appb-000014
包衣液处方：Coating liquid prescription:
表12Table 12
Figure PCTCN2021112293-appb-000015
Figure PCTCN2021112293-appb-000015
注：普通工艺片处方中原辅料用量与实施例1相同，包衣增重占比为3％。Note: The dosage of raw and auxiliary materials in the prescription of the common technology tablet is the same as that of Example 1, and the weight gain of the coating is 3%.
制备方法：Preparation:
1)将处方量的米尔贝肟、吡喹酮与填充剂蔗糖、崩解剂交联羧甲基纤维素钠过50目筛处理，放入湿法制粒机中，混合均匀，得到混合物；1) Milbeoxime of recipe quantity, praziquantel, filler sucrose, disintegrating agent croscarmellose sodium are passed through 50 mesh sieves, put into wet granulator, and mix homogeneously to obtain mixture;
2)向步骤1)中的混合物中加入处方量的黏合剂15％聚维酮水溶液，同时开启剪切机进行制粒，得到湿颗粒；2) in the mixture in step 1), add the adhesive 15% aqueous solution of povidone of recipe quantity, open shearing machine simultaneously and carry out granulation, obtain wet granules;
3)将步骤2)中的湿颗粒转移至烘箱中进行烘干，烘干温度为45℃，颗粒进行过筛，筛网为24目，得到干颗粒；3) transfer the wet granules in step 2) to an oven for drying, the drying temperature is 45° C., the granules are sieved, and the sieve mesh is 24 meshes to obtain dry granules;
4)将步骤3)得到的干颗粒放入混合机，加入处方量的助流剂胶体二氧化 硅和润滑剂硬脂酸镁，混合均匀，压片，得到片芯；4) the dry particles obtained in step 3) are put into mixer, the glidant colloidal silicon dioxide and lubricant magnesium stearate of recipe quantity are added, mix homogeneously, and press tablet to obtain tablet core;
5)将处方量的包衣粉缓慢加入纯化水中，并不断搅拌至均一，得到包衣液；5) slowly adding the coating powder of the recipe amount into the purified water, and stirring continuously until uniform, to obtain a coating liquid;
6)将步骤4)中得到的片芯放入包衣机中，将步骤5)中的包衣液均匀喷洒在米尔贝肟吡喹酮片芯表面，形成包衣层，得到普通工艺米尔贝肟吡喹酮片。6) Put the tablet core obtained in step 4) into a coating machine, and evenly spray the coating solution in step 5) on the surface of the Mirbe oxime praziquantel tablet core to form a coating layer to obtain common technology Mirbe Oxime Praziquantel Tablets.
试验方法：随机选取160只宠物猫分成8组，每组20只，编号为A、B、C、D、E、F、G和H，将进行两项试验：1、分别投食实施例1中的7份样品和普通工艺片的样品，计算每组宠物主动采食率；2、将实施例1中的7份样品和普通工艺片的样品投喂至宠物口腔中，计算每组宠物未服用吐出的数量，试验结果见表13。Test method: 160 pet cats were randomly selected and divided into 8 groups, 20 cats in each group, numbered A, B, C, D, E, F, G and H, and two tests will be carried out: 1. Feeding Example 1 respectively 7 samples in the sample and the samples of the common process sheet, calculate the active feed intake rate of each group of pets; 2, 7 parts of the samples in the embodiment 1 and the samples of the common process sheet are fed into the pet's oral cavity, calculate the pet's unhealthy rate of each group of pets. Take the amount of spit, and the test results are shown in Table 13.
表13Table 13
Figure PCTCN2021112293-appb-000016
Figure PCTCN2021112293-appb-000016
由上表13结果显示，本发明的包衣后所制得的宠物用米尔贝肟吡喹酮风味片样品宠物主动采食率显著提高，远高于片芯样品，本发明的米尔贝肟吡喹酮风味片能解决宠物给药的难题。样品三的主动采食率达到80％，因此，包衣层为片芯的重量占比不要低于2％。The results in Table 13 above show that the active feed intake rate of the pet milbeoxime praziquantel flavored tablet sample prepared after the coating of the present invention is significantly improved, which is much higher than that of the tablet core sample. Quinone-flavored tablets can solve the problem of pet administration. The active feeding rate of sample three reached 80%, therefore, the weight of the coating layer as the tablet core should not be less than 2%.
反吐数为将药物投喂至宠物口腔中，而宠物未服用吐出的数量。从反吐率(表13)结果来看，采用了微丸压片技术工艺的米尔贝肟吡喹酮风味片的反吐率大幅 度降低，能很好的解决宠物反吐现象。The number of regurgitations is the number of drugs that are fed into the pet's mouth without the pet spitting out. Judging from the results of the anti-emesis rate (Table 13), the anti-emesis rate of the Milbeoxime praziquantel-flavored tablet that adopted the pellet compression technology process was greatly reduced, and the pet's emesis phenomenon could be well solved.
宠物用米尔贝肟吡喹酮风味片既要符合质量要求，不影响药物的疗效，又要提高宠物主动采食率，降低宠物反吐率，解决给药困难的难题。测试一和测试二结果表明，米尔贝肟吡喹酮风味片采用微丸压片技术工艺，同时片芯包衣处理，可以显著提高宠物主动采食率，降低宠物的反吐率。Milbeoxime praziquantel flavored tablets for pets should not only meet the quality requirements without affecting the efficacy of the drug, but also improve the pet's active feed intake rate, reduce the pet's regurgitation rate, and solve the difficult problem of drug administration. The results of test 1 and test 2 show that the mirbeoxime praziquantel flavored tablet adopts the technology of pellet compression, and the tablet core coating treatment can significantly improve the active feeding rate of pets and reduce the regurgitation rate of pets.
测试三：Test three:
取实施例1～实施例4所制备得到的样品进行微丸流动性、片面外观、脆碎度和崩解时间检测。The samples prepared in Examples 1 to 4 were taken to test the fluidity, surface appearance, friability and disintegration time of pellets.
微丸流动性的检测指标为：休止角＜40°；The testing index of pellet fluidity is: angle of repose<40°;
片面外观的检测指标为：肉眼观察，片面光滑；The detection index of one-sided appearance is: naked eye observation, one-sided smooth;
脆碎度的检测指标为：减失重量不得过0.8％，且始终不得检出断裂、龟裂及粉碎的片；The detection index of friability is: the weight loss shall not exceed 0.8%, and the broken, cracked and crushed pieces shall not be detected at all times;
崩解时间的检测指标为：崩解时间不得超过15分钟，检测结果见表14。The detection index of the disintegration time is: the disintegration time shall not exceed 15 minutes, and the detection result is shown in Table 14.
表14Table 14
Figure PCTCN2021112293-appb-000017
Figure PCTCN2021112293-appb-000017
由上表14中数据可知，本发明所提供的米尔贝肟吡喹酮风味片通过微丸压片且包衣处理的制备方法，制得的片剂片面外形美观、颗粒流动性好、耐磨性较强、崩解快；通过对处方及工艺的优化，保障了药物在生产过程中的稳定性，提高了产品质量。As can be seen from the data in the above table 14, the mirbene oxime praziquantel flavored tablet provided by the present invention is prepared by pellet compression and coating treatment, and the obtained tablet has a beautiful appearance, good particle fluidity, and wear resistance. It has strong properties and fast disintegration; through the optimization of the prescription and process, the stability of the drug in the production process is guaranteed, and the product quality is improved.
测试四：Test four:
药物在体内吸收速度常常由溶解的快慢而决定，溶出速度太快，可能产生明显的不良反应，维持药效的时间也将缩短，而溶出太慢，药物吸收不了，不能达到治疗作用的血药浓度，因此，药物的溶出速率应予以控制。取实施例1—实施 例4制备得到的样品进行溶出检测，限度要求为30分钟内溶出不低于标示量的80％。溶出介质为0.4％SDS的37℃水溶液，转速100rpm，于30min取样5ml，过滤，取续滤液作为供试品溶液，测定米尔贝肟和吡喹酮溶出，溶出结果见表15和表16。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 cannot achieve therapeutic effects. concentration, and therefore, the dissolution rate of the drug should be controlled. Take the samples prepared in Example 1-Example 4 for dissolution testing, and the limit requirement is that the dissolution is not less than 80% of the declared amount within 30 minutes. The dissolution medium was 0.4% SDS in a 37° C. aqueous solution, the rotation speed was 100 rpm, and 5 ml was sampled in 30 min, filtered, and the subsequent filtrate was taken as the test solution to measure the dissolution of mirbeoxime and praziquantel. The dissolution results are shown in Table 15 and Table 16.
表15 米尔贝肟的溶出度Table 15 Dissolution of Milbeoxime
时间time 30(min)30(min)
实施例1的样品四Sample four of Example 1 98.5％98.5%
实施例2Example 2 96.2％96.2%
实施例3Example 3 93.1％93.1%
实施例4Example 4 93.9％93.9%
表16 吡喹酮的溶出度Table 16 Dissolution of Praziquantel
时间time 30(min)30(min)
实施例1(样品四)Example 1 (sample four) 89.5％89.5%
实施例2Example 2 94.1％94.1%
实施例3Example 3 96.1％96.1%
实施例4Example 4 96.9％96.9%
由上述溶出数据得知，实施例1—实施例4制备得到的样品在30分钟内溶出都超过80％，全部符合质量标准要求。It can be known from the above dissolution data that the samples prepared in Examples 1 to 4 all dissolve more than 80% within 30 minutes, and all meet the requirements of the quality standard.
测试五：Test five:
本发明制备方法所生产的产品进行影响因素试验，将实施例1的样品四分别于高温60℃和40℃、高湿度RH75％和RH92.5％和强光照4500Lx±500Lx条件下放置，分别于5天、10天取样，检测，并与0天相比较，见下表17‐19。The products produced by the preparation method of the present invention are tested for influencing factors, and the samples four of Example 1 are placed under the conditions of high temperature 60°C and 40°C, high humidity RH75% and RH92.5%, and strong light 4500Lx±500Lx, respectively. 5 days, 10 days sampling, testing, and compared with 0 days, see Table 17-19 below.
有关物质的检查符合《中国兽药典》附录5页，片剂项下有关的各项规定，含量测定按照《中国兽药典》附录36页，高效液相色谱法测定。The inspection of relevant substances complies with the relevant provisions under the appendix 5 of the Chinese Veterinary Pharmacopoeia, and the content is determined according to the appendix 36 of the Chinese Veterinary Pharmacopoeia by high performance liquid chromatography.
有关物质：吡喹酮杂质A、B、C均匀不得过0.5％，米尔贝肟杂质D不得过1.5％，其他杂质不得过1.0％，总杂不得过6.0％；Relevant substances: Impurities A, B and C of praziquantel should not exceed 0.5% on average, impurity D of mirbeoxime should not exceed 1.5%, other impurities should not exceed 1.0%, and total impurities should not exceed 6.0%;
含量：米尔贝肟和吡喹酮含量均为标示量的90.0％‐110.0％；Content: Milbeoxime and Praziquantel are both 90.0%-110.0% of the labelled amount;
溶出度：限度要求为30分钟内溶出不低于标示量的80％。Dissolution: The limit is required to dissolve no less than 80% of the declared amount within 30 minutes.
表17 高温试验结果Table 17 High temperature test results
Figure PCTCN2021112293-appb-000018
Figure PCTCN2021112293-appb-000018
表18 光照试验结果Table 18 Illumination test results
Figure PCTCN2021112293-appb-000019
Figure PCTCN2021112293-appb-000019
表19 高湿度试验结果Table 19 High humidity test results
Figure PCTCN2021112293-appb-000020
Figure PCTCN2021112293-appb-000020
Figure PCTCN2021112293-appb-000021
Figure PCTCN2021112293-appb-000021
由上表17-19影响因素数据分析，本发明所提供的处方及根据本发明制备方法制备得到的产品在高温、高湿度和光照条件下的稳定性良好。According to the data analysis of influencing factors in Tables 17-19 above, the formulation 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.
测试六：Test six:
采用本发明制备方法所生产的产品进行临床试验，观察米尔贝肟吡喹酮风味片(实施例1中的样品四)对猫体内寄生虫的临床效果，同时观察其用药期间可能出现的不良反应。The products produced by the preparation method of the present invention are used to carry out clinical trials to observe the clinical effect of mirboxime praziquantel flavored tablets (sample four in Example 1) on parasites in cats, and to observe possible adverse reactions during their administration. .
试验动物：家猫，年龄为1.5月龄至成年。猫运至实验室后分笼饲养7～10d，使猫适应环境和驯服，并观察猫的精神与食欲等。同时逐一采集猫刚排出的粪便， 分别用饱和盐水漂浮法与水洗沉淀法检查蠕虫虫卵。其中，猫弓首蛔虫、毛细线虫、钩虫、华支睾吸虫、棘口吸虫、咽口吸虫、迭宫绦虫、复孔绦虫虫卵中至少之一呈阳性，且精神与食欲良好的猫用于试验。Test animals: domestic cats, aged 1.5 months to adults. After the cats were transported to the laboratory, they were reared in separate cages for 7-10 days, so that the cats could adapt to the environment and tame, and the spirit and appetite of the cats were observed. At the same time, the feces just excreted by the cats were collected one by one, and the worm eggs were examined by the saturated saline flotation method and the water washing sedimentation method respectively. Among them, at least one of the eggs of Toxocara felis, Capillary nematodes, hookworms, Clonorchis sinensis, Acanthostomatosus, Pharyngosomiasis, Taenia trichomoniasis, and Taenia polyporus eggs are positive, and cats with good spirit and appetite are used for test.
试验分组：Test grouping:
按照随机方式，将动物分成3个组，即：In a random manner, animals were divided into 3 groups, namely:
Ⅰ组：米尔贝肟吡喹酮风味片低剂量组，米尔贝肟1mg/kg+吡喹酮2.5mg/kg；Group Ⅰ: Milbeoxime praziquantel flavored tablet low-dose group, milbeoxime 1 mg/kg + praziquantel 2.5 mg/kg;
Ⅱ组：米尔贝肟吡喹酮风味片中剂量组，米尔贝肟2mg/kg+吡喹酮5mg/kg；Group Ⅱ: Milbeoxime praziquantel flavored tablet middle-dose group, milbeoxime 2mg/kg + praziquantel 5mg/kg;
Ⅲ组：米尔贝肟吡喹酮风味片高剂量组，米尔贝肟4mg/kg+吡喹酮10mg/kg。Group III: Milbeoxime praziquantel flavor tablet high-dose group, mirbeoxime 4 mg/kg + praziquantel 10 mg/kg.
每组35只猫，各组间猫感染的虫卵种类相近，如下表20：There are 35 cats in each group, and the types of worm eggs infected by cats in each group are similar, as shown in Table 20 below:
表20 各试验组猫感染的蠕虫种类与猫数量Table 20 Types of worms and the number of cats infected by cats in each experimental group
Figure PCTCN2021112293-appb-000022
Figure PCTCN2021112293-appb-000022
给药方案：Dosing regimen:
米尔贝肟吡喹酮风味片中剂量组口服给药一次。低剂量组与高剂量组的给药方案与中剂量组相似，但剂量减半或加倍。The middle-dose group of mirbeoxime praziquantel flavored tablets was orally administered once. The dosing regimens of the low-dose and high-dose groups were similar to those of the mid-dose group, but the doses were halved or doubled.
临床观察：Clinical Observation:
给药后每天上、下午各一次对给药猫进行以下项目观察：猫的精神状态、饮食欲、活动性；排虫情况，并收集排出的虫体或节片进行虫种鉴定，以了解排出情况和排虫高峰。After administration, the following items were observed on the administered cat once a day in the morning and in the afternoon: the cat's mental state, appetite, activity; worm excretion, and the excreted worms or segments were collected for worm species identification to understand the excretion. Situation and expulsion peak.
粪便虫卵计数：Fecal egg count:
分别在给药前1天和给药后第7天与第14天，收集感染毛细线虫的猫新鲜粪便，用麦克马斯特氏法计算克粪虫卵数。The fresh feces of cats infected with Capillary nematodes were collected on the 1st day before administration and on the 7th and 14th days after administration, respectively, and the number of C. feces eggs was calculated by McMaster's method.
寄生虫学剖检：Parasitological necropsy:
在给药后第15天，所有的试验猫进行安乐死。随后按寄生虫学完全剖检法，收集各只猫消化道、肝脏、气管与肺脏、膀胱内的虫体，鉴定种类，并以虫种类别分别计数。On day 15 after dosing, all test cats were euthanized. Then, according to the complete necropsy method of parasitology, the worms in the digestive tract, liver, trachea, lung, and bladder of each cat were collected, the species were identified, and the species were counted separately.
效果评价：Evaluation:
按粪便虫卵数变化，每只动物的临床药效试验结果按下列标准评价：According to the change in the number of fecal eggs, the clinical efficacy test results of each animal are evaluated according to the following standards:
①治愈：粪便中蠕虫虫卵减少率≥90％，试验动物的体征恢复正常。①Cure: The reduction rate of worm eggs in the feces is ≥90%, and the signs of the experimental animals return to normal.
②有效：粪便中蠕虫虫卵减少率≥60％，动物的体征好转但未完全恢复正常。② Effective: the reduction rate of worm eggs in the feces is more than 60%, and the physical signs of the animals are improved but not completely restored to normal.
③无效：粪便中蠕虫虫卵减少率<60％，动物病情无明显缓解，仍有腹泻、呕吐等临床表现。③ Ineffective: the reduction rate of worm eggs in the feces is less than 60%, the animal's condition is not significantly relieved, and there are still clinical manifestations such as diarrhea and vomiting.
临床观察结果见表21‐27：The clinical observations are shown in Tables 21-27:
在整个试验期间，所有试验猫的精神、食欲、排粪均正常。猫给药后排出虫体的时间，最早在给药后1h，最迟在给药后第6天，但排虫高峰在给药后48～72h。用肉眼在粪便中能检视到的虫体主要是猫弓首蛔虫和绦虫。The spirit, appetite and defecation of all test cats were normal throughout the test period. The time for cats to excrete parasites after administration was 1h after administration at the earliest and 6th day after administration at the latest, but the peak of expelling parasites was 48-72 hours after administration. The worms that can be detected in feces with the naked eye are mainly Toxocara feline and tapeworms.
驱虫效率：Deworming efficiency:
根据在猫体内检获的各种蠕虫的虫体数，按下列公式计算各受试药物剂量组、药物对照组各种蠕虫的驱虫率。According to the number of worms detected in cats, the deworming rate of various helminths in each tested drug dose group and drug control group was calculated according to the following formula.
Figure PCTCN2021112293-appb-000023
Figure PCTCN2021112293-appb-000023
根据给药前及给药后不同时间猫粪便中的毛细线虫卵的变化情况，按下列公式计算各受试药物剂量组与药物对照组毛细线虫卵的减少率与虫卵转阴率。According to the changes of capillary nematode eggs in cat feces before and after administration, the reduction rate of capillary nematode eggs and the negative rate of eggs in each tested drug dose group and drug control group were calculated according to the following formulas.
Figure PCTCN2021112293-appb-000024
Figure PCTCN2021112293-appb-000024
Figure PCTCN2021112293-appb-000025
Figure PCTCN2021112293-appb-000025
用SPSS软件对各组给药前后EPG平均数及组间不同时期虫卵减少率进行描述性统计，并用Duncan氏新复极差法对组间均值进行多重比较(P﹤0.05)。SPSS software was used for descriptive statistics of the mean number of EPG before and after administration in each group and the reduction rate of worm eggs in different periods between groups, and Duncan's new multiple range method was used to conduct multiple comparisons between groups (P﹤0.05).
表21 对华支睾吸虫的驱虫效率Table 21 Deworming efficiency of Clonorchis sinensis
Figure PCTCN2021112293-appb-000026
Figure PCTCN2021112293-appb-000026
表22 对棘口与咽口吸虫的驱虫效率Table 22 Deworming efficiency of mouth flukes and pharyngeal flukes
Figure PCTCN2021112293-appb-000027
Figure PCTCN2021112293-appb-000027
表23 对孟氏迭宫绦虫的驱虫效率Table 23 Efficacy of deworming against T. mongolica
Figure PCTCN2021112293-appb-000028
Figure PCTCN2021112293-appb-000028
Figure PCTCN2021112293-appb-000029
Figure PCTCN2021112293-appb-000029
表24 对复孔绦虫的驱虫效率Table 24 Deworming efficiency against Taenia polyporus
Figure PCTCN2021112293-appb-000030
Figure PCTCN2021112293-appb-000030
表25 对猫弓首蛔虫的驱虫效率Table 25 Deworming efficiency against Toxocara feline
Figure PCTCN2021112293-appb-000031
Figure PCTCN2021112293-appb-000031
表26 对钩虫的驱虫效率Table 26 Deworming efficiency against hookworms
Figure PCTCN2021112293-appb-000032
Figure PCTCN2021112293-appb-000032
表27 对毛细线虫的驱虫效率Table 27 Deworming efficiency against capillary nematodes
Figure PCTCN2021112293-appb-000033
Figure PCTCN2021112293-appb-000033
Figure PCTCN2021112293-appb-000034
Figure PCTCN2021112293-appb-000034
注：同行右上角标注不同字母a和b表示数值间差异显著(P<0.05)。Note: Different letters a and b are marked in the upper right corner of the same line, indicating that there is a significant difference between the values (P<0.05).
综观上述试验结果，表明采用本发明处方及制备方法生产的米尔贝肟吡喹酮风味片，对猫感染的猫弓首蛔虫、毛细线虫、钩虫、华支睾吸虫、棘口吸虫、咽口吸虫、孟氏迭宫绦虫和复孔绦虫均有良好驱虫效果。建议临床上对猫弓首蛔虫、钩虫、棘口吸虫、咽口吸虫和复孔绦虫的用药量为中剂量，一次经口投服；对毛细线虫的用药量为高剂量，一次经口投服；对孟氏迭宫绦虫的用药量为高剂量，需重复用药，连用两天，每天一次。Looking at the above-mentioned test results, it is shown that the mirbeoxime praziquantel flavored tablet produced by the prescription and preparation method of the present invention is effective against Toxocara felis, Capillary nematode, Hookworm, Clonorchis sinensis, Acanthostomia, Pharyngosomiasis infected by cats. , Monteggia serrata and Taenia polypora have good deworming effect. It is recommended that the clinical dosage for Toxocara feline, hookworm, Acanthostomatosus, Pharyngeal fluke and Tapeworm is a medium dose, once orally; for Capillary nematode, a high dose, once orally ; The dosage of M. mongolica tapeworm is high dose, and it needs to be repeated for two days, once a day.
不良反应观察：Adverse reaction observation:
各试验组猫给药后，对用药前与用药后猫的精神状态、饮食欲、活动性进行比较，均未发现与给药相关的异常反应。After administration of 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 administration were found.

Claims (11)

  1. 一种米尔贝肟吡喹酮风味片，其特征在于，所述米尔贝肟吡喹酮风味片由片芯和包覆在片芯表面的不含药的包衣层组成，所述包衣层是一层或多层，所述包衣层中含有至少一种矫味剂；所述片芯由微丸、助流剂、润滑剂组成。A mirboxime praziquantel flavored tablet, characterized in that the mirboxime praziquantel flavored tablet is composed of a tablet core and a drug-free coating layer coated on the surface of the tablet core, and the coating layer It is one or more layers, and the coating layer contains at least one flavoring agent; the tablet core is composed of pellets, glidants, and lubricants.
  2. 根据权利要求1所述的米尔贝肟吡喹酮风味片，其特征在于，所述片芯中微丸、助流剂、润滑剂的重量百分比为Milbeoxime praziquantel flavored tablet according to claim 1, is characterized in that, the weight percent of pellet, glidant, lubricant in described tablet core is
    微丸            95.0％—98.0％Pellets 95.0%—98.0%
    助流剂            1.0％—2.5％Glidant 1.0%—2.5%
    润滑剂            1.0％—2.5％。Lubricant 1.0%-2.5%.
  3. 根据权利要求2所述的米尔贝肟吡喹酮风味片，其特征在于，所述助流剂为硅酸钙、胶体二氧化硅或二氧化硅中的一种或多种的组合；所述润滑剂为硬脂酸镁、滑石粉或山嵛酸甘油酯中的一种或多种的组合。Milbeoxime praziquantel flavored tablet according to claim 2, is characterized in that, described glidant is one or more combination in calcium silicate, colloidal silicon dioxide or silicon dioxide; The lubricant is a combination of one or more of magnesium stearate, talc or glyceryl behenate.
  4. 根据权利要求1或2所述的米尔贝肟吡喹酮风味片，其特征在于，所述微丸的粒径大小在200～400微米之间。The mirboxime praziquantel flavored tablet according to claim 1 or 2, wherein the particle size of the pellets is between 200 and 400 microns.
  5. 根据权利要求1或2所述的米尔贝肟吡喹酮风味片，其特征在于，所述微丸由米尔贝肟、吡喹酮、填充剂、崩解剂、黏合剂组成，其中所述米尔贝肟、吡喹酮、填充剂、崩解剂、黏合剂的重量百分比为The mirboxime praziquantel flavored tablet according to claim 1 or 2, wherein the pellet is composed of mirboxime, praziquantel, a filler, a disintegrating agent and a binding agent, wherein the mirboxime The weight percentages of beoxime, praziquantel, filler, disintegrant, and binder are:
    Figure PCTCN2021112293-appb-100001
    Figure PCTCN2021112293-appb-100001
  6. 根据权利要求5所述的米尔贝肟吡喹酮风味片，其特征在于，所述填充剂为微晶纤维素、麦芽糊精、单水乳糖、蔗糖、淀粉或糊精中的一种或多种的组合；所述崩解剂为干淀粉、羧甲基淀粉钠、交联聚乙烯吡咯烷酮或交联羧甲基纤维素钠中的一种或多种的组合；所述黏合剂为聚维酮、羧甲基纤维素钠或羟丙基甲基纤维素中的一种或多种的组合。Milbeoxime praziquantel flavored tablet according to claim 5, wherein the filler is one or more of microcrystalline cellulose, maltodextrin, lactose monohydrate, sucrose, starch or dextrin The combination of different species; the disintegrating agent is one or more of dry starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone or cross-linked sodium carboxymethyl cellulose; the binding agent is polyvinyl chloride A combination of one or more of ketones, sodium carboxymethylcellulose, or hydroxypropylmethylcellulose.
  7. 根据权利要求1所述的米尔贝肟吡喹酮风味片，其特征在于，所述包衣层占片芯重量的2.0％—8.0％，优选为3.0％—5.0％。The mirbeoxime praziquantel flavored tablet according to claim 1, wherein the coating layer accounts for 2.0%-8.0% of the tablet core weight, preferably 3.0%-5.0%.
  8. 根据权利要求1所述的米尔贝肟吡喹酮风味片，其特征在于，所述包衣层含有着色剂、矫味剂和成膜剂，其中着色剂、矫味剂和成膜剂的重量百分比为Milbeoxime praziquantel flavored tablet according to claim 1, wherein the coating layer contains a colorant, a flavoring agent and a film-forming agent, wherein the weight of the coloring agent, the flavoring agent and the film-forming agent The percentage is
    矫味剂             10％—30％Flavoring agent 10%—30%
    着色剂            1.0％—10％Colorant 1.0%—10%
    成膜剂            60％—89％。Film former 60%-89%.
  9. 根据权利要求8所述的米尔贝肟吡喹酮风味片，其特征在于，所述的矫味剂为鸡肝粉、牛肉香精、牛肉提取物或乐达香中的一种或多种的组合；所述的着色剂为日落黄、日落红、氧化铁红或氧化铁黄中的一种或多种的组合；所述的成膜剂为滑石粉、聚乙二醇6000、羟丙基甲基纤维素中的一种或多种的组合。The mirbeoxime praziquantel flavored tablet according to claim 8, wherein the flavoring agent is a combination of one or more of chicken liver powder, beef essence, beef extract or Ledaxiang ; Described colorant is the combination of one or more in sunset yellow, sunset red, iron oxide red or iron oxide yellow; Described film-forming agent is talcum powder, polyethylene glycol 6000, hydroxypropyl methyl alcohol A combination of one or more of the base celluloses.
  10. 一种如权利要求1所述的米尔贝肟吡喹酮风味片的制备方法，其特征在于，包括如下步骤：A kind of preparation method of mirboxime praziquantel flavor tablet as claimed in claim 1, is characterized in that, comprises the steps:
    1)将处方量的米尔贝肟、吡喹酮、填充剂、崩解剂过50目筛处理，放入流化床中，药物和辅料在流化床下部40℃‐50℃热空气流的作用下，混合均匀，得到混合物；1) Pass the 50 mesh sieve of mirbeoxime, praziquantel, filler and disintegrant in the prescribed amount and put them into the fluidized bed. Under the action, mix uniformly to obtain a mixture;
    2)向步骤1)中的混合物中喷入处方量的黏合剂溶液，吸收了溶液的粉末开始粘结成小颗粒，随着粘合剂溶液的不断加入，小颗粒慢慢聚合形成粗微丸；2) Into the mixture in step 1), spray the adhesive solution of the recipe quantity, the powder that has absorbed the solution starts to bond into small particles, and with the continuous addition of the adhesive solution, the small particles slowly aggregate to form coarse pellets ;
    3)将步骤2)中的得到的粗微丸继续在流化床40℃‐50℃烘干，进行两次过筛，得到微丸；3) continue drying the coarse pellets obtained in step 2) in a fluidized bed at 40°C-50°C, and sieve twice to obtain pellets;
    4)在步骤3)得到的微丸中加入处方量的助流剂和润滑剂，混合均匀，压片，得所述的片芯；4) in the pellet obtained in step 3), add the glidant and lubricant of recipe quantity, mix well, press tablet, and obtain described tablet core;
    5)将处方量的包衣粉缓慢加入纯化水中，并不断搅拌至均一，得到包衣液；5) slowly adding the coating powder of the recipe amount into the purified water, and stirring continuously until uniform, to obtain a coating liquid;
    6)将步骤4)中得到的片芯放入包衣机中，将步骤5)中的包衣液均匀喷洒在米尔贝肟吡喹酮片芯表面，形成包衣层；直至片增重2.0％‐8.0％，得到米尔贝肟吡喹酮风味片。6) Put the tablet core obtained in step 4) into a coating machine, and spray the coating solution in step 5) evenly on the surface of the mirbexime praziquantel tablet core to form a coating layer; until the tablet weight gain is 2.0 %-8.0% to obtain mirbeoxime praziquantel flavored tablets.
  11. 根据权利要求10所述的米尔贝肟吡喹酮风味片的制备方法，其特征在于，所述步骤3)中的两次过筛的筛网孔径依次为400微米和200微米。The preparation method of mirboxime praziquantel flavored tablet according to claim 10, characterized in that, in the step 3), the screen apertures of the two sievings are 400 microns and 200 microns successively.
PCT/CN2021/112293 2020-08-13 2021-08-12 Milbemycin oxime and praziquantel flavor tablets and preparation method therefor WO2022033553A1 (en)

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112220769A (en) * 2020-08-13 2021-01-15 浙江海正动物保健品有限公司 Milbemycin oxime praziquantel flavored tablet and preparation method thereof
CN114796140B (en) * 2022-04-29 2024-04-02 丽珠集团新北江制药股份有限公司 Milbenoxime praziquantel soft chewable tablet with good palatability for animals and preparation method thereof
CN115006364B (en) * 2022-07-01 2024-02-13 丽珠集团新北江制药股份有限公司 Preparation method and product of milbexime praziquantel flavor tablet for pets
CN115487164B (en) * 2022-09-20 2023-08-18 中农华威生物制药(湖北)有限公司 Praziquantel pill capable of being put in unmanned aerial vehicle
CN116585278B (en) * 2023-07-17 2023-09-22 济南广盛源生物科技有限公司 Milbezoxime praziquantel chewable tablet as well as preparation method and application thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030190343A1 (en) * 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals
CN101194672A (en) * 2007-12-24 2008-06-11 新疆维吾尔自治区畜牧科学院兽医研究所 Automatic devouring agent for animals
CN101933929A (en) * 2009-07-02 2011-01-05 天津瑞普生物技术股份有限公司 Compound preparation for expelling in-vivo and in-vitro parasites from dogs and cats and preparation method thereof
CN105796527A (en) * 2016-03-28 2016-07-27 赤峰赛林泰药业有限公司 Pramipexole hydrochloride preparation and preparing technology thereof
CN107510669A (en) * 2016-06-16 2017-12-26 游锡火 A kind of dog containing phagostimulant, cat dropping pill formulation
CN112220769A (en) * 2020-08-13 2021-01-15 浙江海正动物保健品有限公司 Milbemycin oxime praziquantel flavored tablet and preparation method thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CO5400144A1 (en) * 2002-03-11 2004-05-31 Novartis Ag ORGANIC COMPOUNDS
GB2475701B (en) * 2009-11-26 2011-10-19 Michael Hilary Burke A process for the preparation of an orally administered anthelmintic unit dose tablet
CN107496368A (en) * 2016-06-14 2017-12-22 游锡火 A kind of dog containing anti-parasite medicine and phagostimulant, cat pill

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030190343A1 (en) * 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals
CN101194672A (en) * 2007-12-24 2008-06-11 新疆维吾尔自治区畜牧科学院兽医研究所 Automatic devouring agent for animals
CN101933929A (en) * 2009-07-02 2011-01-05 天津瑞普生物技术股份有限公司 Compound preparation for expelling in-vivo and in-vitro parasites from dogs and cats and preparation method thereof
CN105796527A (en) * 2016-03-28 2016-07-27 赤峰赛林泰药业有限公司 Pramipexole hydrochloride preparation and preparing technology thereof
CN107510669A (en) * 2016-06-16 2017-12-26 游锡火 A kind of dog containing phagostimulant, cat dropping pill formulation
CN112220769A (en) * 2020-08-13 2021-01-15 浙江海正动物保健品有限公司 Milbemycin oxime praziquantel flavored tablet and preparation method thereof

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