CN115006364A - Preparation method of milbemycin oxime praziquantel flavored tablets for pets and products - Google Patents
Preparation method of milbemycin oxime praziquantel flavored tablets for pets and products Download PDFInfo
- Publication number
- CN115006364A CN115006364A CN202210770051.7A CN202210770051A CN115006364A CN 115006364 A CN115006364 A CN 115006364A CN 202210770051 A CN202210770051 A CN 202210770051A CN 115006364 A CN115006364 A CN 115006364A
- Authority
- CN
- China
- Prior art keywords
- praziquantel
- tablet
- preparation
- agent
- milbemycin oxime
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960002957 praziquantel Drugs 0.000 title claims abstract description 36
- CKVMAPHTVCTEMM-ALPQRHTBSA-N milbemycin oxime Chemical compound O1[C@H](C)[C@@H](C)CC[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\2)O)C[C@H]4C1.C1C[C@H](C)[C@@H](CC)O[C@@]21O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\1)O)C[C@H]4C2 CKVMAPHTVCTEMM-ALPQRHTBSA-N 0.000 title claims abstract description 34
- 229940099245 milbemycin oxime Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000011248 coating agent Substances 0.000 claims abstract description 31
- 238000000576 coating method Methods 0.000 claims abstract description 31
- 239000011247 coating layer Substances 0.000 claims abstract description 16
- 239000000796 flavoring agent Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000000945 filler Substances 0.000 claims abstract description 12
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000003086 colorant Substances 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 4
- 239000011812 mixed powder Substances 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 238000002156 mixing Methods 0.000 claims description 21
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 14
- 229940069328 povidone Drugs 0.000 claims description 14
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 12
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 10
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 10
- 235000015278 beef Nutrition 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 239000000853 adhesive Substances 0.000 claims description 8
- 230000001070 adhesive effect Effects 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 238000005507 spraying Methods 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 239000004375 Dextrin Substances 0.000 claims description 5
- 229920001353 Dextrin Polymers 0.000 claims description 5
- 241000287828 Gallus gallus Species 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 235000019425 dextrin Nutrition 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940040511 liver extract Drugs 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 235000013336 milk Nutrition 0.000 claims description 2
- 239000008267 milk Substances 0.000 claims description 2
- 210000004080 milk Anatomy 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 229910021487 silica fume Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000005550 wet granulation Methods 0.000 abstract description 6
- 235000019634 flavors Nutrition 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 239000007767 bonding agent Substances 0.000 abstract 1
- 238000007907 direct compression Methods 0.000 abstract 1
- 239000010410 layer Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000002356 single layer Substances 0.000 abstract 1
- 241000282472 Canis lupus familiaris Species 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000005303 weighing Methods 0.000 description 6
- 235000019629 palatability Nutrition 0.000 description 5
- 239000008188 pellet Substances 0.000 description 4
- 239000005434 MCC/mannitol excipient Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000000507 anthelmentic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000019658 bitter taste Nutrition 0.000 description 2
- 239000012496 blank sample Substances 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- -1 pyrazinoisoquinoline compound Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 241001465677 Ancylostomatoidea Species 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- 241001327965 Clonorchis sinensis Species 0.000 description 1
- 241000192043 Echinochloa Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000002163 Mesapamea fractilinea Species 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- 206010038776 Retching Diseases 0.000 description 1
- 241001408636 Toxocarpus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 244000000053 intestinal parasite Species 0.000 description 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
Classifications
-
- 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
- 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
- A61K9/2009—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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/28—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of pet medicines, and particularly relates to a preparation method of a milbemycin oxime praziquantel flavor tablet for pets and a product, wherein the flavor tablet consists of a tablet core and a single-layer or multi-layer coating layer of non-medicinal active ingredients coating the tablet core, and the tablet core is prepared from the following raw materials: milbemycin oxime, praziquantel, a filling agent, a disintegrating agent, a bonding agent, a glidant and a lubricant; the coating layer is prepared from a flavoring agent, a coloring agent and a film forming agent. In some embodiments of the invention, the milbemycin oxime praziquantel flavored tablet with the structure of the tablet core and the coating layer is prepared by a direct compression process, so that the traditional wet granulation process is simplified, the production time is shortened, the production cost is reduced, the yield of a finished product is improved, and the content loss of effective medicinal active ingredients is reduced.
Description
Technical Field
The invention relates to the technical field of pet medicines, in particular to a preparation method and a product of a milbemycin oxime praziquantel flavored tablet for pets.
Background
The milbemycin oxime is a novel semisynthetic macrolide anthelmintic, has an effect of expelling and killing parasites in vivo and in vitro, is a specific medicine for treating heartworm and intestinal parasites of dogs and cats, has the characteristics of broad-spectrum insecticidal activity, good absorption, high safety and the like, is widely used for clinically preventing and treating the parasites in vivo and in vitro of dogs and cats, is a pyrazinoisoquinoline compound and is a preferred medicine for clinically treating schistosomiasis, and has good anthelmintic effects on pet-infected clonorchis sinensis, echinochloa, oropharyngeal fluke, montelukast tapeworm, toxocarpus felis, hookworm and capillary nematode when the milbemycin oxime and the praziquantel are used together.
The tablet is used as one of mainstream dosage forms of pet medication, has good universality and practicability, is convenient and fast, and reduces pet stress and medication difficulty of users, wherein the palatability of the tablet is one of important influence factors of pet medication. The milbemycin oxime praziquantel has certain peculiar smell and bitter taste, which can affect the palatability of the tablet, although the palatability of the tablet can be increased by adding the phagostimulant, the tablet can be chewed in the mouth of a pet and then is bitten, and the effect of covering the bitter taste of the medicine cannot be achieved. The problem of palatability of tablets can be solved by preparing the tablets into a coating layer and a tablet core structure, coating the tablet core with milbemycin oxime praziquantel and using a non-drug-containing coating layer containing a phagostimulant. However, most of the production processes of the pet milbemycin oxime praziquantel tablets on the market are traditional wet granulation, and in the actual production, the wet granulation process is complex, the production time is long, the cost is high, the yield is low, meanwhile, uncertain factors such as moisture and the like can be brought in the slurry spraying process, and factors such as unstable main medicine content and related substances and the like in the long-time drying and drying process affect the product quality. Thus, it is seen that a new tablet formulation is sought.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a preparation method of a milbemycin oxime praziquantel flavored tablet for pets.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
a preparation method of a milbemycin oxime praziquantel flavored tablet for pets comprises the following steps:
1) mixing the milbemycin oxime, the praziquantel, the disintegrating agent, the adhesive and the filler 1/3 according to the amount of the prescription, and then sieving to obtain mixed powder 1;
2) adding 1/3 filler into the mixed powder 1 in the step 1, and uniformly mixing to obtain mixed powder 2;
3) adding the remaining 1/3 amount of filler into the mixed powder 2 obtained in the step 2, and uniformly mixing to obtain mixed powder 3;
4) adding a flow aid in a weight ratio of 1-3% to mix, adding a lubricant in a prescription amount to mix uniformly, and tabletting to obtain a tablet core;
5) adding coating powder into pure water according to the solid content of 12%, and continuously stirring until the mixture is uniform to obtain a coating solution;
6) and (3) putting the tablet core obtained in the step (4) into a coating machine, uniformly spraying the coating liquid obtained in the step (5) on the surface of the tablet core to form a coating layer until the weight of the coating layer is increased to 2% -8% of the weight of the tablet core, and cooling and drying to obtain the milbeoxime praziquantel flavored tablet.
In some embodiments, the tablet core comprises the following components in parts by weight: 1-10% of milbemycin oxime, 1-20% of praziquantel, 40-80% of filling agent, 1-5% of disintegrating agent, 0.1-3% of adhesive, 1-3% of glidant and 0.5-2.5% of lubricant.
In some embodiments, the coating layer comprises 2% to 8% of the tablet core by weight fraction.
In some embodiments, the filler is microcrystalline cellulose, starch, lactose, mannitol, sucrose, fructose, dextrin, or a combination thereof; and/or the disintegrating agent is one or a combination of more of sodium carboxymethyl starch, crospovidone and sodium carboxymethyl cellulose; and/or the adhesive is one or a combination of more of hydroxypropyl methylcellulose, povidone, dry starch and dextrin; and/or the glidant is one or a combination of more of colloidal silicon dioxide, superfine silica gel powder and titanium dioxide; and/or the lubricant is one or a combination of magnesium stearate, talcum powder and sodium stearyl fumarate.
In some embodiments, the coating layer comprises 5-30% of a flavoring agent, 1-10% of a coloring agent, and 60-90% of a film forming agent.
In some embodiments, the flavoring agent is one or a combination of chicken liver extract, beef essence, beef extract and milk essence.
In some embodiments, the colorant is one or a combination of red iron oxide, yellow iron oxide, sunset red, or sunset yellow.
In some embodiments, the film forming agent is one or a combination of polyethylene glycol, talcum powder and hypromellose.
In some embodiments, the tablet core comprises the following components in parts by weight: 1-10% of milbemycin oxime, 1-20% of praziquantel, 40-80% of microcrystalline cellulose and lactose, 1-3% of sodium carboxymethylcellulose, 1-2% of povidone, 1-3% of colloidal silicon dioxide and 0.5-1% of magnesium stearate.
In a second aspect of the present invention, there is provided:
a milbemycin oxime praziquantel flavored tablet for pets, which is prepared by using the preparation method of the first aspect of the invention.
The invention has the beneficial effects that:
simplifies the preparation process of the tablet, shortens the production time, reduces the production cost, improves the yield of the finished product, reduces the influence of the traditional wet granulation on the content of the common tablet, and improves the palatability of the common tablet.
Detailed Description
The technical scheme of the invention is further explained by combining experiments.
Example 1
Tablet core: 40 parts of milbemycin oxime, 100 parts of praziquantel, 800 parts of microcrystalline cellulose, 20 parts of sodium carboxymethylcellulose, 5 parts of povidone, 20 parts of colloidal silicon dioxide and 15 parts of magnesium stearate.
Coating layer: 10 parts of beef flavor, 5 parts of iron oxide yellow, 57 parts of hydroxypropyl methylcellulose and 30 parts of talcum powder.
The preparation method comprises the following steps:
1) dividing microcrystalline cellulose into 3 parts in equal amount, weighing milbemycin oxime, praziquantel, sodium carboxymethylcellulose, povidone and 1/3 parts of microcrystalline cellulose, premixing, and sieving with a 30-mesh sieve to obtain mixed powder 1;
2) adding 1/3 mass of microcrystalline cellulose into the mixed powder 1, and uniformly mixing to obtain mixed powder 2;
3) adding the residual 1/3 mass of microcrystalline cellulose into the mixed powder 2, and mixing uniformly to obtain a mixed part 3;
4) weighing the mixed powder 3, adding a corresponding amount of colloidal silicon dioxide according to a proportion, mixing, adding magnesium stearate, continuously and uniformly mixing to obtain total mixed powder, and tabletting to obtain a tablet core;
5) slowly pouring the coating powder into purified water according to solid content, and continuously stirring until the coating powder is uniform to obtain a coating solution.
6) And (3) uniformly spraying the coating solution obtained in the step (5) on the tablet core through a coating machine until the weight of the coating is increased to 3% of the mass of the tablet core, stopping coating, cooling and drying to obtain the milbemycin oxime praziquantel flavored tablet.
Example 2
Tablet core: 16 parts of milbemycin oxime, 40 parts of praziquantel, 250 parts of microcrystalline cellulose, 150 parts of lactose, 10 parts of sodium carboxymethylcellulose, 10 parts of povidone, 15 parts of colloidal silicon dioxide and 5 parts of magnesium stearate.
Coating layer: 20 parts of chicken liver extract, 5 parts of iron oxide red, 30 parts of hydroxypropyl methylcellulose and 45 parts of polyethylene glycol.
The preparation method comprises the following steps:
1) dividing microcrystalline cellulose into 3 parts in equal amount, weighing milbemycin oxime, praziquantel, sodium carboxymethylcellulose and povidone in the amount of the prescription, premixing microcrystalline cellulose and lactose in the amount of 1/3, sieving with a 30-mesh sieve, and uniformly mixing to obtain mixed powder 1;
2) adding 1/3 amounts of microcrystalline cellulose and lactose mixture into the mixed powder 1, and mixing uniformly to obtain mixed powder 2;
3) adding the rest 1/3 amounts of microcrystalline cellulose and lactose mixture into the mixed powder 2, and mixing to obtain mixed powder 3;
4) weighing the mixed powder 3, adding a corresponding amount of colloidal silicon dioxide according to a proportion, mixing, adding magnesium stearate, continuously and uniformly mixing to obtain total mixed powder, and tabletting to obtain a tablet core;
5) slowly pouring the coating powder into purified water according to solid content, and continuously stirring until the coating powder is uniform to obtain a coating solution.
6) And (3) uniformly spraying the coating solution obtained in the step (5) on the tablet core through a coating machine until the weight of the coating is increased to 3% of the mass of the tablet core, stopping coating, cooling and drying to obtain the milbemycin oxime praziquantel flavored tablet.
Example 3
Tablet core: 50 parts of milbemycin oxime, 200 parts of praziquantel, 500 parts of microcrystalline cellulose, 200 parts of mannitol, 10 parts of sodium carboxymethylcellulose, 5 parts of povidone, 20 parts of colloidal silicon dioxide and 15 parts of magnesium stearate.
Coating layer: 10 parts of chicken liver extract, 5 parts of beef essence, 3 parts of iron oxide red, 2 parts of sunset yellow, 40 parts of hydroxypropyl methylcellulose and 40 parts of talcum powder;
the preparation method comprises the following steps:
1) dividing microcrystalline cellulose into 3 parts in equal amount, weighing a mixture of milbemycin oxime, praziquantel, sodium carboxymethylcellulose, povidone, 1/3 microcrystalline cellulose and mannitol in a formula amount, premixing, sieving with a 30-mesh sieve, and uniformly mixing to obtain mixed powder 1;
2) adding 1/3 microcrystalline cellulose and mannitol mixture into the mixed powder 1, and mixing uniformly to obtain mixed powder 2;
3) adding the rest 1/3 amounts of microcrystalline cellulose and mannitol mixture into the mixed powder 3, and mixing to obtain mixed powder 4;
4) weighing the mixed powder 4, adding a corresponding amount of colloidal silicon dioxide according to a proportion, mixing, adding magnesium stearate, continuously and uniformly mixing to obtain total mixed powder, and tabletting to obtain a tablet core;
5) slowly pouring the coating powder into purified water according to solid content, and continuously stirring until the coating powder is uniform to obtain a coating solution.
6) And (3) uniformly spraying the coating solution obtained in the step (5) on the tablet core through a coating machine until the weight of the coating is increased to 3% of the mass of the tablet core, stopping coating, cooling and drying to obtain the milbemycin oxime praziquantel flavored tablet.
Comparative example 1
Tablet core: 16 parts of milbemycin oxime, 40 parts of praziquantel, 754 parts of cane sugar, 45 parts of crosslinked sodium carboxymethyl starch, 95 parts of povidone, 25 parts of colloidal silicon dioxide, 25 parts of magnesium stearate, 15 parts of beef extract and 15 parts of chicken liver powder.
The preparation method comprises the following steps:
1) the milbemycin oxime, praziquantel, filler sucrose, disintegrant croscarmellose sodium and flavoring agent with the prescribed dosage are sieved by a 50-mesh sieve and are put on a fluidized bed, and the medicine and the auxiliary materials are mixed uniformly under the action of hot air flow at 45 ℃ at the lower part of the fluidized bed to obtain a mixture;
2) spraying 15% povidone aqueous solution of the adhesive in the amount of the prescription into the mixture in the step 1), bonding the powder absorbing the solution into small particles, and slowly polymerizing the small particles to form coarse pellets along with the continuous addition of the povidone aqueous solution of the adhesive;
3) continuously drying the obtained coarse pellets in the step 2)1 at 45 ℃ in a fluidized bed, and sieving for 2 times, wherein the aperture of a sieve is 400 microns and 200 microns in sequence to obtain pellets with the particle size of 200 and 400 microns;
4) adding the glidant colloidal silicon dioxide and the lubricant magnesium stearate in the prescribed amount into the pellets obtained in the step 3), uniformly mixing, and tabletting to obtain the milbemycin oxime praziquantel tablets;
comparative example 2
A tablet core: 90 parts of milbemycin oxime, 200 parts of praziquantel, 300 parts of dextrin, 225 parts of microcrystalline cellulose, 90 parts of povidone, 45 parts of croscarmellose sodium, 25 parts of colloidal silicon dioxide, 25 parts of magnesium stearate, 5 parts of beef extract and 10 parts of beef essence;
the preparation method is the same as that of comparative example 1.
The recovery rates and active material contents of the examples and comparative examples are shown in table 1.
Table 1: recovery and active substance content
The test data in table 1 show that the recovery rate of the preparation method is higher than that of the traditional wet granulation process, and the loss of the effective content of the active ingredients in the wet granulation process can be reduced.
Animal experiments
The test animals are divided into three groups by selecting 12 adult dogs with good health status and similar weight, the weight and male and female of each group are kept balanced as much as possible, 1 dog is fed for each group, the ingestion condition is observed, the feeding samples of each test group are exchanged in turn after every other day, each group is respectively ingested with three test samples and a blank sample group, the blank sample group is not added with a flavoring agent, other components are the same as the test samples, and the final ingestion condition is counted.
Table 2: experimental results on animals of examples and comparative examples
The test data in table 2 show that the dog eating the flavor tablets granulated by different processes shows that the dog eating the flavor tablets without the flavoring agent basically does not eat, but the feed intake of the sample tablet dog is obviously optimized compared with the sample tablet and the comparative example, and a small amount of test dogs in the comparative example suffer from the phenomena of tablet spitting and retching.
The foregoing is a more detailed description of the invention and is not to be taken in a limiting sense. It will be apparent to those skilled in the art that various modifications, additions and substitutions can be made without departing from the spirit and scope of the invention.
Claims (10)
1. A preparation method of a milbemycin oxime praziquantel flavored tablet for pets is characterized by comprising the following steps:
mixing the milbemycin oxime, the praziquantel, the disintegrating agent, the adhesive and the filler 1/3 according to the amount of the prescription, and then sieving to obtain mixed powder 1;
adding 1/3 filler into the mixed powder 1 in the step 1, and uniformly mixing to obtain mixed powder 2;
adding the rest 1/3 filler into the mixed powder 2 in the step 2, and uniformly mixing to obtain mixed powder 3;
adding a flow aid in a weight ratio of 1-3% to mix, adding a lubricant in a prescription amount to mix uniformly, and tabletting to obtain a tablet core;
adding coating powder into pure water according to the solid content of 12%, and continuously stirring until the mixture is uniform to obtain a coating solution;
and (3) putting the tablet core obtained in the step (4) into a coating machine, uniformly spraying the coating liquid obtained in the step (5) on the surface of the tablet core to form a coating layer until the weight of the coating layer is increased to 2% -8% of the weight of the tablet core, and cooling and drying to obtain the milbeoxime praziquantel flavored tablet.
2. The preparation method according to claim 1, characterized in that the tablet core comprises the following components in parts by weight: 1-10% of milbemycin oxime, 1-20% of praziquantel, 40-80% of filling agent, 1-5% of disintegrating agent, 0.1-3% of adhesive, 1-3% of glidant and 0.5-2.5% of lubricant.
3. The process according to claim 2, wherein the coating layer comprises from 2% to 8% by weight of the core.
4. The method of claim 2, wherein: the filler is one or more of microcrystalline cellulose, starch, lactose, mannitol, sucrose, fructose, dextrin and the like; and/or
The disintegrating agent is one or a combination of more of sodium carboxymethyl starch, crospovidone and sodium carboxymethyl cellulose; and/or
The adhesive is one or a combination of more of hydroxypropyl methylcellulose, povidone, dry starch and dextrin; and/or
The glidant is one or a combination of more of colloidal silicon dioxide, micro silica gel and titanium dioxide; and/or
The lubricant is one or a combination of magnesium stearate, talcum powder and sodium stearyl fumarate.
5. The preparation method according to claim 3, wherein the coating layer contains 5-30% of flavoring agent, 1-10% of coloring agent and 60-90% of film-forming agent.
6. The preparation method of claim 5, wherein the flavoring agent is one or more of chicken liver extract, beef essence, beef extract and milk essence.
7. The method of claim 5, wherein: the colorant is one or a combination of several of iron oxide red, iron oxide yellow, sunset red and sunset yellow.
8. The preparation method according to claim 5, wherein the film forming agent is one or more of polyethylene glycol, talcum powder and hydroxypropyl methylcellulose.
9. The preparation method according to claim 2, characterized in that the tablet core comprises the following components in parts by weight: 1-10% of milbemycin oxime, 1-20% of praziquantel, 40-80% of microcrystalline cellulose and lactose, 1-3% of sodium carboxymethylcellulose, 1-2% of povidone, 1-3% of colloidal silicon dioxide and 0.5-1% of magnesium stearate.
10. A milbeoxime praziquantel flavored tablet for pets prepared by the preparation method as set forth in any one of claims 1 to 9.
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