CN116687873A - Vonopraz fumarate tablet and preparation method thereof - Google Patents
Vonopraz fumarate tablet and preparation method thereof Download PDFInfo
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- CN116687873A CN116687873A CN202310604660.XA CN202310604660A CN116687873A CN 116687873 A CN116687873 A CN 116687873A CN 202310604660 A CN202310604660 A CN 202310604660A CN 116687873 A CN116687873 A CN 116687873A
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- parts
- voronoi
- fumarate
- sodium
- tablet
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 63
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 229920005610 lignin Polymers 0.000 claims abstract description 34
- 238000002156 mixing Methods 0.000 claims abstract description 34
- 229920002488 Hemicellulose Polymers 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 26
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 25
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 25
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 25
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 25
- 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 abstract description 21
- 229930195725 Mannitol Natural products 0.000 claims abstract description 21
- 239000000594 mannitol Substances 0.000 claims abstract description 21
- 235000010355 mannitol Nutrition 0.000 claims abstract description 21
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 16
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- 239000004014 plasticizer Substances 0.000 claims abstract description 7
- 239000003381 stabilizer Substances 0.000 claims abstract description 7
- 239000000853 adhesive Substances 0.000 claims abstract description 5
- 230000001070 adhesive effect Effects 0.000 claims abstract description 5
- 238000000576 coating method Methods 0.000 claims description 43
- 239000011248 coating agent Substances 0.000 claims description 35
- YDEXUEFDPVHGHE-GGMCWBHBSA-L disodium;(2r)-3-(2-hydroxy-3-methoxyphenyl)-2-[2-methoxy-4-(3-sulfonatopropyl)phenoxy]propane-1-sulfonate Chemical group [Na+].[Na+].COC1=CC=CC(C[C@H](CS([O-])(=O)=O)OC=2C(=CC(CCCS([O-])(=O)=O)=CC=2)OC)=C1O YDEXUEFDPVHGHE-GGMCWBHBSA-L 0.000 claims description 35
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 22
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 20
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims description 19
- 229920001223 polyethylene glycol Polymers 0.000 claims description 19
- 229920001577 copolymer Polymers 0.000 claims description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 17
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 17
- 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 17
- 239000001509 sodium citrate Substances 0.000 claims description 16
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 16
- 238000005507 spraying Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000001530 fumaric acid Substances 0.000 claims description 14
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 13
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 13
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 13
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 12
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 9
- 238000000889 atomisation Methods 0.000 claims description 8
- 230000001050 lubricating effect Effects 0.000 claims description 8
- 239000011812 mixed powder Substances 0.000 claims description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000006185 dispersion Substances 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 13
- 230000008569 process Effects 0.000 abstract description 7
- 230000002776 aggregation Effects 0.000 abstract description 5
- 238000001179 sorption measurement Methods 0.000 abstract description 5
- 238000005054 agglomeration Methods 0.000 abstract description 4
- 239000000843 powder Substances 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 19
- 238000004090 dissolution Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229920005552 sodium lignosulfonate Polymers 0.000 description 8
- 239000008187 granular material Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 1
- 101710181757 1,2-dihydroxy-3-keto-5-methylthiopentene dioxygenase Proteins 0.000 description 1
- 101710094863 Acireductone dioxygenase Proteins 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229950003825 vonoprazan Drugs 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K9/205—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
- A61K9/2068—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
- A61K9/2095—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
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2813—Inorganic compounds
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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
- A61K9/28—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
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- 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
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- 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)
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/04—Antibacterial agents
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- 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
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Abstract
The invention discloses a fumarate voronoi green sheet and a preparation method thereof, wherein the fumarate voronoi green sheet comprises the following components in parts by mass: 12-15 parts of raw material medicine voronoi fumarate, 36-65 parts of filler, 6-10 parts of disintegrating agent, 8-12 parts of adhesive, 1-3 parts of stabilizer, 3-5 parts of lubricant, 10-15 parts of film forming material, 20-30 parts of plasticizer and 0.2-0.5 part of titanium oxide; the filler is formed by mixing microcrystalline cellulose, hemicellulose, mannitol and lignin, wherein the mass ratio of the microcrystalline cellulose to the hemicellulose to the mannitol to the lignin is (10-20): (5-10): (20-30): 1. the invention can avoid agglomeration and adsorption among the raw materials with small granularity, reduce the electrostatic effect, facilitate the dispersion of the raw materials, ensure good powder fluidity, avoid sticky and astringent impact in the tabletting process, facilitate the preparation of medicines and improve the quality of the medicines.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a voronoi green sheet fumarate and a preparation method thereof.
Background
Vonopraz fumarate tablet is a potassium competitive acid retarder (P-CAB) developed by Takeda, chemical industry Co., ltd. The drug is first marketed in Japan in 12 months of 2014 and is clinically used for treating gastric acid-related diseases (acid-related disorders, ARDs) such as helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, gastric ulcer and the like. The general name of the tablet is Vonolamine fumarate tablet (Vonoprazan fumarate tablets), the commodity name is Wacker, and the specification is 10mg and 20mg, which are approved to be marketed in China in 12 months of 2019.
Japanese wuta pharmacy in China (patent No. CN 102743330B) provides a solid formulation with improved stability during light irradiation, which is prepared by first granulating, then tabletting and coating. In order to improve the dissolution rate and bioavailability of the preparation in the preparation process, the raw materials are crushed, and the raw materials with smaller granularity are easy to be sticky and astringent in the tabletting process after granulating, so that the quality of the preparation is influenced.
Disclosure of Invention
In order to solve the problems, the purpose of the present patent application is to provide a fumosla fumarate green sheet and a preparation method thereof, which can avoid agglomeration and adsorption between raw materials with small granularity, reduce electrostatic effect, facilitate raw material dispersion, avoid sticky and astringent impact in the tabletting process, facilitate medicine preparation and improve medicine quality.
The invention is realized by the following technical scheme:
the invention provides a voronoi green fumarate tablet, which comprises the following components in parts by mass: 12-15 parts of raw material medicine voronoi fumarate, 36-65 parts of filler, 6-10 parts of disintegrating agent, 8-12 parts of adhesive, 1-3 parts of stabilizer, 3-5 parts of lubricant, 10-15 parts of film forming material, 20-30 parts of plasticizer and 0.2-0.5 part of titanium oxide;
the filler is formed by mixing microcrystalline cellulose, hemicellulose, mannitol and lignin, wherein the mass ratio of the microcrystalline cellulose to the hemicellulose to the mannitol to the lignin is (10-20): (5-10): (20-30): 1.
hemicellulose and lignin are added in the filler, microcrystalline cellulose, hemicellulose, mannitol and lignin form a dispersion blending system, and due to the structural characteristics of the microcrystalline cellulose, hemicellulose and lignin, the crushed bulk drug, namely, the voronoi fumarate, is fully dispersed in the dispersion blending system, so that agglomeration and adsorption between small-granularity raw materials can be avoided, the electrostatic effect is reduced, the dispersion of the raw materials is facilitated, the flowability of powder is good, sticking and astringent flushing are avoided in the tabletting process, the preparation of the medicine is facilitated, and the quality of the medicine is improved.
In an alternative embodiment, the composition comprises the following components in parts by mass: 13 parts of raw material medicine voronoi fumarate, 45-55 parts of filler, 8-10 parts of disintegrating agent, 10-11 parts of adhesive, 2 parts of stabilizer, 3-5 parts of lubricant, 12-15 parts of film forming material, 25-28 parts of plasticizer and 0.3 part of titanium oxide;
the filler is formed by mixing microcrystalline cellulose, hemicellulose, mannitol and lignin, wherein the mass ratio of the microcrystalline cellulose to the hemicellulose to the mannitol to the lignin is 15: (6-8): (20-25): 1.
preferably, in the dispersion blending system, microcrystalline cellulose is used as a main component in the system, the mass of lignin is limited at a smaller proportion, the hemicellulose is centered in the proportion, the hemicellulose is positioned outside the microcrystalline cellulose, and the lignin is connected with the hemicellulose, so that a hierarchical dispersion system is formed by the microcrystalline cellulose, the hemicellulose and the lignin with more optimal mass proportion, raw material aggregation and adsorption are greatly reduced, the phenomena of sticky and astringent impact in the tabletting process are eliminated, the compressibility is good, and the active components are not easy to lose. Lignin not only plays a role in dispersing in a dispersion mixed system, but also can be used as a connection to form good cohesiveness with a coating. Meanwhile, the hierarchical dispersion system and other components are mixed according to the optimized proportion, so that a medicine product with good dissolution rate, good bioavailability and uniformity is formed.
In an alternative embodiment, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl cellulose, the stabilizer is fumaric acid, the lubricant is magnesium stearate, the plasticizer is formed by mixing polyethylene glycol and polyvinyl alcohol copolymer and sodium bicarbonate, and the film-forming material comprises hydroxypropyl methylcellulose and an auxiliary agent.
In an alternative embodiment, the auxiliary agent is modified sodium lignin sulfonate, and the modified sodium lignin sulfonate is obtained by modifying sodium lignin sulfonate with sodium citrate.
The coating comprises cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, fumaric acid and magnesium stearate as auxiliary materials, and a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate, hydroxypropyl methylcellulose and modified sodium lignin sulfonate as coating components. The hydroxypropyl methylcellulose is used as a better film forming material, the sodium lignin sulfonate is used as a better dispersing agent, and the hydroxypropyl methylcellulose and the sodium lignin sulfonate are combined to form a multidimensional net complex structure, so that a good dispersing effect is formed on the titanium oxide serving as a light shielding agent, the titanium oxide is dispersed more uniformly in a coating, the light shielding effect is better, and the film forming effect is also better; in the prior art, sodium citrate is added into a tablet core to improve the stability of the tablet, so that degradation of the voronoi fumarate caused by illumination is avoided, in the application of the present invention, sodium citrate is added into a coating, and the sodium citrate is used for modifying sodium lignosulfonate, and sodium lignosulfonate modified by sodium citrate can be combined with lignin in auxiliary materials to improve the bonding effect of the coating and the tablet core. Meanwhile, the copolymer of polyethylene glycol and polyvinyl alcohol also has good effect on the dispersion of titanium oxide and sodium bicarbonate, and the sodium bicarbonate is uniformly dispersed in the coating to play a role in preventing moisture absorption, so that the stability of the medicine is improved. The copolymer of polyethylene glycol and polyvinyl alcohol and modified sodium lignin sulfonate are synergistic to form a network structure with stable structure, so that the copolymer of polyethylene glycol and polyvinyl alcohol is not easy to degrade, sodium lignin sulfonate is not easy to biodegrade, and the network structure is more beneficial to substance dispersion and to dispersing a disintegrating agent to facilitate the dissolution and bioavailability of a drug.
In an alternative embodiment, the mass ratio of sodium citrate to sodium lignin sulfonate is (0.2-0.4): (0.6-1.0), more preferably 0.2:0.8, and the ratio of the modified sodium lignin sulfonate to the lignin in the auxiliary materials can be optimized, so that the bonding effect is better, and the combination ratio of the modified sodium lignin sulfonate and the hydroxypropyl methylcellulose is better, so that the formed multidimensional network structure has better dispersion effect.
The mass ratio of the hydroxypropyl methylcellulose to the modified sodium lignin sulfonate is 1: (0.1 to 0.3), more preferably 1:0.2. The hydroxypropyl methylcellulose and the modified sodium lignin sulfonate have better film forming effect, and the film forming continuity and smoothness are further improved.
In an alternative embodiment, the mass ratio of the modified sodium lignin sulfonate to the copolymer of polyethylene glycol and polyvinyl alcohol is 1: (0.2-0.5).
The second aim of the invention is to provide a preparation method of the voronoi green fumarate tablet, which comprises the following steps:
(1): uniformly mixing the vonolamine crude drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): and finally coating the tablet core to obtain the voronoi fumarate tablet.
In an alternative embodiment, in the step (4), the hydroxypropyl methylcellulose, the modified sodium lignin sulfonate, the copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide are added into the aqueous solution and mixed to obtain the coating solution.
In an alternative embodiment, sodium citrate modifies sodium lignin sulfonate at 50-60 ℃.
In an alternative embodiment, the temperature of the tablet bed during the coating process is 50-55 ℃, the rotating speed is 40-50 rpm, the atomization pressure is 0.6-0.7 Mpa, the spraying speed is 5-8 ml/min, and the coating weight is increased to 7%.
Compared with the prior art, the invention has the following advantages and beneficial effects:
according to the fumosla tablet provided by the embodiment of the invention, hemicellulose and lignin are added into the filler, and the microcrystalline cellulose, the hemicellulose, mannitol and the lignin form a dispersion blending system, so that agglomeration and adsorption between raw materials with small granularity can be avoided, the electrostatic effect is reduced, the raw material dispersion is facilitated, the powder flowability is good, sticking and astringent flushing are avoided in the tabletting process, the preparation of a medicine is facilitated, and the medicine quality is improved.
Detailed Description
The present invention will be described in further detail with reference to the following examples, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, and the description thereof is merely illustrative of the present invention and not intended to be limiting.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that: no such specific details are necessary to practice the invention. In other instances, well-known methods have not been described in detail in order to avoid obscuring the present invention.
Throughout the specification, references to "one embodiment," "an embodiment," "one example," or "an example" mean: a particular feature, structure, or characteristic described in connection with the embodiment or example is included within at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment," "in an example," or "in an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and/or sub-combination in one or more embodiments or examples.
In the description of the present invention, the terms "front," "back," "left," "right," "upper," "lower," "vertical," "horizontal," "high," "low," "inner," "outer," and the like indicate or imply a particular orientation of the device or element to be referred to, but are not intended to limit the scope of the invention.
Example 1:
table 1 dosage forms for each composition of example 1
The preparation method comprises the following steps:
(1) Uniformly mixing the vonolamine fumarate bulk drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): adding hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide into an aqueous solution, mixing to obtain a coating solution, and spraying the coating solution on the tablet core;
sodium lignosulfonate is modified in water by sodium citrate at 50 ℃.
The temperature of the tablet bed in the coating process is 50 ℃, the rotating speed is 50rpm, the atomization pressure is 0.6Mpa, the spraying speed is 8ml/min, and the weight of the coating is increased to 7%.
Example 2:
table 2 table of the amount of each composition of example 2
The preparation method comprises the following steps:
(1) Uniformly mixing the vonolamine fumarate bulk drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): adding hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide into an aqueous solution, mixing to obtain a coating solution, and spraying the coating solution on the tablet core;
sodium lignosulfonate is modified in water by sodium citrate at 60 ℃.
The temperature of the tablet bed in the coating process is 55 ℃, the rotating speed is 40rpm, the atomization pressure is 0.7Mpa, the spraying speed is 5ml/min, and the weight of the coating is increased to 7%.
Example 3:
TABLE 3 dosage forms for each composition of EXAMPLE 3
The preparation method comprises the following steps:
(1) Uniformly mixing the vonolamine fumarate bulk drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): adding hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide into an aqueous solution, mixing to obtain a coating solution, and spraying the coating solution on the tablet core;
sodium lignosulfonate is modified in water by sodium citrate at 60 ℃.
The temperature of the tablet bed in the coating process is 55 ℃, the rotating speed is 40rpm, the atomization pressure is 0.7Mpa, the spraying speed is 5ml/min, and the weight of the coating is increased to 7%.
Example 4:
TABLE 4 dosage form for each composition of example 4
The preparation method comprises the following steps:
(1) Uniformly mixing the vonolamine fumarate bulk drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): adding hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide into an aqueous solution, mixing to obtain a coating solution, and spraying the coating solution on the tablet core;
sodium lignosulfonate is modified in water by sodium citrate at 60 ℃.
The temperature of the tablet bed in the coating process is 55 ℃, the rotating speed is 40rpm, the atomization pressure is 0.7Mpa, the spraying speed is 5ml/min, and the weight of the coating is increased to 7%.
Example 5:
TABLE 5 dosage form for each composition of EXAMPLE 5
The preparation method comprises the following steps:
(1) Uniformly mixing the vonolamine fumarate bulk drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): adding hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide into an aqueous solution, mixing to obtain a coating solution, and spraying the coating solution on the tablet core;
sodium lignosulfonate is modified in water by sodium citrate at 60 ℃.
The temperature of the tablet bed in the coating process is 55 ℃, the rotating speed is 40rpm, the atomization pressure is 0.7Mpa, the spraying speed is 5ml/min, and the weight of the coating is increased to 7%.
Example 6:
TABLE 6 amount of each composition of EXAMPLE 6
The preparation method comprises the following steps:
(1) Uniformly mixing the vonolamine fumarate bulk drug with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): adding hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide into an aqueous solution, mixing to obtain a coating solution, and spraying the coating solution on the tablet core;
sodium lignosulfonate is modified in water by sodium citrate at 60 ℃.
The temperature of the tablet bed in the coating process is 55 ℃, the rotating speed is 40rpm, the atomization pressure is 0.7Mpa, the spraying speed is 5ml/min, and the weight of the coating is increased to 7%.
Comparative example 1:
the preparation method of the voronoi fumarate tablet by referring to the technical scheme of CN102743330A comprises the following steps:
1) Preparing a tablet core: vonolamine fumarate (prepared by the synthesis method of CN 101300229A), mannitol and microcrystalline cellulose pH101 are sieved, mixed for 300 seconds in a wet mixing granulator (stirring speed is 400rpm and shearing speed is 800 rpm), hydroxypropyl cellulose fumaric acid aqueous solution accounting for 20% of the total weight of the aqueous solution is added to prepare soft materials, the soft materials are granulated by a swinging granulator (sieving is carried out by a sieve with 0.8mm and the rotating speed is 500 rpm), the wet granules are placed in a fluidized bed granulator, the materials reach a fluidization state, the temperature of the materials is maintained at 25-35 ℃, and the rest of the aqueous solution of the hydroxypropyl cellulose fumaric acid is sprayed to obtain dry granules (the water content is less than 2%). The obtained dry granules were passed through a 20 mesh sieve to obtain sieved granules. The sieved granules, croscarmellose sodium and magnesium stearate were mixed in a mixer (rotational speed 15 rpm) for 15 minutes to obtain a mixed material. And tabletting the mixed material by using a rotary tablet press to obtain tablet cores.
2) Coating: the tablet core is placed in a coating machine, and is sprayed by adding a pre-configured coating water solution with the mass concentration of 10 percent (the speed of a main machine is 4-8 r/min, the spraying pressure is 0.5-0.7MPa, the air inlet temperature is set to be 50-65 ℃, the temperature of a tablet bed is controlled to be 35-45 ℃, and the spraying speed is 0.4-1.0kg/10 min), so that the voronoi green tablet fumarate is prepared.
Comparative example 2:
the difference from example 1 is that hemicellulose and lignin are not added, the remainder being the same.
Comparative example 3:
the difference from example 1 is that no modified sodium lignin sulfonate was added, the remainder being the same.
Comparative example 4:
the difference from example 1 is that sodium bicarbonate was not added, the remainder being the same.
Comparative example 5:
the difference from example 1 is that no copolymer of polyethylene glycol and polyvinyl alcohol is added, the remainder being the same.
And (3) measuring:
1. tabletting conditions
Table 7 tabletting conditions for each of examples and comparative examples
As is clear from Table 7, the tablets prepared in each example of the present invention were smooth and complete, and the tabletting process was smooth. And the comparative examples 1 and 2 have no synergistic effect of hemicellulose and lignin, so that the tablet has a large degree of sticky impact, and the comparative examples 3 to 5 have the effects of hemicellulose and lignin, so that the obtained tablet is complete and smooth.
2. Release test
The voronoi green sheets of fumaric acid prepared in each example and comparative example were put into 900ml of a 0.1mol/L hydrochloric acid solution at 37 ℃ + -0.5 ℃, a dissolution rate measurement method first method device was adopted, the rotation speed was 100 revolutions per minute, and according to the method operation, 5ml of dissolution solution was obtained after 15, 30, 45, 60 and 120 minutes respectively, filtered, the subsequent filtrate was obtained, and the release rate of each sheet was calculated as determined by high performance liquid chromatography (appendix D of the second edition 2010 of chinese pharmacopoeia), and the results are shown in table 7.
The 0.1mol/L hydrochloric acid solution in each of the above-mentioned elution cups was discarded, and immediately added to 900ml of a phosphate buffer (pH 6.8) at 37.+ -. 0.5 ℃ and the apparatus was operated at a rotational speed of 100 revolutions per minute by the dissolution rate measurement method. According to the method, 5ml of the dissolution liquid is obtained after 45 minutes, the obtained solution is filtered, the obtained filtrate is measured by high performance liquid chromatography (Chinese pharmacopoeia 2010 edition two appendix XD), and the release rate of each tablet is calculated, and the results are shown in Table 8.
Table 8 determination of tablet release
As is clear from Table 8, the tablets prepared in each example of the present invention had a better release than each comparative example, and had a better dissolution rate and bioavailability than each comparative example. In comparative examples 3 and 5, the release rate of the drug was not good because of the absence of the synergy of the copolymer of polyethylene glycol and polyvinyl alcohol and modified sodium lignin sulfonate.
3. Stability test
The stability of each sample was measured by taking the tablet samples of each example and comparative example, sealing them in transparent glass bottles, storing them at 40℃for 1 or 6 months, at 60℃for 1 month, and under light (4500 lux.+ -. 500 lux) for 10 or 30 days, respectively, and the results are shown in tables 9 to 11.
TABLE 9 stability of different samples at 40℃under 75% RH
Table 10 stability of different samples at 60 ℃,75% rh
TABLE 11 stability of different samples under illumination conditions
As can be seen from tables 9 and 10 above, the stability of each example was significantly better than that of each comparative example in long-term storage, and the copolymers of hemicellulose and lignin, modified sodium lignin sulfonate, sodium bicarbonate, polyethylene glycol and polyvinyl alcohol were not added to comparative examples 2, 3, 4, and 5, respectively, and the stability of each example was significantly less good in long-term storage. As is clear from Table 11, similarly, comparative examples 2 and 3 were not added with hemicellulose, lignin and modified sodium lignin sulfonate, respectively, and the stability under light conditions was inferior to that of the examples, whereas comparative example 4 was less affected by the stability without sodium bicarbonate. The poor stability under light conditions in comparative example 5 is probably because the polyethylene glycol-polyvinyl alcohol copolymer was not added to comparative document 5, and a stable network structure was not formed, so that sodium lignin sulfonate was degraded under light and heat.
The foregoing detailed description of the invention has been presented for purposes of illustration and description, and it should be understood that the invention is not limited to the particular embodiments disclosed, but is intended to cover all modifications, equivalents, alternatives, and improvements within the spirit and principles of the invention.
Claims (10)
1. The voronoi green fumarate tablet is characterized by comprising the following components in parts by mass: 12-15 parts of raw material medicine voronoi fumarate, 36-65 parts of filler, 6-10 parts of disintegrating agent, 8-12 parts of adhesive, 1-3 parts of stabilizer, 3-5 parts of lubricant, 10-15 parts of film forming material, 20-30 parts of plasticizer and 0.2-0.5 part of titanium oxide;
the filler is formed by mixing microcrystalline cellulose, hemicellulose, mannitol and lignin, wherein the mass ratio of the microcrystalline cellulose to the hemicellulose to the mannitol to the lignin is (10-20): (5-10): (20-30): 1.
2. the voronoi-generator fumarate tablet according to claim 1, comprising the following components in parts by mass: 13 parts of raw material medicine voronoi fumarate, 45-55 parts of filler, 8-10 parts of disintegrating agent, 10-11 parts of adhesive, 2 parts of stabilizer, 3-5 parts of lubricant, 12-15 parts of film forming material, 25-28 parts of plasticizer and 0.3 part of titanium oxide;
the filler is formed by mixing microcrystalline cellulose, hemicellulose, mannitol and lignin, wherein the mass ratio of the microcrystalline cellulose to the hemicellulose to the mannitol to the lignin is 15: (6-8): (20-25): 1.
3. the voronoi-praecox fumarate tablet according to claim 1, wherein said disintegrant is croscarmellose sodium, said binder is hydroxypropyl cellulose, said stabilizer is fumaric acid, said lubricant is magnesium stearate, said plasticizer is formed by mixing polyethylene glycol and polyvinyl alcohol copolymer with sodium bicarbonate, and said film forming material comprises hydroxypropyl methylcellulose and an auxiliary agent.
4. The voronoi green-sheet according to claim 3, wherein the auxiliary agent is modified sodium lignin sulfonate, and the modified sodium lignin sulfonate is obtained by modifying sodium lignin sulfonate with sodium citrate.
5. The voronoi green-sheet according to claim 4, wherein the mass ratio of sodium citrate to sodium lignin sulfonate is (0.2 to 0.4): (0.6 to 1.0), more preferably 0.2:0.8.
the mass ratio of the hydroxypropyl methylcellulose to the modified sodium lignin sulfonate is 1: (0.1 to 0.3), more preferably 1:0.2.
6. The voronoi green-pack fumarate tablet according to claim 4 or 5, wherein the mass ratio of said modified sodium lignin sulfonate and said copolymer of polyethylene glycol and polyvinyl alcohol is 1: (0.2-0.5).
7. A method for producing the voronoi-green fumarate tablet according to any one of claims 3 to 6, comprising the steps of:
(1): uniformly mixing the vonolamine fumarate with mannitol, microcrystalline cellulose, hemicellulose and lignin;
(2): adding fumaric acid, hydroxypropyl cellulose and pure water into the product obtained in the step (1) to prepare a binder according to the proportion, and granulating in a fluidized bed;
(3): granulating, adding crosslinked sodium carboxymethyl cellulose, mixing uniformly, lubricating magnesium stearate, and tabletting by using mixed powder to obtain tablet cores;
(4): and finally coating the tablet core to obtain the voronoi fumarate tablet.
8. The method of claim 7, wherein in the step (4), hydroxypropyl methylcellulose, modified sodium lignin sulfonate, a copolymer of polyethylene glycol and polyvinyl alcohol, sodium bicarbonate and titanium oxide are added into an aqueous solution and mixed to obtain a coating solution.
9. The method for producing a voronoi green sheet as claimed in claim 8, wherein sodium citrate modifies sodium lignin sulfonate at 50 to 60 ℃.
10. The method for preparing a voronoi green-mular fumarate tablet according to claim 9, wherein the temperature of the tablet bed in the coating process is 50-55 ℃, the rotation speed is 40-50 rpm, the atomization pressure is 0.6-0.7 Mpa, the spraying speed is 5-8 ml/min, and the coating weight is increased to 7%.
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