CN115245494A - Tablet containing Vorinopram fumarate and preparation method thereof - Google Patents
Tablet containing Vorinopram fumarate and preparation method thereof Download PDFInfo
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- CN115245494A CN115245494A CN202110463116.9A CN202110463116A CN115245494A CN 115245494 A CN115245494 A CN 115245494A CN 202110463116 A CN202110463116 A CN 202110463116A CN 115245494 A CN115245494 A CN 115245494A
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- fumarate
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- voranolan
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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 92
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000000463 material Substances 0.000 claims abstract description 39
- 238000005469 granulation Methods 0.000 claims abstract description 28
- 230000003179 granulation Effects 0.000 claims abstract description 28
- 239000000945 filler Substances 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 239000008187 granular material Substances 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 9
- 239000000853 adhesive Substances 0.000 claims abstract description 8
- 230000001070 adhesive effect Effects 0.000 claims abstract description 8
- 239000003381 stabilizer Substances 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 239000011248 coating agent Substances 0.000 claims description 37
- 238000000576 coating method Methods 0.000 claims description 37
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 32
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 26
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 26
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 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 description 20
- 229930195725 Mannitol Natural products 0.000 claims description 20
- 239000000594 mannitol Substances 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 20
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 18
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 18
- 235000019359 magnesium stearate Nutrition 0.000 claims description 18
- 238000007873 sieving Methods 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 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 17
- 229960001681 croscarmellose sodium Drugs 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
- 238000001035 drying Methods 0.000 claims description 15
- 239000001530 fumaric acid Substances 0.000 claims description 15
- 239000002671 adjuvant Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 229920002261 Corn starch Polymers 0.000 claims description 6
- 239000008120 corn starch Substances 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 238000010298 pulverizing process Methods 0.000 claims description 6
- -1 hydroxypropyl Chemical group 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 230000004584 weight gain Effects 0.000 claims description 5
- 235000019786 weight gain Nutrition 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 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 4
- 239000000835 fiber Substances 0.000 claims description 4
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 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 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 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 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 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 2
- 238000004090 dissolution Methods 0.000 abstract description 20
- 230000005611 electricity Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000003068 static effect Effects 0.000 abstract description 4
- 238000001179 sorption measurement Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 56
- 239000000843 powder Substances 0.000 description 31
- 230000000052 comparative effect Effects 0.000 description 21
- 239000002245 particle Substances 0.000 description 18
- 239000002002 slurry Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- 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 7
- 230000000694 effects Effects 0.000 description 7
- 238000005507 spraying Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 6
- 102220042174 rs141655687 Human genes 0.000 description 6
- 238000004513 sizing Methods 0.000 description 6
- 229950003825 vonoprazan Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000005434 MCC/mannitol excipient Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000009472 formulation Methods 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
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229950005770 hyprolose Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
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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
- A61K9/2004—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
- 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
- A61K9/2022—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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
-
- A—HUMAN NECESSITIES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention relates to a tablet containing Vonopalasin fumarate and a preparation method thereof, wherein the tablet or a tablet core thereof comprises Vonopalasin fumarate as an active ingredient, an internal auxiliary material and an external auxiliary material, the active ingredient and one or more internal auxiliary materials are dissolved in the preparation process, one-step granulation is carried out in a fluidized bed with a filler, the obtained dry granules are crushed and sieved by a sieve of 18-40 meshes, and then the dry granules and the external auxiliary material are mixed and tableted; wherein the added auxiliary materials comprise a filling agent, a stabilizing agent and an adhesive; the added auxiliary materials are a disintegrating agent and a lubricating agent. The invention remarkably solves the problem of content loss caused by static electricity and adsorption after crushing small-specification preparation raw materials through simple one-step granulation of the fluidized bed, simultaneously solves the problems of easy sticking and acerbity of tabletting and remarkably improves the dissolution rate and bioavailability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a tablet containing vorexant fumarate and a preparation method thereof.
Background
Vonola fumarate tablets (Vonoprazan fumarate tablets, TAK-438,
) Is a potassium ion competitive acid retarder (P-CAB) developed by Takeda, kyowa chemical industries, ltd. It was first approved in Japan in 2014 12 months and clinically used for treating gastric acid-related diseases (ARDS) such as helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, gastric ulcer, etc. Approved for sale in china 12 months 2019 under the generic name vonoprazen fumarate tablets (Vonoprazan fumarate tablets) and the trade name wacker with the specifications of 10mg and 20mg.
Chemical name 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl]-N-methyl methylamine fumarate; white or white-like crystalline powder with no odor; slightly soluble in water and methanol, hardly soluble in isopropanol and acetonitrile, slightly soluble in N, N-dimethylacetamide, and soluble in dimethylsulfoxide. The molecular formula is as follows: c 17 H 16 FN 3 O 2 S·C 4 H 4 O 4 Molecular weight: 461.46.
the structural formula is as follows:
japanese wutian pharmaceutical in chinese application patent No. CN 102743330B provides a solid preparation with improved stability during light irradiation, which comprises a pharmaceutically active component, titanium dioxide, a plasticizer and a chain organic acid, wherein the chain organic acid is fumaric acid, the content of the chain organic acid is 0.1% to 10%, and the preparation process is wet (fluidized bed) granulation, drying, total mixing, tabletting, coating and the like. However, in practical operation, when the active component has a small particle size, the material is easily delaminated in the fluidized bed, and the material is not easily fluidized due to static electricity, which causes adverse effects on the content and content uniformity of the finished product, and the tablet is easily sticky and astringent.
Chinese patent CN 110538153A provides a high-stability and quick-release solid preparation and a preparation method thereof, wherein the solid preparation is prepared from the following raw materials: co-pulverizing the active ingredient and organic acid, and excipient. The co-crushing powder provided by the patent has the advantages of lower yield in actual operation, obvious material static electricity, poor powder fluidity and unfavorable product preparation process, and the powder direct-pressing process has higher requirements on material fluidity and the like and is not favorable for large-scale production.
The Vonopalafenadine fumarate has poor solubility in water, is slightly soluble, and needs to be crushed before use in order to improve the dissolution rate and bioavailability of the preparation, but the crushed raw materials have obvious electrostatic effect, aggregation, adsorption and higher surface energy, so that the dissolution rate of the preparation product is low and the dissolution is incomplete; the process is not easy to operate, the active components are easy to lose, and the content uniformity of the tablet is poor. At present, no simple and effective means suitable for mass production is available to solve the problem.
Therefore, the method with simple and efficient process is developed to prepare the Voranolan fumarate tablet with qualified content and content uniformity, the dissolution rate of the tablet is improved, and the method has very important significance
Disclosure of Invention
The invention aims to provide a Voranolan fumarate-containing tablet on the basis of the prior art, overcomes adverse effects caused by surface properties of crushed active components, can fully exert the dissolution advantage of a raw material with a fine particle size, and obtains a preparation product with quick and complete dissolution and high bioavailability.
Another object of the present invention is to provide a process for the preparation of the above tablet containing vorexant fumarate.
The technical scheme of the invention is as follows:
a tablet containing Voranolan fumarate, the tablet or its tablet core include Voranolan fumarate of active ingredient, add supplementary product and add supplementary product, after dissolving active ingredient and one or more of adding supplementary product in the preparation process first, carry on one-step granulation in the fluidized bed to add filler, the granule got is sifted through 18-40 mesh; then mixing with additional auxiliary materials for tabletting; the internal auxiliary materials are a filling agent, an adhesive and a stabilizing agent; the additional auxiliary materials are a disintegrating agent and a lubricating agent.
The internal auxiliary materials mentioned in the invention refer to auxiliary materials added in the granulation process; the additional auxiliary materials refer to auxiliary materials added before tabletting after finishing.
For the present invention, the filler may be selected from one or more of microcrystalline cellulose, mannitol or corn starch, and in order to achieve the effects of the present invention, the filler is preferably microcrystalline cellulose and mannitol, such as microcrystalline cellulose 102. The binder may be one or more selected from hypromellose, povidone or hyprolose, preferably hydroxypropyl cellulose, such as hydroxypropyl cellulose L-type.
Wherein the stabilizer is fumaric acid.
The disintegrant may be selected from croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber, or sodium starch glycolate, and may be, but is not limited to, croscarmellose sodium.
The lubricant is selected from magnesium stearate, calcium stearate, silica gel micropowder, pulvis Talci or hydrogenated vegetable oil, preferably magnesium stearate.
In a preferable scheme, the Volvala fumarate-containing tablet provided by the invention comprises a tablet core and a coating, wherein the tablet core comprises the following components in parts by mass: 10 to 20 parts of vonola fumarate, 60 to 70 parts of mannitol, 5 to 15 parts of microcrystalline cellulose, 2 to 4 parts of hydroxypropyl cellulose L-type, 2 to 3 parts of fumaric acid, 3 to 7 parts of cross-linked sodium carboxymethyl cellulose and 0.5 to 1.5 parts of magnesium stearate.
In a more preferable mode, the Voranolan fumarate-containing tablet is characterized by comprising a tablet core and a coating, wherein the tablet core comprises the following components in parts by mass: 12.15 parts of vorexane fumarate, 66.35 parts of mannitol, 10 parts of microcrystalline cellulose, 3 parts of hydroxypropyl cellulose L-type, 2.5 parts of fumaric acid, 5 parts of croscarmellose sodium and 1 part of magnesium stearate.
The invention also provides a preparation method of the tablet containing the Voranolan fumarate, which comprises the following steps:
(1) Pretreatment: pulverizing the active components, sieving, and sieving the adjuvants;
(2) One-step granulation: dissolving the active component and one or more internal auxiliary materials, and then performing one-step granulation in a fluidized bed added with a filling agent to obtain granules which are sieved by a sieve with 18-40 meshes;
(3) Tabletting and coating: mixing the granulated dry granules with additional auxiliary materials, tabletting and coating;
wherein the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol or corn starch, preferably microcrystalline cellulose and mannitol;
wherein, the adhesive can be selected from one or more of hypromellose, povidone or hydroxypropyl cellulose, preferably hydroxypropyl cellulose, more preferably hydroxypropyl cellulose L type;
the disintegrant is selected from croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber or carboxymethyl starch sodium, preferably croscarmellose sodium;
the lubricant is selected from magnesium stearate, calcium stearate, silica gel micropowder, pulvis Talci or hydrogenated vegetable oil, preferably magnesium stearate.
In a preferable scheme, in the step (1), the active component is crushed and sieved by a 40-80 mesh sieve, preferably a 60 mesh sieve; the auxiliary materials are sieved by a 30-50 mesh sieve, preferably 40 mesh.
In a preferable scheme, in the step (2), during granulation, the granulation temperature is 27-40 ℃, preferably 30-35 ℃; further, the drying temperature is 38-40 ℃, the moisture is controlled to be less than 3%, and preferably, the drying temperature is 39 ℃; further, crushing the dried mixture and sieving the crushed mixture by a sieve with the aperture of 0.8-1.2 mm, preferably 1.0mm; further, in the step (3), the coating adopts a gastric-soluble film coating material, and the weight of the coating is controlled to be increased by 2-5%.
The invention also provides a dissolution testing method of the tablet containing the Voranolan fumarate, which comprises the following steps: referring to dissolution determination method (0931 second method of the four general rules of the 2020 edition of Chinese pharmacopoeia), adopting paddle method, taking 900ml of acetate buffer solution with pH4.5 as dissolution medium, rotating at 50 rpm, and taking 10ml of dissolution solution at 5min, 10min, 15min, 20min, 30min, and 45 min; taking a Vonoprazan fumarate control substance, and diluting the Vonoprazan fumarate control substance to 1ml of 20 micrograms Vonoprazan fumarate control substance by using a dissolution medium; the determination is carried out according to the high performance liquid chromatography 0512 of the general rules of four departments in 2015 edition of Chinese pharmacopoeia.
By adopting the technical scheme of the invention, the advantages are as follows:
(1) The tablet containing the Voranolan fumarate prepared by the preparation method disclosed by the invention is simple in process, high in production efficiency and capable of being directly granulated by a fluidized bed in one step;
(2) The Voranolan fumarate tablet prepared by the method has the advantages of good granule fluidity and compressibility, no sticking and impact, no astringent impact, smooth surface, qualified friability and qualified content and content uniformity.
(3) The tablet of Voranolan fumarate prepared by the invention has a dissolution rate obviously superior to that of a common prescription process, and can take effect more quickly to relieve the symptoms of patients.
Drawings
FIG. 1 is a dissolution profile of a film coated tablet comprising Voranolan fumarate
Detailed Description
The tablets and the process for their preparation according to the invention are further illustrated by the following examples, which are not intended to limit the invention in any way.
The present invention is further described below with reference to examples.
Example 1
A tablet containing Voranolan fumarate has the following formula (1000 dosage tablets):
* The particle size of the active component after being crushed is D90=123.21 μm;
the preparation method of the tablet comprises the following steps:
(1) Pretreatment: pulverizing Vorinostat fumarate with universal pulverizer, and sieving with 60 mesh sieve; sieving other adjuvants for use;
(2) Slurry preparation: adding the screened voronoi fumarate, fumaric acid, part of mannitol and hydroxypropyl cellulose into purified water (110 g) for dissolving for later use;
(3) One-step granulation: mannitol 100G and microcrystalline cellulose 22G were placed in a multifunctional fluidized bed (WBF-2G, chongqing England granulation coating technology Co., ltd.) and the material was preheated and mixed. Granulating the mixture, and spraying the prepared hydroxypropyl cellulose slurry at the same time, wherein the granulating temperature is 30-35 ℃, obtaining granulated powder and drying, the drying temperature is 38-40 ℃, and the moisture content is controlled to be less than 3%. The obtained granulated powder was passed through a crushing and sizing machine (FZB-150, torontal pharmaceutical machinery, ltd., zhejiang) to obtain a sieved powder having a particle size of 1.0mm.
(4) Tabletting and coating: the sieved powder, croscarmellose sodium and magnesium stearate were placed in a three-dimensional mixer (shanghai tianxiangjian pharmaceutical machinery co., ltd., STC/HD 15) and mixed uniformly. Using 11 x 6mm special-shaped punch head of a rotary tablet press (ZP-8 of Shanghai Xinyuan pharmaceutical machinery Co., ltd.) to perform tabletting, controlling the hardness to be 100-150N, and finally adopting a gastric-soluble film coating material to perform coating, controlling the weight gain of the coating to be 2-5%.
Example 2
A tablet containing Voranolan fumarate has the following formula (1000 dosage tablets):
* The particle size of the active component after being crushed is D90=123.21 μm;
the preparation method of the tablet comprises the following steps:
(1) Pretreatment: crushing the Vonopalasin fumarate by a universal crusher and sieving the Vonopalasin fumarate by a 60-mesh sieve for later use; sieving other adjuvants for use;
(2) Slurry preparation: adding the screened voronoi fumarate, fumaric acid, mannitol and hydroxypropyl cellulose into purified water (110 g) for dissolving for later use;
(3) One-step granulation: mannitol 100G and microcrystalline cellulose 22G were placed in a multifunctional fluidized bed (WBF-2G, chongqing England granulation coating technology Co., ltd.) and the material was preheated and mixed. Granulating the mixture, and spraying the prepared hydroxypropyl cellulose slurry at the same time, wherein the granulating temperature is 30-35 ℃, obtaining granulated powder and drying, the drying temperature is 38-40 ℃, and the moisture content is controlled to be less than 3%. The obtained granulated powder was passed through a crushing and sizing machine (FZB-150, torontal pharmaceutical machinery, ltd., zhejiang) to obtain a sieved powder having a particle size of 1.0mm.
(4) Tabletting and coating: the sieved powder, croscarmellose sodium and magnesium stearate were placed in a three-dimensional mixer (shanghai tianxiangjian pharmaceutical machinery co., ltd., STC/HD 15) and mixed uniformly. Using a rotary tablet press (Shanghai Xinyuan pharmaceutical machinery Co., ltd. ZP-8) 11 x 6mm special-shaped punch to perform tabletting, controlling the hardness to be 100-150N, and finally adopting a gastric-soluble film coating material to perform coating, wherein the coating weight is controlled to be 2-5%.
Example 3
A tablet containing Voranolan fumarate has the following formula (1000 dosage tablets):
* The particle size of the active component after being crushed is D90=123.21 μm;
the preparation method of the tablet comprises the following steps:
(1) Pretreatment: crushing the Vonopalasin fumarate by a universal crusher and sieving the Vonopalasin fumarate by a 60-mesh sieve for later use; sieving other adjuvants for use;
(2) Slurry preparation: adding the screened voronoi fumarate, fumaric acid, mannitol and hydroxypropyl cellulose into purified water (110 g) for dissolving for later use;
(3) One-step granulation: mannitol 100G and microcrystalline cellulose 22G were placed in a multifunctional fluidized bed (WBF-2G, chongqing England granulation coating technology Co., ltd.) and the material was preheated and mixed. Granulating the mixture, and spraying the prepared hydroxypropyl cellulose slurry at the same time, wherein the granulating temperature is 30-35 ℃, obtaining granulated powder and drying, the drying temperature is 38-40 ℃, and the moisture content is controlled to be less than 3%. The obtained granulated powder was passed through a crushing and sizing machine (FZB-150, torontal pharmaceutical machinery, ltd., zhejiang) to obtain a sieved powder having a particle size of 1.0mm.
(4) Tabletting and coating: the sieved powder, croscarmellose sodium and magnesium stearate were placed in a three-dimensional mixer (shanghai tianxiangjian pharmaceutical machinery ltd STC/HD 15) and mixed uniformly. Using a rotary tablet press (Shanghai Xinyuan pharmaceutical machinery Co., ltd. ZP-8) 11 x 6mm special-shaped punch to perform tabletting, controlling the hardness to be 100-150N, and finally adopting a gastric-soluble film coating material to perform coating, wherein the coating weight is controlled to be 2-5%.
Comparative example 1
A tablet containing voronoi fumarate, having the following formulation (1000 tablets in amount):
* The particle size of the active component after being crushed is D90=123.21 μm;
the preparation method of the tablet comprises the following steps:
(1) Pretreatment: crushing the Vonopalasin fumarate by a universal crusher and sieving the Vonopalasin fumarate by a 60-mesh sieve for later use; sieving other adjuvants for use;
(2) Slurry preparation: adding the screened vorexant fumarate, fumaric acid and hydroxypropyl cellulose into purified water (110 g) for dissolving for later use;
(3) One-step granulation: mannitol 100G and microcrystalline cellulose 22G were placed in a multifunctional fluidized bed (WBF-2G, chongqing England granulation coating technology Co., ltd.) and the material was preheated and mixed. Granulating the mixture, and spraying the prepared hydroxypropyl cellulose slurry at the same time, wherein the granulating temperature is 30-35 ℃, the granulated powder is obtained and dried, the drying temperature is 38-40 ℃, and the moisture is controlled to be less than 3%. The obtained granulated powder was passed through a crushing and sizing machine (FZB-150, torontal pharmaceutical machinery, ltd., zhejiang) to obtain a sieved powder having a particle size of 1.0mm.
(4) Tabletting and coating: the sieved powder, croscarmellose sodium and magnesium stearate were placed in a three-dimensional mixer (shanghai tianxiangjian pharmaceutical machinery co., ltd., STC/HD 15) and mixed uniformly. Using 11 x 6mm special-shaped punch head of a rotary tablet press (ZP-8 of Shanghai Xinyuan pharmaceutical machinery Co., ltd.) to perform tabletting, controlling the hardness to be 100-150N, and finally adopting a gastric-soluble film coating material to perform coating, controlling the weight gain of the coating to be 2-5%.
Comparative example 2 refers to chinese patent CN 102743330B.
A tablet containing Voranolan fumarate has the following formula (1000 dosage tablets):
* The particle size of the active component after being crushed is D90=123.21 μm;
the preparation method of the tablet comprises the following steps:
(1) Pretreatment: pulverizing Vorinostat fumarate with universal pulverizer, and sieving with 60 mesh sieve; sieving other adjuvants for use;
(2) Slurry preparation: adding the screened fumaric acid and hydroxypropyl cellulose into purified water (110 g) for dissolving for later use;
(3) One-step granulation: active ingredient 26.72G, mannitol 145.98G and microcrystalline cellulose 22G were placed in a multi-functional fluid bed (WBF-2G, chongqing Engel granulation coating technology, inc.), and the materials were preheated and mixed. Granulating the mixture, and spraying the prepared hydroxypropyl cellulose slurry at the same time, wherein the granulating temperature is 30-35 ℃, the granulated powder is obtained and dried, the drying temperature is 38-40 ℃, and the moisture is controlled to be less than 3%. The obtained granulated powder was passed through a crushing and sizing machine (FZB-150, torontal pharmaceutical machinery, ltd., zhejiang) to obtain a sieved powder having a particle size of 1.0mm.
(4) Tabletting and coating: the sieved powder, croscarmellose sodium and magnesium stearate were placed in a three-dimensional mixer (shanghai tianxiangjian pharmaceutical machinery ltd STC/HD 15) and mixed uniformly. Using 11 x 6mm special-shaped punch head of a rotary tablet press (ZP-8 of Shanghai Xinyuan pharmaceutical machinery Co., ltd.) to perform tabletting, controlling the hardness to be 100-150N, and finally adopting a gastric-soluble film coating material to perform coating, controlling the weight gain of the coating to be 2-5%.
Comparative example 3 refers to chinese patent CN 102743330B.
A tablet containing Voranolan fumarate has the following formula (1000 dosage tablets):
* The particle size of the active component after being crushed is D90=27.81 μm;
the preparation method of the tablet comprises the following steps:
(1) Pretreatment: crushing the Vonopalasin fumarate by a universal crusher and sieving the Vonopalasin fumarate by a 60-mesh sieve for later use; sieving other adjuvants for use;
(2) Slurry preparation: adding the screened fumaric acid and hydroxypropyl cellulose into purified water (110 g) for dissolving for later use;
(3) One-step granulation: active ingredient 26.72G, mannitol 145.98G and microcrystalline cellulose 22G were placed in a multi-functional fluid bed (WBF-2G, chongqing Engel granulation coating technology, inc.), and the materials were preheated and mixed. Granulating the mixture, and spraying the prepared hydroxypropyl cellulose slurry at the same time, wherein the granulating temperature is 30-35 ℃, obtaining granulated powder and drying, the drying temperature is 38-40 ℃, and the moisture content is controlled to be less than 3%. The obtained granulated powder was passed through a pulverizing and sizing machine (FZB-150, tokyo Torontal pharmaceutical machinery, ltd.) to obtain a sieved powder having a particle size of 1.0mm.
(4) Tabletting and coating: the sieved powder, croscarmellose sodium and magnesium stearate were placed in a three-dimensional mixer (shanghai tianxiangjian pharmaceutical machinery ltd STC/HD 15) and mixed uniformly. Using 11 x 6mm special-shaped punch head of a rotary tablet press (ZP-8 of Shanghai Xinyuan pharmaceutical machinery Co., ltd.) to perform tabletting, controlling the hardness to be 100-150N, and finally adopting a gastric-soluble film coating material to perform coating, controlling the weight gain of the coating to be 2-5%.
The effect of the invention is verified.
The intermediate granular state and the tabletting condition of the samples of the examples and the comparative examples were measured
TABLE 1 flow property, powder/granule form, and tablet shape test results of intermediate particles of examples and comparative examples
As is clear from the results of Table 1, examples 1 to 3 showed no astringent flushing and better powder flowability than comparative examples; the comparative example 1 uses the dissolved active ingredient and the binder for granulation, and the comparative example 2 uses the large-particle-size active ingredient and the dissolved binder for granulation, and the result is superior to that of the comparative example 3 in terms of sticking and punching; comparative example 3 adopts small-particle size active components, has strong static electricity and more fine powder, and has the risk of sticking and flushing; the above results indicate that the granules prepared by the process of this patent are in a good condition in all aspects.
The samples of the examples and the comparative examples were examined for friability, hardness, content uniformity, etc., and the specific results are shown in Table 2.
Table 2 results of friability, hardness, content uniformity, etc. of the samples of examples and comparative examples.
Comparing the results in Table 2, the results of content uniformity of examples are superior to those of comparative examples due to the uniform spraying of the active component and mannitol, and the finished product has good glossiness; comparative example 3, content loss in the fluidized bed was caused by small particle size of the active ingredient and large difference in properties from the adjuvant; the above results show that the content, content uniformity and appearance of the finished product of the tablet prepared by the method meet the requirements and are continuously stable.
Dissolution of the samples of examples and comparative examples was measured (general rule 0931) by literature methods and the methods of this patent, and the specific results are shown in Table 3. The dissolution measuring method of the present invention comprises the steps of: referring to dissolution determination method (0931 second method of the four general rules of the 2020 edition of Chinese pharmacopoeia), adopting paddle method, taking 900ml of acetate buffer solution with pH4.5 as dissolution medium, rotating at 50 rpm, and taking 10ml of dissolution solution at 5min, 10min, 15min, 20min, 30min, and 45 min; taking a Voranolan fumarate reference substance, and diluting the Voranolan fumarate reference substance to 1ml by using a dissolution medium to obtain 20 mu g of the Voranolan fumarate reference substance; the determination is carried out according to the high performance liquid chromatography 0512 of the four ministry of communications in the 2020 edition of Chinese pharmacopoeia.
Table 3 comparison of the dissolution test results of the examples and comparative examples with the original test sample:
the results in table 3 show that the dissolution rates of the samples prepared in comparative example 2 and comparative example 3 are significantly lower than those of the examples and the original ground products, and the dissolution tends to increase when the particle size of the active component in comparative example 3 is smaller; comparative example 1 a sample was prepared by dissolving the active ingredient, the dissolution rate was improved, but the problem of tableting in table 1 could not be solved; the dissolution rate of the examples 1-3 prepared by the method is obviously improved and is superior to that of the comparative example.
By combining the results in tables 1 to 3, the Voranolan fumarate tablet prepared by the method has simple process, is directly granulated by a fluidized bed in one step, and has high production efficiency;
the Voranolan fumarate tablet prepared by the method has the advantages of good particle flowability and compressibility, no sticking and impact, no astringent impact, smooth surface, qualified friability and qualified content and content uniformity.
The tablet of Voranolan fumarate prepared by the invention has a dissolution rate obviously superior to that of a common prescription process, and can take effect more quickly to relieve the symptoms of patients.
Claims (10)
1. A tablet containing Voranolan fumarate, characterized in that the tablet or its chip comprises Voranolan fumarate as active ingredient, internal adjuvants and external adjuvants, wherein in the preparation process, after dissolving the active ingredient and one or more of the internal adjuvants, one-step granulation is carried out in a fluidized bed with filler, and the obtained granules are sieved with 18-40 mesh sieve; then mixing with additional auxiliary materials for tabletting; the internal auxiliary materials are filler, adhesive and stabilizer; the additional auxiliary materials are a disintegrating agent and a lubricating agent.
2. The vorexant fumarate-containing tablet of claim 1, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, or corn starch; the adhesive is selected from one or more of hydroxypropyl methylcellulose, povidone or hydroxypropyl cellulose; the stabilizer is fumaric acid; the disintegrant is selected from croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber or carboxymethyl starch sodium; the lubricant is selected from magnesium stearate, calcium stearate, silica gel micropowder, pulvis Talci or hydrogenated vegetable oil.
3. The vorexant fumarate-containing tablet of claim 2, wherein the filler is microcrystalline cellulose, mannitol, and corn starch; the adhesive is hydroxypropyl cellulose L type; the stabilizer is fumaric acid; the disintegrant is croscarmellose sodium; the lubricant is magnesium stearate.
4. The Voranolazine fumarate-containing tablet according to claim 3, which comprises a tablet core and a coating, wherein the tablet core comprises the following components in parts by mass: 10-20 parts of vonolania fumarate, 60-70 parts of mannitol, 5-15 parts of microcrystalline cellulose, 2-4 parts of hydroxypropyl cellulose L-type, 2-3 parts of fumaric acid, 3-7 parts of croscarmellose sodium and 0.5-1.5 parts of magnesium stearate.
5. The Voranolan fumarate-containing tablet according to claim 4, which comprises a tablet core and a coating, wherein the tablet core comprises the following components in parts by mass: 12.15 parts of vorexane fumarate, 66.35 parts of mannitol, 10 parts of microcrystalline cellulose, 3 parts of hydroxypropyl cellulose L-type, 2.5 parts of fumaric acid, 5 parts of croscarmellose sodium and 1 part of magnesium stearate.
6. A method for preparing a tablet containing vorexant fumarate, comprising the steps of:
(1) Pretreatment: pulverizing the active components, sieving, and sieving the adjuvants;
(2) One-step granulation: dissolving the active component and one or more internal auxiliary materials, and then performing one-step granulation in a fluidized bed added with a filling agent to obtain granules which are sieved by a sieve with 18-40 meshes;
(3) Tabletting and coating: mixing the dried granules with adjuvants, tabletting, and coating.
7. The method for preparing a Voranolan fumarate-containing tablet according to claim 6, wherein the filler is one or more selected from microcrystalline cellulose, lactose, mannitol, and corn starch; the adhesive is selected from one or more of hydroxypropyl methylcellulose, povidone or hydroxypropyl cellulose; the disintegrant is selected from croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber or carboxymethyl starch sodium; the lubricant is selected from magnesium stearate, calcium stearate, silica gel micropowder, pulvis Talci or hydrogenated vegetable oil.
8. The Voranolan fumarate-containing tablet according to claim 7, wherein the filler is microcrystalline cellulose, mannitol and corn starch; the adhesive is hydroxypropyl cellulose L type; the stabilizer is fumaric acid; the disintegrant is croscarmellose sodium; the lubricant is magnesium stearate.
9. The process for producing a Voranolan fumarate-containing tablet according to claim 8, wherein in the step (1), the active ingredient is pulverized and sieved with a 40-80 mesh sieve; the auxiliary materials are sieved by a 30-50 mesh sieve, preferably 40 mesh. In the step (2), during granulation, the granulation temperature is 27-40 ℃, the drying temperature is 38-40 ℃, and the water content is controlled to be less than 3%; drying, crushing and sieving by a sieve with the aperture of 0.8-1.2 mm.
10. The method for preparing Voranolan fumarate-containing tablets as claimed in claim 5, wherein in the step (3), the coating is a gastric-soluble film coating material, and the weight gain of the coating is controlled to 2-5%.
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