CN118384117A - Olmesartan medoxomil orally disintegrating tablet and preparation method thereof - Google Patents
Olmesartan medoxomil orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN118384117A CN118384117A CN202410507736.1A CN202410507736A CN118384117A CN 118384117 A CN118384117 A CN 118384117A CN 202410507736 A CN202410507736 A CN 202410507736A CN 118384117 A CN118384117 A CN 118384117A
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- parts
- olmesartan medoxomil
- orally disintegrating
- mannitol
- essence
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- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 69
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 69
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 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 63
- 229930195725 Mannitol Natural products 0.000 claims abstract description 63
- 239000000594 mannitol Substances 0.000 claims abstract description 63
- 235000010355 mannitol Nutrition 0.000 claims abstract description 63
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 50
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims abstract description 31
- 235000010358 acesulfame potassium Nutrition 0.000 claims abstract description 31
- 229960004998 acesulfame potassium Drugs 0.000 claims abstract description 31
- 239000000619 acesulfame-K Substances 0.000 claims abstract description 31
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 27
- 238000007334 copolymerization reaction Methods 0.000 claims abstract description 25
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 25
- 239000003826 tablet Substances 0.000 claims abstract description 25
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims abstract description 24
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 21
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 19
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 16
- 235000010356 sorbitol Nutrition 0.000 claims abstract description 16
- 239000000600 sorbitol Substances 0.000 claims abstract description 16
- 239000000945 filler Substances 0.000 claims abstract description 14
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 14
- 239000000845 maltitol Substances 0.000 claims abstract description 14
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims abstract description 14
- 235000010449 maltitol Nutrition 0.000 claims abstract description 14
- 229940035436 maltitol Drugs 0.000 claims abstract description 14
- 239000003765 sweetening agent Substances 0.000 claims abstract description 14
- 229920001531 copovidone Polymers 0.000 claims abstract description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 9
- 229940069328 povidone Drugs 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 26
- 239000004376 Sucralose Substances 0.000 claims description 24
- 239000000843 powder Substances 0.000 claims description 24
- 235000019408 sucralose Nutrition 0.000 claims description 24
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 24
- 235000005976 Citrus sinensis Nutrition 0.000 claims description 22
- 240000002319 Citrus sinensis Species 0.000 claims description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 19
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 19
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 19
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 17
- 229960000913 crospovidone Drugs 0.000 claims description 10
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 10
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 10
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 235000001727 glucose Nutrition 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229960001031 glucose Drugs 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 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 2
- 239000004383 Steviol glycoside Substances 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 239000000686 essence Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 235000019411 steviol glycoside Nutrition 0.000 claims description 2
- 229930182488 steviol glycoside Natural products 0.000 claims description 2
- 150000008144 steviol glycosides Chemical class 0.000 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims 2
- 238000000576 coating method Methods 0.000 claims 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims 1
- 235000011837 pasties Nutrition 0.000 claims 1
- 229940085605 saccharin sodium Drugs 0.000 claims 1
- 229960002920 sorbitol Drugs 0.000 claims 1
- 235000020357 syrup Nutrition 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 19
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 13
- 229920000858 Cyclodextrin Polymers 0.000 description 11
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 11
- 239000000126 substance Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 8
- 239000010935 stainless steel Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 6
- 239000011812 mixed powder Substances 0.000 description 6
- 238000007907 direct compression Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000005480 Olmesartan Substances 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 230000000873 masking effect Effects 0.000 description 4
- 229960005117 olmesartan Drugs 0.000 description 4
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000009747 swallowing Effects 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
- A61K9/2004—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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2068—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Botany (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof, wherein the tablet comprises the following components in parts by weight: 1 to 20 parts of olmesartan medoxomil, 20 to 80 parts of mannitol cross-polymerization and copolymerization Maishan co-processed matter, 10 to 50 parts of filler, 1 to 20 parts of low-substituted hydroxypropyl cellulose, 0.02 to 2.0 parts of sweetener, 0.02 to 2.0 parts of acesulfame potassium, 0.02 to 2.0 parts of essence and 0.02 to 5.0 parts of magnesium stearate; the mannitol cross-polymerization copolymerization Maishan co-processed matter comprises the following components in parts by mass: 50-80 parts of mannitol, 1-5 parts of crosslinked povidone, 1-5 parts of copovidone, 1-5 parts of maltitol and 5-10 parts of sorbitol. The problem in the production of the existing orally disintegrating tablet is solved by innovatively adding the novel co-processed auxiliary material mannitol cross-polymerized and copolymerized Maishan co-processed material.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Olmesartan orally disintegrating tablet (Olmesartan Medoxomil Orally Disintegrating Tablets) is an angiotensin receptor blocker antihypertensive drug developed successfully in 2015 by the first co-product of japan. The medicine is only marketed in Japan at present, and provides convenience for old people, children and other patients with difficulty in swallowing tablets. The development of the orally disintegrating tablet is not only suitable for specific people, but also the characteristic that the orally disintegrating tablet can be taken without water is adopted, so that the medicine taking is more convenient.
In addition to the rapid disintegration in the oral cavity, orally disintegrating tablets, like ordinary tablets, are required to have sufficient hardness to withstand physical impact in order to maintain integrity during manufacture, transportation and use. In addition, such tablets are required to have no unpleasant odor, to suppress unpleasant taste and irritation when contained in the mouth, and to have good mouthfeel. This makes patients more receptive when taking the drug to improve drug compliance. Olmesartan medoxomil (formula I) is a prodrug which is easily degraded in aqueous solution to give olmesartan as an impurity (impurity a, formula II), and olmesartan medoxomil contains a2, 3-butanedione (hereinafter referred to as "diacetyl") structure, and diacetyl is a known substance having a specific odor.
In order to improve the medication compliance of the olmesartan orally disintegrating tablets, the prior method is to use cyclodextrin for odor inclusion and taste masking.
However, this technique has the following disadvantages:
Firstly, stability problems: the cyclodextrin has a large amount of hydroxyl groups in the molecular structure, the moisture content is higher (usually 8% -14%), the cyclodextrin is easy to lose water in the high-temperature 60 ℃ environment, and the produced small amount of water can lead to the disintegration of the orally disintegrating tablet, so that a sample can not keep a complete tablet shape and becomes a particle shape; meanwhile, a large number of hydroxyl groups exist in the molecular structure and can form hydrogen bonds with water molecules, so that cyclodextrin is easy to absorb moisture, and the taste masking effect is affected.
Secondly, the taste problem is that: cyclodextrin belongs to odorless and slightly sweet substances, and the orally disintegrating tablet prepared from the cyclodextrin can mask bad taste, but the orally disintegrating tablet prepared from the cyclodextrin has poor taste and poor administration compliance.
And then the problem of disintegration time limit: the tablet prepared by cyclodextrin has the problem of longer disintegration time, usually requires 50 to 3 minutes to completely disintegrate, and does not meet the requirement of the Chinese pharmacopoeia on the disintegration time limit of orally disintegrating tablets (the orally disintegrating tablets are disintegrated in the current edition of Chinese pharmacopoeia rule, if the orally disintegrating tablets are fully disintegrated within 60 seconds and pass through a screen, a small amount of the orally disintegrating tablets float on or adhere to the inner wall of a stainless steel tube or the screen, but a hard core person does not exist, the tablet can be subjected to rule compliance, 6 tablets are repeatedly measured, and the requirement of rule compliance is met, if 1 tablet does not meet rule, 6 tablets are additionally taken for retesting, and the requirement of rule compliance is met).
Finally, the production difficulty is as follows: the product prepared by using cyclodextrin cannot be included and masked effectively after using a powder direct compression process, and the product is usually subjected to tabletting after preparing particles by adopting a dry method or a wet method, so that the process is relatively complicated, and large-scale industrialized production is not facilitated.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide an olmesartan medoxomil orally disintegrating tablet and a preparation method thereof, wherein the olmesartan medoxomil orally disintegrating tablet provided by the invention not only has good taste and smell, but also has good medicine taking compliance, and the disintegration time limit can meet the requirement of Chinese pharmacopoeia on the standard of the disintegration time limit of the orally disintegrating tablet (the disintegration time limit is not more than 1 minute); and the preparation process is a powder direct compression process, so that the steps of a tabletting process can be reduced, the production time and energy are saved, and the simplification and the economy are realized.
In order to achieve the above object, the present invention is realized by the following technical scheme:
In a first aspect, the invention provides an olmesartan medoxomil orally disintegrating tablet, which comprises the following components in parts by weight: 1 to 20 parts of olmesartan medoxomil, 20 to 80 parts of mannitol cross-polymerization and copolymerization Maishan co-processed matter, 10 to 50 parts of filler, 1 to 20 parts of low-substituted hydroxypropyl cellulose, 0.02 to 2.0 parts of sweetener, 0.02 to 2.0 parts of acesulfame potassium, 0.02 to 2.0 parts of essence and 0.02 to 5.0 parts of magnesium stearate;
the mannitol cross-polymerization copolymerization Maishan co-processed matter comprises the following components in parts by mass: 50-80 parts of mannitol, 1-5 parts of crosslinked povidone, 1-5 parts of copovidone, 1-5 parts of maltitol and 5-10 parts of sorbitol.
In the invention, in an olmesartan medoxomil orally disintegrating tablet system taking olmesartan medoxomil as an active ingredient and adding mannitol cross-polymerization and copolymerization maillard coprocessing matter, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, a sweetener (sucralose), acesulfame potassium, essence (sweet orange and powdery essence) and magnesium stearate, the problem in the production of the existing orally disintegrating tablet is solved by innovatively adding mannitol cross-polymerization and copolymerization maillard coprocessing matter serving as a novel auxiliary material, wherein the coprocessing matter consists of mannitol, cross-linked povidone, copovidone, maltitol and sorbitol, and mannitol is taken as a main component of the coprocessing matter, so that the stability and bioavailability of the coprocessing matter are improved, and the solubility of the substance and the permeability of the medicine are improved; polymers such as crospovidone, copovidone and the like can form a three-dimensional network structure, so that the mechanical properties of the co-processed matters such as hardness and friability are improved, and meanwhile, the network structure also provides high porosity for the co-processed matters, and is beneficial to rapid release and disintegration of medicines; the polyols of maltitol and sorbitol can improve the mouthfeel of the co-processed product, make it smoother and more comfortable, and can also be used as a solvent or plasticizer to improve the processability and stability of the co-processed product. The synergistic effect among the components is the key for realizing the unique performance of the mannitol cross-polymerization and copolymerization maishan co-processed matter, so that the preparation product can be rapidly disintegrated while obtaining enough hardness, has the characteristics of high porosity, high hardness and high stability, and can be rapidly disintegrated.
Meanwhile, the filling agent (microcrystalline cellulose) is added in the olmesartan medoxomil orally disintegrating tablet system to achieve good filling effect, so that the product has good hardness; meanwhile, a disintegrating agent low-substituted hydroxypropyl cellulose is further added to generate a synergistic disintegration effect on the olmesartan medoxomil orally disintegrating tablet system and the crosslinked povidone in the mannitol crosslinked copolymer maishan co-processed substance, and the disintegration time limit is obviously reduced in the disintegration time limit investigation process. Meanwhile, the sweetener such as sucralose and the mixed powder essence of acesulfame potassium and sweet orange are added in the prescription, so that the taste compliance of the product is further improved, the product is convenient for patients to take, and the inadaptability is reduced.
In some embodiments, the mannitol cross-copolymerized maishan co-processed material comprises the following components in parts by mass: 75 parts of mannitol, 5 parts of crospovidone, 5 parts of copovidone, 5 parts of maltitol and 10 parts of sorbitol.
In some embodiments, the olmesartan medoxomil orally disintegrating tablet consists of, in parts by weight: 5 to 20 parts of olmesartan medoxomil, 30 to 70 parts of mannitol cross-polymerization and copolymerization Maishan co-processed matter, 15 to 35 parts of filler, 5 to 20 parts of low-substituted hydroxypropyl cellulose, 0.02 to 1.0 part of sweetener, 0.02 to 1.0 part of acesulfame potassium, 0.02 to 1.0 part of essence and 0.02 to 4.0 parts of magnesium stearate.
Preferably, the mass percentage of the mannitol cross-polymerized and copolymerized Maishan co-processed matters in the tablet is 35-65%.
In some embodiments, the filler is selected from one or a combination of microcrystalline cellulose, lactose, sucrose, glucose, starch, corn starch, sucrose, compressible starch, mannitol, sorbitol, or calcium phosphate.
Preferably, the mass percentage of the filler in the tablet is 17-32%.
In some embodiments, the sweetener is selected from one or a combination of sucralose, acesulfame potassium, sucrose, mono-syrup, mannitol, sorbitol, sodium saccharin, aspartame, steviol glycosides, glucose, xylitol, or maltitol.
Preferably, the sweetener is a mixture of sucralose and acesulfame potassium, and the mass ratio of the sucralose to the acesulfame potassium is 1-10:1-10. The combination of the two sweeteners can lead the orally disintegrating tablet to have better taste comfort and medication compliance of patients.
In some embodiments, the low substituted hydroxypropylcellulose is 8-17% by mass of the tablet.
In some embodiments, the essence is orange mix type powder essence, liquid essence, emulsified essence, paste essence, or capsule essence.
Preferably, the essence is sweet orange mixing type powder essence. The essence can be uniformly mixed with other components, the preparation process is simple, the special smell of olmesartan medoxomil medicine is covered, and the medicine taking compliance of patients is improved.
In a second aspect, the present invention provides a process for the preparation of said olmesartan medoxomil orally disintegrating tablet comprising the steps of:
Mixing olmesartan medoxomil, mannitol cross-polymerized Maishan co-processed matter, filler, low-substituted hydroxypropyl cellulose, sweetener, acesulfame potassium and essence in a preset proportion;
and (3) uniformly mixing the uniformly mixed mixture with magnesium stearate, and directly tabletting the powder to obtain the magnesium stearate.
The powder direct compression process can reduce the tabletting process steps, save the production time and energy, and realize simplification and economy; in addition, the direct tabletting process does not need to remove the solvent applied in the granulating process by heating, thereby avoiding the generation of impurity olmesartan by the hydrolysis of olmesartan medoxomil and improving the stability of the active ingredients of the medicine; meanwhile, compared with a cyclodextrin prescription, the water content of the tablet is lower, and the phenomenon that the product disintegrates into powder at a high temperature of 60 ℃ can be avoided. Due to the porous structure of the mannitol cross-polymerization and copolymerization maishan co-processing material, the medicine powder olmesartan medoxomil can be filled in the gaps in the mixing process, so that the odor of the medicine is effectively covered. Meanwhile, the added sweet orange mixing type powder essence can also produce a synergistic taste masking effect with mannitol cross-polymerized and copolymerized Maishan co-processed matters, and realizes a taste masking effect comparable with that of auxiliary cyclodextrin.
The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:
1. In the olmesartan medoxomil orally disintegrating tablet of the invention, a co-processing auxiliary material mannitol cross-polymerized and co-processed material is adopted as a filler and a disintegrating agent. The selection not only utilizes the porosity of the auxiliary material, ensures the mixing uniformity of the tablet, but also obviously improves the medication compliance of patients due to the high drug loading and comfortable taste. The product can be used as a filling agent, and the cross-linked povidone contained in the mixed auxiliary materials can greatly enhance the disintegration effect of the product, so that the product can be rapidly disintegrated, and the disintegration time limit meets the standard requirements of Chinese pharmacopoeia. In addition, the addition of the auxiliary materials simplifies the production process, shortens the production time and energy consumption, and realizes the simplification and economy of the process. More importantly, the solvent is not required to be removed by heating, so that the hydrolysis reaction of the olmesartan medoxomil is avoided, and the stability of the active ingredient is improved.
2. In the olmesartan medoxomil orally disintegrating tablet of the present invention, low-substituted hydroxypropylcellulose was selected as the disintegrant. When it is combined with mannitol cross-polymerized and copolymerized Maishan co-processed matter, it can produce synergistic disintegration effect and further reduce disintegration time. In addition, its addition imparts a certain hardness to the product.
3. In the olmesartan medoxomil orally disintegrating tablet, auxiliary materials such as sucralose, acesulfame potassium, sweet orange mixing type powder essence and the like are added in addition to the main active ingredient olmesartan medoxomil. The addition of the auxiliary materials reduces the discomfort of human bodies possibly caused by diacetyl, and the product has good taste and smell, thereby improving the medication compliance of patients and leading the medicine to be more popular in clinic.
4. The olmesartan medoxomil orally disintegrating tablet provided by the invention shows stability of preparation quality, simplicity of process and good mouthfeel. The disintegration time limit is short, and the mannitol cross-polymerization and copolymerization Mount common processed product has lower moisture content, so that the sample is ensured not to lose water or influence the disintegration effect due to high temperature. Overall, the process shows good stability and is very suitable for industrial production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
Fig. 1 is a picture of an orally disintegrating tablet disintegrating instrument;
fig. 2 is a picture of a disintegration basket on a disintegration apparatus.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil (D50 is not more than 10 mu m, D90 is in the range of 10 mu m to 25 mu m), 50% of mannitol cross-polymerization copolymerization Maishan co-processed matter, 22.7% of microcrystalline cellulose, 12.5% of low-substituted hydroxypropyl cellulose, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
The mannitol cross-polymerization and copolymerization Maishan co-processed product comprises the following components: 75 parts of mannitol, 5 parts of crospovidone, 5 parts of copovidone, 5 parts of maltitol and 10 parts of sorbitol.
The preparation method of the mannitol cross-polymerization and copolymerization Maishan co-processed product comprises the following steps:
Adding 75 parts of sorbitol, 10 parts of crosslinked povidone and 5 parts of crosslinked povidone into a fluidized bed, spraying an adhesive solution prepared from 50% ethanol and containing 5 parts of maltitol and 5 parts of copovidone, setting the air inlet temperature to 55 ℃, the fan frequency to 25Hz, the atomization pressure to 0.3MPa, the peristaltic pump rotating speed to 25rpm, and continuing fluidization after spraying liquid to dry wet particles until the moisture is below 2.0%.
The preparation method comprises the following steps:
Placing olmesartan medoxomil, mannitol cross-polymerized Maishan co-processed matter, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sucralose, acesulfame potassium and sweet orange mixed powder essence in a forced mixer according to the proportion, setting the mixing speed to be 10rpm, mixing for 30min, adding magnesium stearate into the mixed material, mixing again, setting the mixing speed to be 10rpm, mixing for 7min, and detecting the content of an intermediate. And determining the weight to be tabletted according to the content of the intermediate, and then tabletting.
Example 2
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 45% of mannitol cross-polymerization copolymer Maishan co-processed matter, 27.7% of microcrystalline cellulose, 12.5% of low-substituted hydroxypropyl cellulose, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
The mannitol cross-polymerization and copolymerization Maishan co-processed product comprises the following components: mannitol (50-80), crospovidone 3, copovidone 1, maltitol 3 and sorbitol 8.
Samples were prepared according to the preparation method of example 1.
Example 3
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 47.5% of mannitol cross-polymerization copolymerization Mount common processed product, 22.7% of microcrystalline cellulose, 15% of low-substituted hydroxypropyl cellulose, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
The mannitol cross-polymerization and copolymerization Maishan co-processed product comprises the following components: mannitol (50-80), crospovidone 3, copovidone 5, maltitol 2 and sorbitol 8.
Samples were prepared according to the preparation method of example 1.
Example 4
The olmesartan medoxomil orally disintegrating tablet comprises the following components: the prescription comprises the following components in percentage by mass: 12.5% of olmesartan medoxomil, 50% of mannitol cross-polymerization and copolymerization Mount common processed product, 22.7% of microcrystalline cellulose, 12.5% of low-substituted hydroxypropyl cellulose, 0.4% of sucralose, 0.25% of acesulfame potassium, 0.15% of sweet orange mixing type powder essence and 1.5% of magnesium stearate.
The mannitol cross-polymerization and copolymerization Maishan co-processed product comprises the following components: 80 parts of mannitol, 5 parts of crospovidone, 1 part of copovidone, 5 parts of maltitol and 5 parts of sorbitol.
Samples were prepared according to the preparation method of example 1.
Comparative example 1
The "low substituted hydroxypropylcellulose" in example 1 was replaced with "croscarmellose sodium".
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 50% of mannitol cross-polymerized and copolymerized Maishan co-processed matter, 22.7% of microcrystalline cellulose, 12.5% of croscarmellose sodium, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
The preparation method comprises the steps of placing olmesartan medoxomil, mannitol cross-polymerized maishan co-processed matters, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, sucralose, acesulfame potassium and sweet orange mixed powder essence with a prescription amount into a forced mixer, setting a mixing rotating speed of 10rpm, mixing for 30min, adding magnesium stearate into the mixed materials, mixing, setting a mixing rotating speed of 10rpm, mixing for 7min, and detecting the content of intermediate. And determining the weight to be tabletted according to the content of the intermediate, and then tabletting.
Comparative example 2
The "low substituted hydroxypropylcellulose" in example 1 was replaced with "magnesium aluminum silicate".
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 50% of mannitol cross-polymerization and copolymerization Mount common processed product, 22.7% of microcrystalline cellulose, 12.5% of magnesium aluminum silicate, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
Mixing olmesartan medoxomil, mannitol cross-polymerization and copolymerization Maishan co-processed product, microcrystalline cellulose, magnesium aluminum silicate, sucralose, acesulfame potassium and sweet orange mixed powder essence with a prescription amount in a forced mixer, setting a mixing rotating speed of 10rpm for 30min, mixing, adding magnesium stearate into the mixed material, mixing, setting a mixing rotating speed of 10rpm, mixing for 7min, and detecting the content of an intermediate. And determining the weight to be tabletted according to the content of the intermediate, and then tabletting.
Comparative example 3
The "low substituted hydroxypropylcellulose" in example 1 was replaced with "crospovidone".
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 50% of mannitol cross-polymerization and copolymerization Maishan coprocessing substance, 22.7% of microcrystalline cellulose, 12.5% of crospovidone, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
Mixing olmesartan medoxomil, mannitol cross-polymerized Maishan co-processed product, microcrystalline cellulose, cross-linked povidone, sucralose, acesulfame potassium and sweet orange mixed powder essence with a prescription amount in a forced mixer at a mixing speed of 10rpm for 30min, adding magnesium stearate into the mixed material, mixing at a mixing speed of 10rpm for 7min, and detecting the content of the intermediate. And determining the weight to be tabletted according to the content of the intermediate, and then tabletting.
Comparative example 4
The difference from example 1 is that: the mannitol cross-polymerized and copolymerized Maishan co-processed product is replaced by mannitol.
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 50% of mannitol, 22.7% of microcrystalline cellulose, 12.5% of low-substituted hydroxypropyl cellulose, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
Mixing olmesartan medoxomil, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sucralose, acesulfame potassium and sweet orange according to the prescription amount in a forced mixer, setting the mixing rotating speed to 10rpm for 30min, mixing, adding magnesium stearate into the mixed material, mixing, setting the mixing rotating speed to 10rpm for 7min, and detecting the content of the intermediate. And determining the weight to be tabletted according to the content of the intermediate, and then tabletting.
Comparative example 5
The olmesartan medoxomil orally disintegrating tablet comprises the following components: 12.5% of olmesartan medoxomil, 50% of mannitol cross-polymerized and copolymerized Maishan co-processed matter, 22.7% of microcrystalline cellulose, 12.5% of croscarmellose sodium, 0.46% of sucralose, 0.15% of acesulfame potassium, 0.09% of sweet orange mixing type powder essence and 1.6% of magnesium stearate.
Mixing olmesartan medoxomil, mannitol cross-polymerized maishan co-processed matter, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, sucralose, acesulfame potassium and sweet orange mixed powder essence in a forced mixer at a mixing speed of 10rpm for 30min, adding the mixed materials into a GL4-50 dry granulator, feeding the materials with a feeding frequency target value of 7Hz (allowed range of 6-10 Hz), a tabletting frequency target value of 10Hz (allowed range of 8-12 Hz) and a granulating frequency target value of 12Hz (allowed range of 10-14 Hz), performing dry granulation by adopting a 1.2mm screen, sieving with a 20-mesh sieve to obtain dry granulation particles, adding magnesium stearate, mixing again at a mixing speed of 10rpm for 7min, detecting the intermediate content, determining the weight of the tablets according to the intermediate content, and tabletting.
Comparative example 6
The difference from example 1 is that: low-substituted hydroxypropyl cellulose was omitted. The other components are the same as in example 1.
Performance testing
400 Pieces of olmesartan medoxomil orally disintegrating tablets of examples 1 to 4 and comparative examples 1 to 6, respectively, were placed in a surface dish, and sampled at 15 days and 30 days in an acceleration test chamber (40 ℃/RH 75%), respectively, and the disintegration time, moisture, dissolution rate and the related substances were examined, and the results are shown in table 1.
The dissolution method comprises the following steps: paddle method, rotational speed: 50rpm, volume: 900mL, dissolution medium: phosphate buffer (ph 6.8), sampling time: 30min.
The disintegration time limit measuring method comprises the following steps:
instrument device: as shown in figure 1, the main structure is a lifting bracket and a stainless steel pipe with a screen embedded at the lower end. The up-and-down moving distance of the lifting bracket is 10mm plus or minus 1mm, and the round-trip frequency is 30 times per minute.
Disintegrating basket: as shown in FIG. 2, the stainless steel tube has a tube length of 30mm and an inner diameter of 13.0mm, and a stainless steel screen (embedded in the bottom of the stainless steel tube) has a mesh diameter of 710. Mu.m.
The disintegration method comprises the following steps: the stainless steel tube is fixed on a bracket, immersed in a 1000ml cup, and the cup is filled with about 900ml of water with the temperature of 37+/-1 ℃ and the water level is adjusted to ensure that the screen is 15 mm+/-1 mm below the water surface when the stainless steel tube is at the lowest position. The instrument is started. Taking 1 tablet of the product, placing the tablet into the disintegrating basket to disintegrate, if a small amount of the tablet floats upwards or adheres to the inner wall of a stainless steel pipe or a screen, and if the tablet does not have a hard core, the tablet can be subjected to repeated measurement of 6 tablets according with the rule.
Table 1 examples 1 to 4 and comparative examples 1 to 6 olmesartan medoxomil orally disintegrating tablets disintegration time limit, moisture, dissolution rate and data on the related substances
The data in Table 1 shows that the products of examples 1-4 have no significant change in moisture under accelerated experimental conditions, the disintegration time accords with the requirements of Chinese pharmacopoeia, the dissolution rate is not reduced, and the related substances are not obviously increased. Comparative examples 1 to 3, when the disintegrating agent was changed from low-substituted hydroxypropylcellulose to common croscarmellose sodium, magnesium aluminum silicate and crospovidone, the time limit of disintegration tended to increase. Comparative example 4, in which the disintegration time was prolonged and the dissolution rate was also decreased when the binder was changed from mannitol cross-polymerization co-processed with maishan to common mannitol; comparative example 5, after the preparation process is changed to dry granulation, the disintegration time is prolonged and the dissolution rate is also reduced compared with the powder direct compression process; in comparative example 6, after the preparation process was changed to dry granulation, the disintegration time was prolonged and the dissolution rate was also decreased compared with the powder direct compression process.
In conclusion, the olmesartan medoxomil orally disintegrating tablet prepared by the invention has very stable properties, has no obvious changes of disintegration time limit, dissolution rate and related substances in the process of stable placement, has very good quality stability, and is suitable for industrial production.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An olmesartan medoxomil orally disintegrating tablet, characterized in that: the coating comprises the following components in parts by weight: 1 to 20 parts of olmesartan medoxomil, 20 to 80 parts of mannitol cross-polymerization and copolymerization Maishan co-processed matter, 10 to 50 parts of filler, 1 to 20 parts of low-substituted hydroxypropyl cellulose, 0.02 to 2.0 parts of sweetener, 0.02 to 2.0 parts of acesulfame potassium, 0.02 to 2.0 parts of essence and 0.02 to 5.0 parts of magnesium stearate;
the mannitol cross-polymerization copolymerization Maishan co-processed matter comprises the following components in parts by mass: 50-80 parts of mannitol, 1-5 parts of crosslinked povidone, 1-5 parts of copovidone, 1-5 parts of maltitol and 5-10 parts of sorbitol.
2. An olmesartan medoxomil orally disintegrating tablet according to claim 1, characterized in that: the coating comprises the following components in parts by weight: the mannitol cross-polymerization copolymerization Maishan co-processed matter comprises the following components in parts by mass: 75 parts of mannitol, 5 parts of crospovidone, 5 parts of copovidone, 5 parts of maltitol and 10 parts of sorbitol;
Preferably, 5 to 20 parts of olmesartan medoxomil, 30 to 70 parts of mannitol cross-polymerization and copolymerization Maishan co-processed matter, 15 to 35 parts of filler, 5 to 20 parts of low-substituted hydroxypropyl cellulose, 0.02 to 1.0 part of sweetener, 0.02 to 1.0 part of acesulfame potassium, 0.02 to 1.0 part of essence and 0.02 to 4.0 parts of magnesium stearate.
3. An olmesartan medoxomil orally disintegrating tablet according to claim 1, characterized in that: the mass percentage of the mannitol cross-polymerized and copolymerized Maishan co-processed product in the tablet is 35-65%.
4. An olmesartan medoxomil orally disintegrating tablet according to claim 1, characterized in that: the filler is selected from one or a combination of microcrystalline cellulose, lactose, sucrose, glucose, starch, corn starch, sucrose, compressible starch, mannitol, sorbitol or calcium phosphate;
preferably, the mass percentage of the filler in the tablet is 17-32%.
5. An olmesartan medoxomil orally disintegrating tablet according to claim 1, characterized in that: the sweetener is selected from one or a combination of sucralose, acesulfame potassium, sucrose, single syrup, mannitol, sorbitol, saccharin sodium, aspartame, steviol glycoside, glucose, xylitol or maltitol.
6. An olmesartan medoxomil orally disintegrating tablet according to claim 5, characterized in that: the sweetener is a mixture of sucralose and acesulfame potassium, and the mass ratio of the sucralose to the acesulfame potassium is 1-10:1-10.
7. An olmesartan medoxomil orally disintegrating tablet according to claim 1, characterized in that: the mass percentage of the low-substituted hydroxypropyl cellulose in the tablet is 8-17%.
8. An olmesartan medoxomil orally disintegrating tablet according to claim 1, characterized in that: the essence is sweet orange mixed type powder essence, liquid essence, emulsified essence, pasty essence or capsule essence.
9. An olmesartan medoxomil orally disintegrating tablet according to claim 8, characterized in that: the essence is sweet orange mixed type powder essence.
10. A process for the preparation of an orally disintegrating tablet of olmesartan medoxomil according to any one of claims 1 to 9, characterized in that: the method comprises the following steps:
Mixing olmesartan medoxomil, mannitol cross-polymerized Maishan co-processed matter, filler, low-substituted hydroxypropyl cellulose, sweetener, acesulfame potassium and essence in a preset proportion;
and (3) uniformly mixing the uniformly mixed mixture with magnesium stearate, and directly tabletting the powder to obtain the magnesium stearate.
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