CN115569123B - 一种富马酸伏诺拉生片剂及其制备方法 - Google Patents
一种富马酸伏诺拉生片剂及其制备方法 Download PDFInfo
- Publication number
- CN115569123B CN115569123B CN202211570168.7A CN202211570168A CN115569123B CN 115569123 B CN115569123 B CN 115569123B CN 202211570168 A CN202211570168 A CN 202211570168A CN 115569123 B CN115569123 B CN 115569123B
- Authority
- CN
- China
- Prior art keywords
- fumarate
- tablet
- film coating
- parts
- vorexant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 66
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical group CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000007888 film coating Substances 0.000 claims abstract description 29
- 238000009501 film coating Methods 0.000 claims abstract description 29
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical group CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000004408 titanium dioxide Substances 0.000 claims abstract description 20
- 239000000473 propyl gallate Substances 0.000 claims abstract description 18
- 229940075579 propyl gallate Drugs 0.000 claims abstract description 18
- 235000010388 propyl gallate Nutrition 0.000 claims abstract description 18
- 239000004014 plasticizer Substances 0.000 claims abstract description 16
- 229960004926 chlorobutanol Drugs 0.000 claims abstract description 13
- 239000003381 stabilizer Substances 0.000 claims abstract description 13
- 239000003085 diluting agent Substances 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000007884 disintegrant Substances 0.000 claims abstract description 10
- 239000010410 layer Substances 0.000 claims abstract description 7
- 239000007767 bonding agent Substances 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 239000011812 mixed powder Substances 0.000 claims description 16
- 239000001509 sodium citrate Substances 0.000 claims description 16
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 9
- 238000005507 spraying Methods 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
- 229940079593 drug Drugs 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 229960000913 crospovidone Drugs 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 7
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 7
- 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 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 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 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000000853 adhesive Substances 0.000 claims description 3
- 230000001070 adhesive effect Effects 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 229940083542 sodium Drugs 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 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 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229910002012 Aerosil® Inorganic materials 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 238000005286 illumination Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229910001868 water Inorganic materials 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 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 description 5
- 229940050411 fumarate Drugs 0.000 description 5
- 229960001375 lactose Drugs 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229960001790 sodium citrate Drugs 0.000 description 3
- 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 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 206010000059 abdominal discomfort Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 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 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 208000000689 peptic esophagitis Diseases 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229950003825 vonoprazan Drugs 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940123359 Potassium antagonist Drugs 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- -1 pyridin-3-ylsulfonyl Chemical group 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2813—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种富马酸伏诺拉生片剂及其制备方法，属于医药制剂技术领域，具体包括片芯和薄膜包衣层；所述片芯包括富马酸伏诺拉生，稳定剂，稀释剂，崩解剂和粘合剂；所述薄膜包衣层包括成膜材料，增塑剂和二氧化钛；其中，所述稳定剂为没食子酸丙酯，所述增塑剂为三氯叔丁醇。本发明富马酸伏诺拉生片剂在不改变药物组合物本身酸度的情况下，得到一种可以在光照期间提高富马酸伏诺拉生稳定性的片剂，保证患者服用的安全有效，适合工业化大规模生产。
Description
技术领域
本发明属于医药制剂技术领域，具体地说，涉及一种富马酸伏诺拉生片剂及其制备方法。
背景技术
富马酸伏诺拉生是由日本武田公司开发的一种新型的PPI-钾离子竞争性酸阻滞剂，通过竞争性抑制氢离子/钠离子-ATP酶中的钾离子而起作用，是一种可逆的钾离子拮抗剂，于2014年12月首次在日本获批上市，商品名Takecab。2019年12月在中国上市，商品名“沃克”，是首款获批进入中国市场的钾离子竞争性酸阻滞剂，为反流性食管炎治疗的临床用药提供了新的选择，将大幅度改善反流性食管炎患者的生活质量。
富马酸伏诺拉生，又名富马酸沃诺拉赞(Vonoprazan fumarate)，化学名为1-[5-(2- 氟苯基)-1-(吡啶-3-基磺酰基)-1H-吡咯3-基]-N-甲基甲胺富马酸单盐，其结构式为：
中国专利CN102743330A指出通过加入二氧化钛、增塑剂和链状有机酸可提高富马酸伏诺拉生的固体制剂的光稳定性。其原因为聚乙二醇(增塑剂)等醇类物质与二氧化钛在光照条件下形成的自由基发生反应，导致药物发生降解，该专利通过将链状有机酸加入到药物组合物核芯或膜中，达到药物组合物在光照期间抑制分解产物的作用。然而，与传统PPI类抑制剂在肠道崩解释放不同，富马酸伏诺拉生片剂在酸性条件下稳定，口服后在胃内迅速崩解释放并离子化，离子化形式通过离子型结合抑制氢离子/钾离子-ATP酶，升高胃内pH值。处方中加入链状有机酸后降低了药物组合物本身酸度，导致人体口服富马酸伏诺拉生片剂后，在富马酸伏诺拉生发挥抑酸作用前，胃内接触过酸的药物组合物，造成胃部不适。
因此，需要进一步研究富马酸伏诺拉生片剂，在不改变药物组合物本身酸度的情况下，得到一种可以在光照期间提高富马酸伏诺拉生稳定性的片剂。
发明内容
鉴于此，本发明提供一种富马酸伏诺拉生片剂，旨在实现在不改变药物制剂本身酸度的情况下，得到一种可以在光照期间提高富马酸伏诺拉生稳定性的片剂。本发明的富马酸伏诺拉生片剂光稳定性好，避免胃内接触过酸药物制剂而造成胃部不适，保证患者服用的安全有效，适合工业化大规模生产。
本发明提供一种富马酸伏诺拉生片剂，所述片剂包括片芯和薄膜包衣层；所述片芯包括富马酸伏诺拉生，稳定剂，稀释剂，崩解剂和粘合剂；所述薄膜包衣层包括成膜材料，增塑剂和二氧化钛；其中，所述稳定剂为没食子酸丙酯，所述增塑剂为三氯叔丁醇。
本发明的富马酸伏诺拉生对光不稳定，发明人为了得到稳定的富马酸伏诺拉生片剂，经过了大量的研究发现，以三氯叔丁醇作为增塑剂，与成膜材料和二氧化钛对富马酸伏诺拉生片芯包衣，并配合在富马酸伏诺拉生片芯中加入没食子酸丙酯稳定剂，可以有效阻隔光照对富马酸伏诺拉生的影响，减少二氧化钛的光屏蔽效应对富马酸伏诺拉生产生的降解效应。
上述的富马酸伏诺拉生片剂中，所述片芯还包括枸橼酸钠。发明人发现，上述的富马酸伏诺拉生片剂中，加入枸橼酸钠可进一步增加富马酸伏诺拉生片剂的稳定性，避免富马酸伏诺拉生因光照影响而发生降解。进一步的通过筛选没食子酸丙酯与枸橼酸钠的用量比，当没食子酸丙酯与枸橼酸钠的质量用量比为1-3:1时，光照稳定性得到进一步提高。
上述的富马酸伏诺拉生片剂中，所述稀释剂选自乳糖，微晶纤维素，甘露醇，预胶化淀粉，磷酸氢钙，山梨醇，蔗糖，硫酸钙，碳酸钙中的一种或几种。
上述的富马酸伏诺拉生片剂中，所述崩解剂选自交联羧甲基纤维素钠，交联聚维酮，羧甲基淀粉钠，低取代羟丙基纤维素中的一种或几种。
上述的富马酸伏诺拉生片剂中，所述粘合剂选自羟丙基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，聚维酮中的一种或几种。
上述的富马酸伏诺拉生片剂中，还包括润滑剂，所述润滑剂选自硬脂酸镁，硬脂富马酸钠，微粉硅胶，滑石粉中的一种或几种。润滑剂的用量可根据本领域技术人员的一般认知水平得到。
上述的富马酸伏诺拉生片剂，所述片芯的各组分的用量以质量份数计为：富马酸伏诺拉生为10-20份，没食子酸丙酯为2.5-6份，稀释剂为65-105份，崩解剂为2-6.5份，粘合剂为2-5份，其中富马酸伏诺拉生的用量以伏诺拉生计算；所述薄膜包衣层的各组分的用量以质量份数计为：成膜材料为2-6份，增塑剂为0.6-1.5份，二氧化钛为0.4-1份。
本发明还提供一种上述富马酸伏诺拉生片剂的制备方法，方法包括以下步骤：
（1）将富马酸伏诺拉生，稳定剂，稀释剂和崩解剂混合均匀，得药物混粉；
（2）将含粘合剂的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒压片，得片芯；
（4）将成膜材料，增塑剂和二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
上述富马酸伏诺拉生片剂的制备方法，所述步骤（1）中可选择性加入枸橼酸钠，和\或所述步骤（3）中可选择性加入润滑剂。在一些实施方式中，在上述制备方法中的步骤（1）中加入枸橼酸钠，枸橼酸钠与富马酸伏诺拉生，稳定剂，稀释剂和崩解剂共同混合均匀。在一些实施方式中，在上述制备方法中的步骤（3）中加入润滑剂，润滑剂与药物颗粒混合均匀后压片。在一些实施方式中，在上述制备方法中的步骤（1）中加入枸橼酸钠，枸橼酸钠与富马酸伏诺拉生，稳定剂，稀释剂和崩解剂共同混合均匀；步骤（3）中加入润滑剂，润滑剂与药物颗粒混合均匀后压片。
本发明中的成膜材料为本领域常用的成膜材料，包括但不限于羟丙基纤维素、羟丙甲基纤维素、聚乙烯醇、丙烯酸树脂等。成膜材料与增塑剂、二氧化钛溶于纯化水中制得薄膜包衣溶液，用于为片芯进行薄膜包衣。
与现有技术相比，本发明的有益效果为：
本发明通过增塑剂三氯叔丁醇和稳定剂没食子酸丙酯的配合，克服了因富马酸伏诺拉生对光不稳定，以及薄膜包衣中二氧化钛产生的光屏蔽效应对富马酸伏诺拉生的影响，增加富马酸伏诺拉生片剂在制备和存储过程中的稳定性。
具体实施方式
实施例1
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，乳糖，微晶纤维素和交联聚维酮混合均匀，得药物混粉；
（2）将含羟丙基甲基纤维素的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒压片，得片芯；
（4）将羟丙基纤维素，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
实施例2
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，山梨醇，磷酸氢钙和低取代羟丙基纤维素混合均匀，得药物混粉；
（2）将含羟丙基纤维素的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒压片，得片芯；
（4）将羟丙基纤维素，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
实施例3
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，甘露醇，微晶纤维素和羧甲基淀粉钠混合均匀，得药物混粉；
（2）将含聚维酮的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒压片，得片芯；
（4）将羟丙基甲基纤维素，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
实施例4
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，预胶化淀粉和交联聚维酮混合均匀，得药物混粉；
（2）将含羟丙基甲基纤维素和羧甲基纤维素钠的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒与硬脂酸镁混合均匀压片，得片芯；
（4）将羟丙基纤维素，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
实施例5
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，枸橼酸钠，乳糖，微晶纤维素，交联聚维酮和交联羧甲基纤维素钠混合均匀，得药物混粉；
（2）将含羟丙基甲基纤维素的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒压片，得片芯；
（4）将羟丙基纤维素，聚乙烯醇，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，获得片剂。
实施例6
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，枸橼酸钠，乳糖，微晶纤维素和交联聚维酮混合均匀，得药物混粉；
（2）将含羟丙基甲基纤维素的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒与微粉硅胶混合均匀压片，得片芯；
（4）将羟丙基纤维素，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
实施例7
制备方法：
（1）将富马酸伏诺拉生，没食子酸丙酯，枸橼酸钠，乳糖，微晶纤维素和交联聚维酮混合均匀，得药物混粉；
（2）将含羟丙基甲基纤维素的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒，硬脂富马酸钠和滑石粉混合均匀压片，得片芯；
（4）将羟丙基纤维素，三氯叔丁醇，二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
对比例
制备方法同实施例1。
稳定性考察
取实施例和对比例制得的富马酸伏诺拉生片剂样品放在透明的玻璃瓶中，紧密地密封，并在光照(4500lux±500lux)下保存30天。分别在0天和30天，通过HPLC测定其总杂质（%），用流动相A：流动相B=3:1的混合溶剂提取片剂，从而测定总杂质。HPLC试验条件如下：
仪器及试剂：高效液相色谱仪、电子分析天平、乙腈、磷酸二氢钾、磷酸、水。
色谱条件：
色谱柱：十八烷基硅烷键合硅胶为填充剂(Waters Xbridge BEH 2.5μm×4 .6mm×100mm或柱效类似的色谱柱)；流速为每分钟1.0ml；紫外分光光度计检测波长为230nm；柱温为25℃；进样体积为20μl。
流动相A：pH3 .0磷酸盐缓冲液，(称取磷酸二氢钾约13 .6g，加水约900ml使溶解，用磷酸调节pH至3 .0，再加水至1000ml)过滤，脱气。
流动相B：乙腈。
按下表进行梯度洗脱(流动相量可缩放、比例可适当调整)
峰面积的测定范围为60分钟。
结果如下：
对上述实施例和对比例得到的样品进行稳定性试验考察得出，本发明实施例1-7中，通过增塑剂三氯叔丁醇与稳定剂没食子酸丙酯的配合，得到的富马酸伏诺拉生片剂具有较好的光稳定性；当片芯中加入枸橼酸钠时，片剂的稳定性进一步提高，保证患者的用药安全。
Claims (6)
1.一种富马酸伏诺拉生片剂，其特征在于，所述片剂包括片芯和薄膜包衣层；所述片芯包括富马酸伏诺拉生，稳定剂，稀释剂，崩解剂和粘合剂；所述薄膜包衣层包括成膜材料，增塑剂和二氧化钛；其中，所述稳定剂为没食子酸丙酯，所述增塑剂为三氯叔丁醇；所述稀释剂选自乳糖，微晶纤维素，甘露醇，预胶化淀粉，磷酸氢钙，山梨醇，蔗糖，硫酸钙，碳酸钙中的一种或几种；所述崩解剂选自交联羧甲基纤维素钠，交联聚维酮，羧甲基淀粉钠，低取代羟丙基纤维素中的一种或几种；粘合剂选自羟丙基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，聚维酮中的一种或几种；所述片芯的各组分的用量以质量份数计为：富马酸伏诺拉生为10-20份，没食子酸丙酯为2.5-6份，稀释剂为65-105份，崩解剂为2-6.5份，粘合剂为2-5份，其中富马酸伏诺拉生的用量以伏诺拉生计算；所述薄膜包衣层的各组分的用量以质量份数计为：成膜材料为2-6份，增塑剂为0.6-1.5份，二氧化钛为0.4-1份。
2.根据权利要求1所述的富马酸伏诺拉生片剂，其特征在于，所述片芯还包括枸橼酸钠。
3.根据权利要求2所述的富马酸伏诺拉生片剂，其特征在于，所述没食子酸丙酯与枸橼酸钠的质量用量比为1-3:1。
4.根据权利要求1所述的富马酸伏诺拉生片剂，其特征在于，还包括润滑剂，所述润滑剂选自硬脂酸镁，硬脂富马酸钠，微粉硅胶，滑石粉中的一种或几种。
5.一种权利要求1所述富马酸伏诺拉生片剂的制备方法，其特征在于，方法包括以下步骤：
（1）将富马酸伏诺拉生，稳定剂，稀释剂和崩解剂混合均匀，得药物混粉；
（2）将含粘合剂的水溶液对药物混粉进行制粒，制成药物颗粒；
（3）将药物颗粒压片，得片芯；
（4）将成膜材料，增塑剂和二氧化钛制得薄膜包衣溶液，用薄膜包衣溶液喷涂片芯，得片剂。
6.根据权利要求5所述富马酸伏诺拉生片剂的制备方法，其特征在于，所述步骤（1）中可选择性加入枸橼酸钠，和\或所述步骤（3）中可选择性加入润滑剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211570168.7A CN115569123B (zh) | 2022-12-08 | 2022-12-08 | 一种富马酸伏诺拉生片剂及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211570168.7A CN115569123B (zh) | 2022-12-08 | 2022-12-08 | 一种富马酸伏诺拉生片剂及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115569123A CN115569123A (zh) | 2023-01-06 |
| CN115569123B true CN115569123B (zh) | 2023-03-14 |
Family
ID=84590742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211570168.7A Active CN115569123B (zh) | 2022-12-08 | 2022-12-08 | 一种富马酸伏诺拉生片剂及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115569123B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117462507B (zh) * | 2023-12-28 | 2024-03-15 | 山东齐都药业有限公司 | 富马酸伏诺拉生药物组合物及其制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003080030A1 (en) * | 2002-03-26 | 2003-10-02 | Bernard Charles Sherman | Stable tablets comprising pergolide mesylate |
| CN101670096A (zh) * | 2008-09-11 | 2010-03-17 | 杭州九源基因工程有限公司 | 含有艾塞那肽的药物制剂 |
| CN101686978A (zh) * | 2006-08-31 | 2010-03-31 | 索尔瓦药物有限公司 | 用于治疗精神分裂症的联苯芦诺的剂量渐增方案及其中所使用的试剂盒 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA014443B1 (ru) * | 2004-06-29 | 2010-12-30 | Никомед Данмарк Апс | Фармацевтическая композиция (варианты) и способ ее производства |
| CN1919194A (zh) * | 2006-08-17 | 2007-02-28 | 刘瑜玲 | 西罗莫司的液体组合物 |
-
2022
- 2022-12-08 CN CN202211570168.7A patent/CN115569123B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003080030A1 (en) * | 2002-03-26 | 2003-10-02 | Bernard Charles Sherman | Stable tablets comprising pergolide mesylate |
| CN101686978A (zh) * | 2006-08-31 | 2010-03-31 | 索尔瓦药物有限公司 | 用于治疗精神分裂症的联苯芦诺的剂量渐增方案及其中所使用的试剂盒 |
| CN101670096A (zh) * | 2008-09-11 | 2010-03-17 | 杭州九源基因工程有限公司 | 含有艾塞那肽的药物制剂 |
Non-Patent Citations (1)
| Title |
|---|
| 药剂学;《国外医学.药学分册》(第09期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115569123A (zh) | 2023-01-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115569123B (zh) | 一种富马酸伏诺拉生片剂及其制备方法 | |
| KR102246657B1 (ko) | 타다라필 및 탐수로신을 함유하는 약학적 캡슐 복합 제제 | |
| CN111670030A (zh) | 包含埃索美拉唑及碳酸氢钠的药剂学制剂 | |
| AU2017304029B2 (en) | Formulation having improved pH-dependent drug-release characteristics, containing esomeprazole or pharmaceutically acceptable salt thereof | |
| KR20200023185A (ko) | 에스오메프라졸 및 탄산수소나트륨을 포함하는 우수한 방출특성을 갖는 약제학적 제제 | |
| JP2021512081A (ja) | エソメプラゾール及び炭酸水素ナトリウムを含む安定な薬剤学的組成物 | |
| KR20160054216A (ko) | 콜린알포세레이트를 함유하는 정제 및 그 제조방법 | |
| CN103655570A (zh) | 西格列汀与二甲双胍复方缓释制剂及其制备方法 | |
| KR100429694B1 (ko) | 밸프로산금속염의서방성정제 | |
| KR20130078101A (ko) | 로자탄, 암로디핀 및 히드로클로로티아자이드를 포함하는 고정 용량 조합 제형 | |
| EP3648745B1 (en) | Pharmaceutical composition including multi-unit spheroidal tablet containing esomeprazole and spheroidal pharmaceutically acceptable salt thereof, and method of preparing the pharmaceutical composition | |
| CN112999181B (zh) | 一种富马酸沃诺拉赞片剂 | |
| US20220288056A1 (en) | Pharmaceutical composition containing nitroxoline, nitroxoline oral solid tablet, preparation method therefor and use thereof | |
| WO2023208068A1 (zh) | 一种治疗肝病的药物缓释片及其制备方法和用途 | |
| KR20160026714A (ko) | 콜린 알포세레이트-함유 정제 및 이의 제조방법 | |
| WO2022174268A1 (en) | Irak4 degraders and uses thereof | |
| KR20170115384A (ko) | 은행잎 추출물을 포함하는 경구용 서방 제제 | |
| CN111053747A (zh) | 一种阿卡波糖药物制剂 | |
| KR101910707B1 (ko) | 복용순응도가 향상된 메트포르민 서방성 정제 및 이의 제조방법 | |
| KR101641319B1 (ko) | 안정성이 개선된 에카베트와 라니티딘의 복합 제제 | |
| CN115025057B (zh) | 一种苯磺酸氨氯地平叶酸片及其制备方法 | |
| KR102585644B1 (ko) | 1-(3-시아노-1-아이소프로필-인돌-5-일)피라졸-4-카르복실산을 포함하는 경구용 제제 | |
| KR101485177B1 (ko) | 쓴맛이 차폐된 실데나필 시트레이트의 저작정 및 그 제조방법 | |
| WO2023163510A1 (ko) | 리나글립틴 또는 이의 약학적으로 허용가능한 염과 메트포르민 또는 이의 약학적으로 허용가능한 염을 포함하는 약물방출이 조절된 약제학적 복합제제 | |
| KR102146724B1 (ko) | 벤즈이미다졸계 화합물을 포함하는 약제학적 조성물 및 이의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240207 Address after: Building 16, No. 66 Huiyuan Road, Jiading District, Shanghai, 201800 Patentee after: Shanghai Zezheng Biopharmaceutical Co.,Ltd. Country or region after: China Patentee after: Zezheng (Jinan) Biotechnology Co.,Ltd. Address before: 250101 508, Building 2, Aosheng Building, 1166 Xinluo Street, Jinan Area, Jinan Free Trade Pilot Zone, Shandong Province Patentee before: Zezheng (Jinan) Biotechnology Co.,Ltd. Country or region before: China |
|
| TR01 | Transfer of patent right |