CN105663095A - Preparation method of (R)-lansoprazole sustained-release capsule - Google Patents
Preparation method of (R)-lansoprazole sustained-release capsule Download PDFInfo
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- CN105663095A CN105663095A CN201510981088.4A CN201510981088A CN105663095A CN 105663095 A CN105663095 A CN 105663095A CN 201510981088 A CN201510981088 A CN 201510981088A CN 105663095 A CN105663095 A CN 105663095A
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- Prior art keywords
- enteric
- coat
- layer
- micropill
- slow releasing
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- 239000002775 capsule Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 title claims abstract description 34
- 229960003568 dexlansoprazole Drugs 0.000 title claims abstract description 34
- 238000013268 sustained release Methods 0.000 title claims abstract description 13
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 13
- 239000008188 pellet Substances 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 6
- 230000006378 damage Effects 0.000 claims abstract 2
- 239000011248 coating agent Substances 0.000 claims description 30
- 238000000576 coating method Methods 0.000 claims description 30
- 239000010410 layer Substances 0.000 claims description 17
- 238000007789 sealing Methods 0.000 claims description 17
- 230000001070 adhesive effect Effects 0.000 claims description 15
- 239000012055 enteric layer Substances 0.000 claims description 13
- 239000000853 adhesive Substances 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 7
- 239000004014 plasticizer Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000000945 filler Substances 0.000 claims description 5
- 239000003605 opacifier Substances 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims description 4
- 230000000857 drug effect Effects 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 210000004211 gastric acid Anatomy 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical compound OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 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
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical group CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 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 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group 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 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical group [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- IWVKTOUOPHGZRX-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-N 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- 239000006184 cosolvent Substances 0.000 claims 4
- 239000011812 mixed powder Substances 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- USEBIPUIVPERGC-UHFFFAOYSA-N Dibutylone Chemical compound CCC(N(C)C)C(=O)C1=CC=C2OCOC2=C1 USEBIPUIVPERGC-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- -1 copolyvidone Polymers 0.000 claims 1
- 229920000058 polyacrylate Polymers 0.000 claims 1
- 239000002861 polymer material Substances 0.000 claims 1
- 238000005096 rolling process Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 4
- 229940126409 proton pump inhibitor Drugs 0.000 abstract description 3
- 239000000612 proton pump inhibitor Substances 0.000 abstract description 3
- 239000003405 delayed action preparation Substances 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 7
- 239000012530 fluid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 201000006549 dyspepsia Diseases 0.000 description 2
- 208000024798 heartburn Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- MMJMSRMOAUITKN-UHFFFAOYSA-N 2-sulfinylbenzimidazole Chemical compound C1=CC=CC2=NC(=S=O)N=C21 MMJMSRMOAUITKN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 235000010894 Artemisia argyi Nutrition 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 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 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 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 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical group [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an (R)-lansoprazole sustained-release capsule and a preparation method thereof and belongs to the field of sustained-release preparations, and particularly relates to a preparation method of an acid-sensitive proton pump inhibitor sustained-release enteric-coated pellets. The capsule is filled with two kinds of pellets of which the releasing speed are different, one is enteric-coated quick-release pellets and the other one is enteric-coated sustained-release pellets. In the invention, damage on the (R)-lansoprazole is avoided and the (R)-lansoprazole is orientedly released in intestinal tracts, so that the capsule is quick in action, is prolonged in medicine effect and is improved in bioavailability, and is mainly improved significantly in stability of medicine active molecules in the preparation.
Description
Technical field
The present invention is the preparation method of a kind of R-lansoprazole slow releasing capsule, the preparation method being specifically related to a kind of R-lansoprazole enteric sustained-release pellet, belongs to sustained-release preparation technical field.
Background technology
R-lansoprazole (dexlansoprazole) chemical structural formula is as follows:
Its molecular formula is: C16H14F3N3O2S
Its chemical name is: (+)-2-[(R)-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole.
U.S. FDA is in esophagitis treatment new drug R-lansoprazole (the general Dexlansoprazole by name) listing of Takeda Pharmaceutical Company Limited of approval on January 30th, 2009 Japan research and development. Belonging to proton pump inhibitor class (PPIS) antiulcerative, it acts on the H+/K+-ATP enzyme of parietal cell, closes gastric much acid pump and reduces the generation of gastric acid. Clinically for treating the heartburn relevant to Non-erosive gastroesophageal reflux disease and erosive esophagitis in various degree, such as duodenal ulcer, gastric ulcer, reflux esophagitis, the first from left Chinese mugwort (Zollinger-Ellison) syndromic treatment etc., evident in efficacy.
This time listing dosage form is for providing the proton pump inhibitor class slow releasing capsule of point dual controlled release of 2 releases, medicine can be made 1-2 hour and two peak plasma concentrations occur after 4-5 hour respectively upon administration, and administration time unable to take food thing and the impact of meal time, can in the daytime or accompany night the gastroesophageal reflux disease of heartburn symptom to provide the Acidinhibitor up to 24 hours and lasting remission effect.
R-lansoprazole is the optical voidness medicine of racemization lansoprazole, there is the chemical constitution of sulfinyl benzimidazole in its structure, is subject to light, heavy metal ion, oxidisability and reproducibility and becomes the impact of grading factors to make stability reduce. Especially in acid condition, can there is destructive change in its chemical constitution, variable color and polymerism occur. In dosage form, R-lansoprazole interacts with other adjunct ingredients in preparation and makes stability reduce, and produces at preparation and variable color and decomposition be can be observed in storage. It addition, unstable in the solution of slant acidity, after oral administration, it is subject to gastric acid and destroys and reduce drug effect speed and bioavailability.
For increasing the stability of this class medicine, generally the materials such as medicine and alkaline, inorganic salts are mixed with, to provide the alkaline microenvironment of drug substance stable, outer layer is enteric coated, avoid degraded under one's belt, but, the subacidity of enteric-coating material own, the degraded of acid labile drug can be caused, thus causing that in enteric coated process or in storage, medicated layer surface color changes. Therefore, how to avoid this phenomenon, be the critical process in this preparation method.
Summary of the invention:
The object of the invention, for providing a kind of R-lansoprazole slow releasing capsule and preparation method thereof, is advantageous in that and can either ensure drug effect, can be obviously enhanced again R-lansoprazole active component stability in this dosage form.
The present invention adopts below scheme:
The capsule that human body compliance is higher, includes enteric-coated quick releasing micropill and enteric sustained-release pellet two kinds, has following specific sequential layer: celphere, medicated layer, sub-coat, sealing coat, enteric layer. Two kinds of micropill mass ratioes are 1:1-1.5, R-lansoprazole active component mass ratio 1:2.5-3.5.
Wherein, enteric coated micropill medicated layer, sub-coat preparation method be the medicine-feeding of celphere coating pan, bag sub-coat, this medicine-feeding method is low for equipment requirements, and efficiency is high, and yield is high, and micropill roundness is high. The enteric layers of micropill outer layer is that PH relies on the polymeric material dissolved, and intestinal location release can quickly be absorbed by the body, and effectively raises bioavailability, extends drug effect.
It is magnesium hydroxide that adjuvant used in the preparation of each sequential layer of micropill includes stabilizer, magnesium carbonate, sodium carbonate, sodium hydroxide, sodium dihydrogen phosphate etc., filler is microcrystalline Cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, mannitol, starch, dextrin, sucrose, lactose, pre-paying starch etc., adhesive is hydroxypropyl methylcellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvidone, polyvinylpolypyrrolidone, polyvinylpyrrolidone, methylcellulose, starch slurry, syrup etc., lubricant is magnesium stearate, Pulvis Talci, micropowder silica gel, one or more in Polyethylene Glycol, opacifier is titanium dioxide, solvent is purified water, 75%-95% ethanol. coating materials is methacrylic acid-acrylic acid polymerizable methacrylate thing, methacrylic acid-methyl methacrylate polymer etc., and plasticizer is triethyl citrate, Polyethylene Glycol, dibutyl phthalate, propylene glycol etc.
Wherein, R-lansoprazole micropill sub-coat weightening finish 30-40%, the weightening finish of R-lansoprazole micropill sealing coat is 5%-15%, and the weightening finish of R-lansoprazole micropill enteric layer is 10%-40%. Micropill water content is less than 3%.
The preparation method of R-lansoprazole micropill, concrete operation step is as follows:
A. two kinds of micropills all adopt celphere method of the round as a ball medicine-feeding of coating pan under adhesive effect, prepare pellet core.
B. two kinds of micropills all adopt pellet core coating pan under adhesive effect round as a ball on the method for powder, prepare sub-coat micropill.
C. two kinds of micropills all adopt fluid bed by method to sub-coat capsule core coating of the insulating liquid that stirs, prepare sealing coat micropill.
D. two kinds of micropills all adopt fluid bed by method to sealing coat capsule core coating of the enteric liquid that stirs, prepare the enteric coated micropill of two kinds of different release Mechanisms.
E. by the micropill of two kinds of prepared release Mechanisms, by the mass ratio of 1:1-1.5, make active component content ratio for 1:2.5-3.5, add moderate lubrication agent, mix homogeneously, fill capsule, prepare R-lansoprazole slow releasing capsule.
Detailed description of the invention
Embodiment 1:
The preparation (centrifugal coating pan medicine-feeding) of enteric-coated quick releasing micropill pellet core:
Preparation technology:
A. each supplementary material, mix homogeneously are weighed in proportion.
B. adhesive is got out. Adjusting coating pan rotating disk 300r/min, hydrojet 7-15r/min, atomizing pressure 0-0.5mpa, air feed 30hz carries out the preparation of pellet core.
C. dry, make pellet core water content lower than 3%.
D. the pellet core collecting 30-40 order of sieving is standby.
Embodiment 2:
The preparation (centrifugal coating pan medicine-feeding) of enteric sustained-release pellet pellet core:
Preparation technology:
A. each supplementary material, mix homogeneously are weighed in proportion.
B. adhesive is got out.
C. adjusting coating pan rotating disk 300r/min, hydrojet 7-15r/min, atomizing pressure 0-0.5mpa, air feed 30hz carries out the preparation of pellet core.
D. dry, make pellet core water content lower than 3%.
E. the pellet core collecting 30-40 order of sieving is standby.
Embodiment 3:
The preparation that enteric coated micropill sub-coat capsule core (includes rapid release with slow release):
Preparation technology:
A. each adjuvant, mix homogeneously are weighed in proportion.
B. adhesive 50% syrup is got out.
C. adjusting coating pan rotating disk 300r/min, hydrojet 7-15r/min, atomizing pressure 0.1-0.4mpa, air feed 30hz carries out the preparation of sub-coat capsule core.
D. dry, make sub-coat capsule core water content lower than 3%.
E. the sub-coat capsule core collecting 20-30 order of sieving is standby.
Embodiment 4:
The preparation of sealing coat capsule core that enteric coated micropill (includes rapid release and slow release):
Preparation technology:
A. weigh each adjuvant in proportion, appropriate purified water stirs.
B. adjusting fluid bed blower fan 25-35hz, hydrojet 10-15hz, atomizing pressure 0.1-0.4mpa, inlet temperature 50 DEG C, carry out the preparation of isolation capsule core, sealing coat weightening finish is 5%-15%.
C. dry, make sealing coat capsule core water content lower than 3%.
D. the sealing coat capsule core collecting 20-30 order of sieving is standby.
Embodiment 5:
The preparation of enteric-coated quick releasing micropill:
Preparation technology:
A. weigh each adjuvant in proportion, appropriate purified water stirs.
B. adjusting fluid bed blower fan 25-35hz, hydrojet 10-20hz, atomizing pressure 0.1-0.4mpa, inlet temperature 45 DEG C, carry out the preparation of enteric-coated quick releasing micropill, the weightening finish of fast release micropill enteric layer is 10%-20%.
C. dry, make fast release micropill water content lower than 3%.
D. the enteric-coated quick releasing micropill collecting 20-30 order that sieves is standby.
Embodiment 6:
The preparation of enteric sustained-release pellet:
Preparation technology:
A. weigh each adjuvant in proportion, appropriate 75%-95% ethanol stirs.
B. adjusting fluid bed blower fan 25-35hz, hydrojet 10-25hz, atomizing pressure 0.1-0.4mpa, inlet temperature 40 DEG C, carry out the preparation of enteric sustained-release pellet, the weightening finish of slow-release micro-pill enteric layer is 20%-40%.
C. dry, make slow-release micro-pill water content lower than 3%.
D. the enteric sustained-release pellet collecting 20-30 order that sieves is standby.
Embodiment 7:
Taking R-lansoprazole fast release micropill and slow-release micro-pill, weigh by 1:1-1.5, making R-lansoprazole active component mass ratio is 1:2.5-3.5, and three-dimensional mixer mixes, No. 3 capsule fills.
So far, R-lansoprazole slow releasing capsule completes.
Quality control:
By prepared R-lansoprazole slow releasing capsule being carried out standard test, character, differentiating, have the equal conformance with standard of index such as related substance, uniformity of dosage units, dissolution, loss on drying, assay.
Study on the stability:
Place 9 months under acceleration environment after taking R-lansoprazole slow releasing capsule dummy packages, preserve 15 months under long-term conditions, be periodically subject to product stability respectively and investigate, investigate result in Table 1.
Table 1 R-lansoprazole slow releasing capsule study on the stability result
The to sum up result of stability study, the R-lansoprazole slow releasing capsule demonstrating the present invention has the stability of excellence, and all experimental datas under long-term storage conditions all meet the requirements of the standard, and the stability data between each batch is showed no notable difference. By contrasting, the stability of the present invention is better than commercially available product. It is enough to demonstrate the interpolation sub-coat contribution to this dosage form stability.
The explanation of above example is only intended to help to understand method and the core concept thereof of the present invention.It should be pointed out that, for those skilled in the art, under the premise without departing from the principles of the invention, it is also possible to the present invention carries out some improvement and modification, these improve and modify in the protection domain also falling into the claims in the present invention.
Claims (14)
1. a R-lansoprazole slow releasing capsule, it is characterised in that: capsule is built with two kinds of micropills, and one is enteric-coated quick releasing micropill, and one is enteric sustained-release pellet.
2. slow releasing capsule according to claim 1; it is characterized in that; enteric-coated quick releasing micropill and slow-release micro-pill; there is following specific sequential layer: celphere, medicated layer, sub-coat, sealing coat, enteric layer; the sub-coat increased together with sealing coat higher intensity intercepted contacting of acidic enteric layer and basic activated medicine layer; protect medicine layer; make that enteric layer is more effective has kept out the gastric acid environment destruction to active component simultaneously, enhance active constituents of medicine stability in this dosage form significantly.
3. the slow releasing capsule according to any one of claim 1-2, it is characterised in that wherein, R-lansoprazole micropill sub-coat weightening finish 30-40%, the weightening finish of R-lansoprazole micropill sealing coat is 5%-15%, and the weightening finish of R-lansoprazole micropill enteric layer is 10%-40%.
4. the slow releasing capsule according to any one of claim 1-3, it is characterised in that enteric coated micropill medicated layer is obtained by the medicine-feeding of celphere coating pan rolling manipulation.
5. the slow releasing capsule according to any one of claim 1-4, it is characterised in that the enteric layer of micropill outer layer is that pH relies on the acrylic polymer materials dissolved, the release of intestinal location effectively raises bioavailability, extends drug effect.
6. the slow releasing capsule according to any one of claim 1-5, it is characterised in that also including adjuvant in each sequential layer of micropill, described adjuvant includes one or more in stabilizer, filler, adhesive, lubricant, opacifier, coating materials, plasticizer.
7. the slow releasing capsule according to any one of claim 1-6, it is characterized in that, described stabilizer is magnesium carbonate, sodium carbonate, one or more in sodium dihydrogen phosphate, filler is microcrystalline Cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, mannitol, starch, sucrose, one or more in pre-paying starch, adhesive is hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone, copolyvidone, polyvinylpyrrolidone, one or more in methylcellulose, lubricant is magnesium stearate, Pulvis Talci, one or more in micropowder silica gel, opacifier is titanium dioxide, coating materials is methacrylic acid-acrylic acid polymerizable methacrylate thing, one or more in methacrylic acid-methyl methacrylate polymer, plasticizer is triethyl citrate, Polyethylene Glycol, dibutyl phthalate, one or more in propylene glycol.
8. the slow releasing capsule according to any one of claim 1-7, it is characterised in that activity capsule core is prepared by the mixed powder of celphere and medicine layer, the mixed powder of described medicine layer includes active component R-lansoprazole, stabilizer, filler, adhesive, disintegrating agent, lubricant.
9. the slow releasing capsule according to any one of claim 1-8, it is characterised in that sub-coat capsule core is by activity capsule core, and the mixed powder of sub-coat and the centrifugal coating pan coating of adhesive obtain.
10. the slow releasing capsule according to any one of claim 1-9, it is characterised in that sealing coat capsule core is obtained by sub-coat capsule core and sealing coat coating solution fluidized bed coating, and wherein sealing coat coating solution includes adhesive, cosolvent, lubricant, opacifier.
11. the slow releasing capsule according to any one of claim 1-10, it is characterised in that rapid release enteric layer coating solution includes polymer 50-100 part, plasticizer 10-20 part, cosolvent 10-20 part, lubricant 20-30 part.
12. the slow releasing capsule according to any one of claim 1-11, it is characterised in that enteric-coated sustained release coating solution includes polymer 150-170 part, plasticizer 10-20 part, lubricant 50-80 part.
13. the preparation method of the slow releasing capsule according to any one of claim 1-12, it is characterised in that concrete operation step is as follows:
A. the preparation of activity capsule core: taking celphere mass parts is 300 parts, containing mixing mixed 1000 parts of the powder of uniform medicine layer, wherein active component R-lansoprazole 100-120 part, stabilizer 80-100 part, filler 500-550 part, adhesive 10-20 part, disintegrating agent 80-100 part, lubricant 10-30 part, under adhesive effect, centrifugal coating pan medicine-feeding;
B. the preparation of sub-coat capsule core: take activity capsule core 300 parts, sub-coat mixes powder 150-180 part, adhesive 10-20 part, centrifugal coating pan coating;
C. the preparation of sealing coat capsule core: take sub-coat capsule core 100 parts, sealing coat coating solution 200 parts, wherein adhesive 30-60 part, cosolvent 10-20 part, lubricant 10-20 part, opacifier 10-20 part, stir, fluidized bed coating;
D. the preparation of enteric coated micropill: take sealing coat micropill 100 parts, enteric layer coating solution 300 parts, stir, fluidized bed coating;
E. two kinds of micropills are weighed mixing in 1:1-1.5 ratio, and active component mass ratio is 1::2.5-3.5, fill capsule.
14. the method described in claim 13, rapid release enteric layer coating solution includes polymer 50-100 part, plasticizer 10-20 part, cosolvent 10-20 part, lubricant 20-30 part; Enteric-coated sustained release coating solution includes polymer 150-170 part, plasticizer 10-20 part, lubricant 50-80 part.
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