CN113101276A - Esciprazole magnesium enteric-coated pellet and capsule and preparation method thereof - Google Patents
Esciprazole magnesium enteric-coated pellet and capsule and preparation method thereof Download PDFInfo
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- CN113101276A CN113101276A CN202110262957.3A CN202110262957A CN113101276A CN 113101276 A CN113101276 A CN 113101276A CN 202110262957 A CN202110262957 A CN 202110262957A CN 113101276 A CN113101276 A CN 113101276A
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- coating layer
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- 239000008188 pellet Substances 0.000 title claims abstract description 192
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 239000002775 capsule Substances 0.000 title claims abstract description 19
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 title description 2
- 239000011777 magnesium Substances 0.000 title description 2
- 229910052749 magnesium Inorganic materials 0.000 title description 2
- 239000010410 layer Substances 0.000 claims abstract description 147
- 239000011247 coating layer Substances 0.000 claims abstract description 128
- 239000003814 drug Substances 0.000 claims abstract description 106
- 229940079593 drug Drugs 0.000 claims abstract description 91
- 229960000197 esomeprazole magnesium Drugs 0.000 claims abstract description 85
- KWORUUGOSLYAGD-WLHYKHABSA-N magnesium;5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-WLHYKHABSA-N 0.000 claims abstract description 85
- 238000002955 isolation Methods 0.000 claims abstract description 79
- 238000009505 enteric coating Methods 0.000 claims abstract description 75
- 239000002702 enteric coating Substances 0.000 claims abstract description 75
- 239000006187 pill Substances 0.000 claims abstract description 63
- 239000000463 material Substances 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 35
- 230000008569 process Effects 0.000 claims abstract description 31
- 238000011068 loading method Methods 0.000 claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 17
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 45
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 44
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 44
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 43
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 43
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 43
- 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 42
- 238000000576 coating method Methods 0.000 claims description 34
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 34
- 239000011248 coating agent Substances 0.000 claims description 33
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 30
- 238000005507 spraying Methods 0.000 claims description 29
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 24
- 239000001069 triethyl citrate Substances 0.000 claims description 24
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 24
- 235000013769 triethyl citrate Nutrition 0.000 claims description 24
- 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 21
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 19
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 19
- 239000006185 dispersion Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 235000019359 magnesium stearate Nutrition 0.000 claims description 17
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 17
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 13
- 229920000053 polysorbate 80 Polymers 0.000 claims description 13
- 238000000889 atomisation Methods 0.000 claims description 8
- 229960004770 esomeprazole Drugs 0.000 claims description 7
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 5
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004925 Acrylic resin Substances 0.000 claims description 4
- 229920000178 Acrylic resin Polymers 0.000 claims description 4
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 229940074045 glyceryl distearate Drugs 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000013341 scale-up Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 230000004584 weight gain Effects 0.000 description 18
- 235000019786 weight gain Nutrition 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 11
- 238000005303 weighing Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 238000007873 sieving Methods 0.000 description 6
- 239000000243 solution Substances 0.000 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 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 238000004364 calculation method Methods 0.000 description 5
- 229960004793 sucrose Drugs 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000012055 enteric layer Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- 208000023514 Barrett esophagus Diseases 0.000 description 2
- 208000023665 Barrett oesophagus Diseases 0.000 description 2
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 2
- 108010083204 Proton Pumps Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 208000000689 peptic esophagitis Diseases 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001914 gastric parietal cell Anatomy 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- MQEUGMWHWPYFDD-UHFFFAOYSA-N magnesium;6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound [Mg].N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C MQEUGMWHWPYFDD-UHFFFAOYSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000009736 wetting Methods 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
- A61K9/48—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
- A61K9/5089—Processes
-
- 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
- A61K9/501—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
- A61K9/48—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
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/5026—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
- A61K9/48—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
- A61K9/5047—Cellulose ethers containing no ester groups, 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
- A61K9/48—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to 'esomeprazole magnesium enteric-coated pellets, capsules and a preparation method thereof', belonging to the pharmaceutical technology, wherein the esomeprazole magnesium enteric-coated pellets comprise a blank pellet core, a blank pellet core coating layer, a drug-loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside; wherein the blank pill core has a particle size of 0.25-0.355mm and contains no medicine; the weight of the blank pill core coating layer is 2-4%, the weight of the drug-carrying layer is 60-260%, the weight of the isolation coating layer is 20-25%, and the weight of the enteric coating layer (I) is 38-65%. The esomeprazole magnesium enteric-coated pellet has the advantages of small variety of auxiliary materials, small dosage, excellent stability and release degree, simplified process, suitability for scale-up production, and capability of meeting the clinical medication requirements of the obtained medicine.
Description
Technical Field
The invention belongs to the pharmaceutical technology, and particularly relates to esomeprazole magnesium enteric-coated pellets and capsules and a preparation method thereof.
Background
Gastroesophageal reflux disease (GERD) refers to a disease in which the gastroduodenal contents reflux into the esophagus, causing maladaptive symptoms and/or complications, and includes non-erosive reflux disease (NERD), Reflux Esophagitis (RE), and Barrett's Esophagus (BE). Typical symptoms of the traditional Chinese medicine are heartburn and reflux, abdominal distension and discomfort, nausea and vomiting, poor breathing and other related symptoms, which have obvious negative effects on the life quality of patients. The incidence rate of GERD in western countries is 10-20%, but as the life style is westernized, the obesity population is increased, and the disease tends to rise in Asian regions in recent 20 years. Relevant researches show that the gastroesophageal reflux disease becomes a common disease in China, and the morbidity of China is 8.9 percent, wherein the morbidity of Beijing is 10.19 percent, the morbidity of Shanghai is 7.79 percent, and the morbidity of Xian is 16.9 percent.
Esomeprazole magnesium is the S-isomer of omeprazole, a specific inhibitor of the proton pump in gastric parietal cells, and reduces gastric acid secretion by specific proton pump inhibition. The S-isomer and R-isomer of omeprazole have similar pharmacodynamic properties, but the S-isomer has obvious advantages in pharmacokinetics, AUC and CmaxAre all significantly higher than the R-configuration. The chemical name of esomeprazole magnesium is: bis-S-5-methoxy-2- { [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl]Sulfinyl } -1H-benzimidazole magnesium trihydrate having the formula: c34H36MgN6O6S2·3H2O, the chemical structural formula is:
the esomeprazole bulk drug is easy to degrade when being contacted with acidic and neutral media, and the stability of the esomeprazole bulk drug can be influenced by illumination, temperature, humidity and solvents used by auxiliary materials. The esomeprazole magnesium enteric-coated pellet is required to be storage-resistant in process, is not dissolved in gastric juice after being taken, and can be quickly and thoroughly released after reaching the intestinal tract to achieve the drug effect. In the aspect of drug effect, the fewer the types of the auxiliary materials are, the better the stability and the release of the composition are not influenced, and the simpler the process flow is, the better the scale of the pharmaceutical process is.
In the prior art, in order to improve the stability of the drugs in the esomeprazole magnesium enteric-coated pellet, for example, in patent document CN105106168B, the pH value of a blank pellet core is adjusted, so that the pH value of the pellet core auxiliary material is 9-11; an alkaline stabilizer and an antioxidant are added into the prescription of the drug-loaded layer; designing two isolation layers and respectively adjusting the pH values of the two isolation layers to 9-11 and 8-10 by adopting an alkaline regulator; a surfactant and a light-screening agent are added into the enteric coating layer; the outermost layer is also added with a gastric soluble film coating layer; the variety of the required auxiliary materials is too many and the preparation process is complex.
Therefore, on the basis of the technology of the esomeprazole magnesium enteric-coated pellet, more exploration and optimization are needed to be carried out on the formula and the preparation process, the process is simplified and efficient, the scale-up production is suitable, the medicine quality is improved, and the clinical requirements are met.
Disclosure of Invention
According to the needs in the field, the invention provides the esomeprazole magnesium enteric-coated pellet and the preparation method thereof, the esomeprazole magnesium enteric-coated pellet has the advantages of small auxiliary material variety, small dosage, excellent stability and release degree, simplified process, suitability for scale-up production, and capability of meeting the clinical medication requirements of the obtained medicine. The technical scheme provided by the invention is as follows:
an esomeprazole magnesium enteric-coated pellet is characterized by comprising a blank pellet core, a blank pellet core coating layer, a drug-loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside;
wherein the blank pill core has a particle size of 0.25-0.355mm and contains no medicine;
the weight of the blank pill core coating layer is 2-4%, the weight of the drug-carrying layer is 60-260%, the weight of the isolation coating layer is 20-25%, and the weight of the enteric coating layer (I) is 38-65%.
In most preferred embodiments, the blank pellet core coating layer has a weight gain of 3% and the isolation coating layer has a weight gain of 22% to 23%.
In some preferred embodiments, the drug-loaded layer weight gain is from 61% to 252%; preferably, the weight is increased by 61%, 61-125%, 125-194%, 125-252% or 194-252%.
In some preferred embodiments, the weight gain of the enteric coating layer (one) is 38% to 65%, preferably 38-40%, 40-49% or 49-61%.
In a preferred embodiment of the above embodiments, the material of the blank pill core coating layer is hydroxypropyl cellulose;
the drug-loaded layer consists of esomeprazole magnesium and hypromellose in a weight ratio of 3.5-4.5: 1;
the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate in a weight ratio of 2.5-4:3-5.5:2-3: 1; preferably, the weight ratio of the hydroxypropyl methylcellulose to the hydroxypropyl cellulose is 1: 1.
In a preferred embodiment of the above embodiments, the enteric coating layer (one) is composed of a film-forming agent, a plasticizer and a surfactant in a weight ratio of 45-50:5-10: 1; further preferably 46-48:9.4-10: 1;
the film forming agent is selected from one or more of Eudragit LD30-55, acrylic resin, hydroxypropyl methyl cellulose phthalate, and acrylic resin emulsion;
the plasticizer is selected from one or more of polyethylene glycol, propylene glycol, triethyl citrate, diethyl phthalate, tributyl citrate, glyceryl monostearate and glyceryl distearate; preferably, the plasticizer consists of triethyl citrate and glyceryl monostearate in a weight ratio of 3: 1;
the surfactant is tween-80.
In a preferred embodiment of the above embodiments, the esomeprazole magnesium enteric-coated pellet further comprises an enteric coating layer (two), wherein the weight of the enteric coating layer (two) is increased by 8-12%, and the enteric coating layer (two) consists of an aqueous dispersion of eudragit LD30-55 and triethyl citrate in a weight ratio of 20-25: 1; preferably in a weight ratio of 22.2-22.3: 1.
In a preferred embodiment of the above embodiments:
the weight ratio of the esomeprazole magnesium to all auxiliary materials reaches 0.18-0.6;
preferably, the weight ratio of the esomeprazole magnesium to all auxiliary materials reaches 0.29-0.46;
preferably, the weight ratio of the esomeprazole magnesium to all auxiliary materials is 0.4-0.46.
In another aspect of the present invention, a preparation method of any esomeprazole magnesium enteric-coated pellet is provided, which is characterized by comprising the following steps:
(1) preparing a blank pellet core with a coating: coating the blank pill core with a blank pill core coating layer to obtain a coated blank pill core;
(2) preparing a drug-loaded pill core: coating the drug-loaded layer composition on the blank pill core with the coating to prepare a drug-loaded pill core;
(3) preparing a drug-loaded pill core with an isolation coating layer: coating the drug-loaded pill core with the isolation coating layer composition to prepare the drug-loaded pill core with the isolation coating layer;
(4) preparing enteric pellets (I): and coating the drug-loaded pellet core with the isolation coating layer with the enteric coating layer (I) composition to prepare the enteric coated pellet (I).
Preferably, in preparing coated, empty cores, the fluid bed operating parameters are as follows: the air volume is 30-40 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 35-40 ℃, the maximum liquid spraying speed is 5ml/min, and the liquid spraying stirring speed is 50-100 rpm;
in the process of preparing the drug-loaded pill core, the operating parameters of the fluidized bed are as follows: the air volume is 30-40 m3H, atomization pressure 0.18×106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 32-35 ℃, the maximum liquid spraying speed is 10ml/min, and the liquid spraying stirring speed is 50-100 rpm;
in the process of preparing the drug-loaded pill core with the isolation coating layer, the operating parameters of the fluidized bed are as follows: the air volume is 30-60 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 35-40 ℃, the maximum liquid spraying speed is 12ml/min, and the liquid spraying stirring speed is 50-100 rpm;
in the process of preparing the enteric-coated pellets, the operating parameters of the fluidized bed are as follows: the air volume is 30-60 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 35-40 ℃, the maximum liquid spraying speed is 12ml/min, and the liquid spraying stirring speed is 50-100 rpm.
In a further aspect of the invention, the capsule prepared from the esomeprazole magnesium enteric-coated pellet is provided, and the specification of the capsule is 20mg per capsule calculated by the esomeprazole magnesium enteric-coated pellet.
The weight gain calculation mode in the invention is as follows:
(1) weight increment of blank pellet core coating layer: taking the blank pellet core as a base number, and obtaining the ratio of the material (dry matter) of the required blank pellet core coating layer to the blank pellet core as the weight increment of the blank pellet core coating layer;
(2) weight increment of the drug-loaded layer: based on the base number of the blank pellet core with the coating, the ratio of the material (dry matter) of the required drug-loaded layer to the blank pellet core with the coating is the weight gain of the drug-loaded layer;
(3) weight increment of the isolation coating layer: taking the medicine-carrying pill core as a base number, and taking the ratio of the material (dry matter) of the required isolation coating layer to the medicine-carrying pill core as the weight gain of the isolation coating layer;
(4) weight gain of enteric coating layer (one): taking the medicine-carrying pill core with the isolation coating layer as a base number, and obtaining the ratio of the material (dry matter) of the enteric coating layer (one) to the medicine-carrying pill core with the isolation coating layer as the weight gain of the enteric coating layer (one);
(5) weight gain of the enteric coating layer (II): taking the enteric coating pellet (I) as a base number, and the ratio of the material (dry matter) of the required enteric coating layer (II) to the enteric coating pellet (I) is the weight gain of the enteric coating layer (II).
According to the invention, by selecting and optimizing the auxiliary material formula and the specific gravity, the obtained preparation formula has the advantages of less auxiliary material types, less dosage, simple process operation and production cost reduction; meanwhile, no organic solvent is used in the preparation process, so that the preparation method is more environment-friendly.
The invention coats the blank pill core, avoids the direct contact of the medicine with cane sugar and the like in the blank pill core, and improves the stability of the medicine; meanwhile, the blank pellet core with the coating has good friability, and is more beneficial to subsequent production and processing.
According to the invention, on the basis of coating the blank pellet core, the formula of the isolating layer and the formula of the isolating layer obtained by researching the weight increment are within the range of 20-25% of the weight increment, so that the isolating layer is ensured to have suitable film density, the membrane density can not be released in advance, the stability of the medicine can be ensured, the release performance is considered, the release degree reaches more than 85% in 30 minutes, and most of the release degree reaches more than 90%, even more than 95%; the new formula and the process provided by the invention enable the ratio of the drugs and the auxiliary materials in the drug-carrying layer to reach 3.5-4.5:1, the ratio of the drugs and the auxiliary materials in the pellet can reach more than 0.4, the dosage of the auxiliary materials is greatly reduced, and the drug-carrying rate is obviously higher than that of the prior art.
The pellet provided by the invention is obtained by integrally researching the formula and weight increment of the drug-loaded layer, the formula and weight increment of the isolation layer, the formula and weight increment of the enteric layer and the preparation process of each layer, and has the advantages of high drug loading rate, good stability and release degree, healthy formula and process, economy and environmental protection. The pellet can ensure the stability of the product in the in-vivo environment and good release degree in intestinal tracts, ensure that the medicine has good clinical treatment effect, maximally reduce the types and the dosage of auxiliary materials, greatly improve the quality of the pellet, and is suitable for an amplification process.
The esomeprazole magnesium enteric-coated capsule prepared by the technical scheme of the invention is stored for one year at the temperature of 25 +/-2 ℃ and the relative humidity of 75 +/-5%, and the appearance shape, related substances, release degree and content of the esomeprazole magnesium enteric-coated capsule are not obviously changed compared with 0 month.
Three batches of pilot plant test and amplification process verification are continuously carried out on the prior process; the stability and reproducibility of the esomeprazole enteric-coated capsule process and the rationality of various parameters are further verified: the weight of the prepared blank pellet core with the coating meets the requirement, the blank pellet core with the coating has white-like properties, and the material balance rate is more than 95 percent; the weight gain and the water content of the prepared drug-loaded pill core meet the requirements, the properties are light yellow, and the material balance rate is more than 95 percent; the weight gain and the water content of the prepared drug-loaded pill core with the isolation coating layer meet the requirements, the properties are light yellow, and the material balance rate is more than 95 percent; the weight gain and water content of the prepared enteric-coated pellet (I) and the enteric-coated pellet (II) meet the requirements, the properties are light yellow, and the material balance rate is more than 95 percent; the intermediate content and the moisture content of the three batches of pilot test and amplified samples meet the requirements; the capsule filling amount of the three pilot test samples and the amplified samples meets the requirement.
In summary, compared with the prior art, the technical scheme of the invention has the following beneficial effects:
(1) the auxiliary materials required by the formula are few in types and dosage; the process operation is simple, and the production cost is reduced; meanwhile, no organic solvent is used in the preparation process, so that the preparation method is more green, healthy and environment-friendly.
(2) Coating the blank pill core to avoid direct contact of the medicine with sucrose and the like in the blank pill core and avoid decomposition of the medicine; the blank pellet core with the coating has good friability and is more beneficial to subsequent production and processing.
(3) The pellet is obtained by integrally researching the formula and weight increment of the drug-loaded layer, the formula and weight increment of the isolating layer, the formula and weight increment of the enteric layer and the preparation process of each layer, and has the advantages of high drug loading rate, good stability and release degree, healthy formula and process, economy and environmental protection.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments. However, it will be understood by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the present invention in any way.
Blank pellet cores: the materials are sucrose and starch, and are available from Karlukang (Shanghai) trade Co., Ltd
TABLE 1 EXAMPLES 1-5 formulations
Example 1
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 61%, the weight of the isolation coating layer is 15%, and the weight of the enteric coating layer (I) is 44%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate and talcum powder. The formula of the esomeprazole magnesium enteric-coated pellet is shown in the following table 1 in terms of preparing 1000 finished products.
The preparation steps are as follows:
s1 preparing coated blank cores:
s1, weighing hydroxypropyl cellulose, pouring the hydroxypropyl cellulose into purified water, magnetically stirring the mixture overnight, fully swelling the mixture, and sieving the mixture with a 80-mesh sieve to obtain a hydroxypropyl cellulose aqueous solution;
s1, weighing blank pellet cores, placing the blank pellet cores in a fluidized bed, controlling the temperature of materials, and spraying and coating the blank pellet core coating layer material prepared in the step S1 on the blank pellet cores, wherein the spraying process is continuously stirred;
s1, drying after the coating material is sprayed, drying until the free moisture is less than or equal to 1.5%, and preparing the blank pellet core with the coating;
s2 preparation of drug-loaded pill cores:
s2, weighing hydroxypropyl methylcellulose, pouring the hydroxypropyl methylcellulose into water, and magnetically stirring the hydroxypropyl methylcellulose until the hydroxypropyl methylcellulose is fully swelled to obtain a hydroxypropyl methylcellulose water solution;
s2, weighing esomeprazole magnesium, slowly adding the 5-hydroxypropyl methylcellulose aqueous solution prepared in the S2 step under magnetic stirring, fully wetting, homogenizing and stirring for 10 minutes, adding purified water, fully stirring after high-speed shearing until suspension becomes emulsion, and sieving with a 80-mesh sieve to obtain suspension liquid medicine;
s2, placing the coated blank pellet core in a fluidized bed, preheating to 35 ℃, controlling the material temperature in the coating process, uniformly spraying the drug-containing suspension prepared in the step S2 on the coated blank pellet core, and continuously stirring in the spraying process;
s2, drying the drug-containing suspension after the drug-containing suspension is sprayed, and drying until the free water content is less than or equal to 4.5% to obtain a drug-loaded pellet core;
s3 preparation of drug-loaded pill cores with isolation coating layers:
s3, weighing hydroxypropyl methylcellulose and hydroxypropyl cellulose, adding the hydroxypropyl methylcellulose and the hydroxypropyl cellulose into purified water, and performing magnetic stirring until the hydroxypropyl methylcellulose and the hydroxypropyl cellulose are fully swelled to obtain 8 hydroxypropyl methylcellulose and hydroxypropyl cellulose mixed water solution;
s3, weighing magnesium stearate and talcum powder, adding the 8 hydroxypropyl methylcellulose and hydroxypropyl cellulose mixed aqueous solution prepared in the S3 step I, adding purified water, shearing and homogenizing at high speed for 10 minutes, stirring by magnetic force until the mixture is fully and uniformly mixed, and sieving by a 80-mesh sieve;
s3, placing the drug-loaded pill core in a fluidized bed, controlling the temperature of the material, spraying the isolation coating material prepared in the step S3 on the drug-loaded pill core, and continuously stirring the suspension in the spraying process;
s3, after spraying the material of the isolation coating layer, drying until the free moisture is less than or equal to 4.5 percent to prepare the drug-loaded pill core with the isolation coating layer;
s4 preparing enteric pellets (one):
s4, adding triethyl citrate and talcum powder into purified water, fully and uniformly mixing, adding the rest purified water, stirring and cooling to room temperature;
s4, weighing Eudragit L30D-55 (solid content is 30%), slowly adding the suspension obtained in the S4 step into the Eudragit water dispersion, stirring until the mixture is fully mixed uniformly, and sieving with a 80-mesh sieve;
s4, placing the drug-loaded pill core with the isolation coating layer in a fluidized bed, controlling the temperature of the materials, and spraying the enteric coating layer (I) material prepared in the step S4 on the drug-loaded pill core with the isolation coating layer, wherein the spraying process is carried out continuously;
s4, spraying the enteric coating layer (I) material, drying until the free water content is less than or equal to 4.5%, and making into enteric pellet (I).
In this example, the process parameters of each operation step are shown in the following table
Example 2
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the blank pellet core coating layer with the particle size of 0.1-0.25mm is subjected to 3% weight increase, the drug loading layer is subjected to 61% weight increase, the isolation coating layer is subjected to 15% weight increase, the enteric coating layer (I) is subjected to 52% weight increase, and the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80. The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 1, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 1000 finished products.
The preparation method and parameters are the same as in example 1
Example 3
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.355-1.0mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 61%, the weight of the isolation coating layer is 15%, and the weight of the enteric coating layer (I) is 79%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80.
The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 1, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 1000 finished products.
The preparation method and parameters are the same as in example 1
Example 4
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 61%, the weight of the isolation coating layer is 15%, and the weight of the enteric coating layer (I) is 62%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate and talcum powder. The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 1, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 1000 finished products.
The preparation method and parameters are the same as those of example 1.
Example 5
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 61%, the weight of the isolation coating layer is 15%, and the weight of the enteric coating layer (I) is 93%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate and talcum powder.
The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 1, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 1000 finished products.
The preparation method and parameters are the same as those of example 1.
Example 6
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 62.5%, the weight of the isolation coating layer is 22.5%, and the weight of the enteric coating layer (I) is 48.8%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80. The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 2, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 5000 finished products.
The preparation method and the parameters are the same as those of the example 1, and the process parameters of each operation step are as follows:
example 7
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 62.5%, the weight of the isolation coating layer is 22.5%, and the weight of the enteric coating layer (I) is 61.1%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80. The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 2, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 5000 finished products.
The preparation method and parameters are the same as those of example 1.
Example 8
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loaded layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug-loaded layer is 125%, the weight of the isolation coating layer is 22.5%, and the weight of the enteric coating layer (I) is 48.8%, wherein the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80. The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 2, wherein the esomeprazole magnesium enteric-coated pellet is prepared into 6000 finished products.
The preparation method and parameters are the same as those of example 1.
Example 9
An esomeprazole magnesium enteric-coated pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, and the formula of the finished product is shown in table 2.
Wherein the particle size of the blank pill core is 0.25-0.355mm, the weight of the blank pill core coating layer is 3%, the weight of the drug-carrying layer is 125%, the weight of the isolation coating layer is 22.5%, and the weight of the enteric coating layer (I) is 61.1%, wherein the blank pill core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80.
The preparation method and parameters are the same as those of example 1.
Example 10
An esomeprazole magnesium enteric-coated pellet comprises a blank pellet core, a blank pellet core coating layer, a drug-loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, and is prepared into 6500 finished products, and the formula of the finished product is shown in table 2.
Wherein the particle size of the blank pill core is 0.25-0.355mm, the weight of the blank pill core coating layer is 3%, the weight of the drug-carrying layer is 193.3%, the weight of the isolating coating layer is 22.5%, and the weight of the enteric coating layer (I) is 48.8%, wherein the blank pill core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80.
The preparation method and parameters are the same as those of example 1.
Example 11
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside, and the formula is shown in table 2 when 6500 finished products are prepared, wherein the blank pellet core has the grain diameter of 0.25-0.355mm, the blank pellet core coating layer has the weight increment of 3%, the drug loading layer has the weight increment of 250%, the isolation coating layer has the weight increment of 22.5%, and the enteric coating layer (I) has the weight increment of 48.8%, wherein the blank pellet core coating layer consists of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80.
The preparation method and parameters are the same as those of example 1.
Example 12
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug loading layer, an isolation coating layer, an enteric coating layer (I) and an enteric coating layer (II) from inside to outside, and the formula of the finished product is shown in table 2 according to 10000 pellets, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug loading layer is 250%, the weight of the isolation coating layer is 22.5%, the weight of the enteric coating layer (I) is 39.1%, the weight of the enteric coating layer (II) is 12.6%, and the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (I) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80; the enteric coating layer (II) consists of an aqueous dispersion of Ettqi LD30-55 and triethyl citrate.
The preparation method is the same as example 1, and comprises the following steps:
s5 preparing enteric pellets (II):
s5, weighing triethyl citrate, Eudragit L30D-55 (solid content 30%) and purified water, stirring to mix well, and sieving with 80 mesh sieve;
s5, placing the enteric-coated pellet (I) in a fluidized bed, setting the material temperature, spraying the enteric-coated layer (II) material prepared in the step S5 on the enteric-coated pellet (I), and maintaining the suspension to be stirred in the spraying process;
s5, spraying the enteric coating layer (II) material, drying until the free water content is less than or equal to 4.5%, and making into enteric coated pellet (II). The preparation method of the esomeprazole magnesium enteric-coated pellet comprises the following steps of:
example 13
An esomeprazole magnesium enteric pellet comprises a blank pellet core, a blank pellet core coating layer, a drug loading layer, an isolation coating layer, an enteric coating layer (I) and an enteric coating layer (II) from inside to outside, and the formula of 19000 finished products is shown in table 2, wherein the particle size of the blank pellet core is 0.25-0.355mm, the weight of the blank pellet core coating layer is 3%, the weight of the drug loading layer is 244%, the weight of the isolation coating layer is 22.9%, the weight of the enteric coating layer (I) is 39.6%, the weight of the enteric coating layer (II) is 9.2%, and the blank pellet core coating layer is composed of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (I) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80; the enteric coating layer (II) consists of an aqueous dispersion of Ettqi LD30-55 and triethyl citrate.
The preparation method is the same as example 12, and the process parameters of each operation step are as follows:
example 14
The formula of the esomeprazole magnesium enteric-coated pellet is shown in table 2 according to 10000 finished products, wherein the blank pellet core has a particle size of 0.25-0.355mm, the blank pellet core coating has a weight increment of 3%, the drug-loaded layer has a weight increment of 244%, the isolation coating has a weight increment of 45.0%, and the enteric coating (one) has a weight increment of 41.3%, wherein the blank pellet core coating consists of hydroxypropyl cellulose; the drug-loaded layer consists of esomeprazole magnesium and hydroxypropyl methylcellulose; the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate; the enteric coating layer (one) consists of Eudragit LD30-55 aqueous dispersion, triethyl citrate, glyceryl monostearate and Tween-80.
The preparation method is the same as example 1, and the process parameters of each operation step are as follows:
test example 1
Weighing a sucrose blank pellet core (made of sucrose and starch) with the particle size range of 0.25-0.355mm, coating with hydroxypropyl cellulose, wherein the weight of a blank pellet core coating layer is increased to 3%, and drying after coating. The friability of the coated empty pellet cores was compared to untreated empty pellet cores as specified in the following table:
F％*＝[(m1-m2)/m1]X％
m1the weight of the pellets before coating; m is2The weight of the coated pellets; sieving with 80 mesh sieve before and after coating, and weighing the cores.
Test example 2 evaluation of Release degree
Taking each esomeprazole enteric-coated capsule pellet prepared in the embodiments 6 to 14 of the invention, the release degree is determined according to the second method (appendix X D of second part of 2010 edition of Chinese pharmacopoeia), and whether the following is concrete:
taking the product (esomeprazole enteric-coated pellet capsule) in the embodiment of the invention, adopting a dissolution measuring device, taking 300ml of 0.1mol/L hydrochloric acid solution as a release medium, rotating at 100rpm per minute, operating according to the method, adding 700ml of 0.086mol/L disodium hydrogen phosphate solution preheated to 37 +/-0.5 ℃ into an operating container after 2 hours, uniformly mixing, keeping the rotating speed unchanged, continuing to operate according to the method, taking the solution for filtration after about 30 minutes, precisely taking 5ml of filtrate, adding 1ml of 0.25mol/L sodium hydroxide solution, shaking uniformly to serve as a test sample solution, measuring according to the method specified in each medicine item, and calculating the release amount and the release curve, wherein the results are as follows:
the experiment of the invention finds that the color change is inspected at high temperature and the release degree evaluation is not carried out any more because the weight of the isolating layer is not increased enough in the examples 1-5;
among them, the data of examples 6, 7 and 8 in which the release rate was lower than that of the previous data at 30-45 minutes are due to detection errors and degradation in the dissolution medium with the passage of time after the release of the drug, which are normal phenomena.
The release rate results show that the esomeprazole magnesium enteric capsules in example 7, example 8, example 9, example 11 and example 12 have a release rate of substantially more than 90% at 20-30min, and especially, the examples 11 and 12 have good release rates.
Test example 3 stability examination
Capsules prepared from the esomeprazole magnesium enteric-coated pellets in example 12 were respectively placed under the conditions of high temperature of 60 ℃, light illumination of 5000 +/-500 LX, high humidity RH 75% +/-1% high humidity RH 92.5% +/-5% for examination, samples were taken on days 5 and 10 respectively, properties, moisture, contents and release degrees of the samples were examined, and the examination results were compared with 0 day. The results are shown in the following table:
from the above test results, it can be seen that under the conditions of high temperature, high humidity and strong light irradiation, the capsule prepared from the esomeprazole magnesium enteric-coated pellet of example 12 has increased moisture under the high humidity condition, no obvious change in properties, no obvious change in release degree, no obvious change in content, and good stability.
Three batches of pilot scale tests and amplification process verification are continuously carried out on the preparation process disclosed by the invention, the stability and reproducibility of the esomeprazole enteric capsule process and the reasonability of various parameters are further verified, and the detection results of the material balance rate are as follows:
wherein the pellet core pretreatment material balance calculation formula and the result are as follows:
(weight of qualified pretreated pellets + sample size + number of waste pellets) ÷ weight of theoretical pretreated pellets × 100%
Wherein, the material balance calculation formula of the drug-loaded layer of the tundish is as follows:
(qualified pill-loading + sample volume + weight of waste pill) ÷ theoretical pill-loading weight × 100%
Wherein, the material balance calculation formula of the middle-package isolation layer is as follows:
(weight gain of qualified isolation pill + sample weight + weight of waste pill) ÷ weight of theoretical isolation pill × 100%
Wherein, the material balance calculation formula of the coating enteric layer is as follows:
(qualified enteric-coated pill + sample size + waste pill weight) ÷ theoretical enteric-coated pill weight × 100%
The weight of the prepared blank pellet core with the coating meets the requirement, the properties are all white-like, and the material balance rate is more than 95 percent; the weight gain and the water content of the prepared drug-loaded pill core meet the requirements, the properties are light yellow, and the material balance rate is more than 95 percent; the weight gain and the water content of the prepared drug-loaded pill core with the isolation coating layer meet the requirements, the properties are light yellow, and the material balance rate is more than 95 percent; the weight gain and water content of the prepared enteric-coated pellet (I) and the enteric-coated pellet (II) meet the requirements, the properties are light yellow, and the material balance rate is more than 95 percent;
the intermediate content and the moisture content of the three batches of pilot test and amplified samples meet the requirements; the capsule filling amount of the three pilot test samples and the amplified samples meets the requirement.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. An esomeprazole magnesium enteric-coated pellet is characterized by comprising a blank pellet core, a blank pellet core coating layer, a drug-loading layer, an isolation coating layer and an enteric coating layer (I) from inside to outside;
wherein the blank pill core has a particle size of 0.25-0.355mm and contains no medicine;
the weight of the blank pill core coating layer is 2-4%, the weight of the drug-carrying layer is 60-260%, the weight of the isolation coating layer is 20-25%, and the weight of the enteric coating layer (I) is 38-65%.
2. The esomeprazole magnesium enteric pellet of claim 1, wherein:
the weight of the blank pill core coating layer is 3%, and the weight of the isolation coating layer is 22% -23%.
3. The esomeprazole magnesium enteric pellet of claim 1, wherein:
the weight of the drug-loaded layer is increased by 61-252%; preferably, the weight is increased by 61%, 61-125%, 125-194%, 125-252% or 194-252%.
4. The esomeprazole magnesium enteric pellet of any one of claims 1-3, wherein:
the weight of the enteric coating layer (I) is 38-65%, preferably 38-40%, 40-49% or 49-61%.
5. The esomeprazole magnesium enteric pellet of claim 4, wherein:
the blank pill core coating layer is made of hydroxypropyl cellulose;
the drug-loaded layer consists of esomeprazole magnesium and hypromellose in a weight ratio of 3.5-4.5: 1;
the isolation coating layer is composed of hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder and magnesium stearate in a weight ratio of 2.5-4:3-5.5:2-3: 1; preferably, the weight ratio of the hydroxypropyl methylcellulose to the hydroxypropyl cellulose is 1: 1.
6. The esomeprazole magnesium enteric pellet of claim 5, wherein:
the enteric coating layer (I) consists of a film-forming agent, a plasticizer and a surfactant in a weight ratio of 45-50:5-10: 1; preferably 46-48:9.4-10: 1;
the film forming agent is selected from one or more of Eudragit LD30-55, acrylic resin, hydroxypropyl methyl cellulose phthalate, and acrylic resin emulsion;
the plasticizer is selected from one or more of polyethylene glycol, propylene glycol, triethyl citrate, diethyl phthalate, tributyl citrate, glyceryl monostearate and glyceryl distearate; preferably, the plasticizer consists of triethyl citrate and glyceryl monostearate in a weight ratio of 3: 1;
the surfactant is tween-80.
7. The esomeprazole magnesium enteric pellet of any one of claims 1-6, wherein: the enteric coating layer (II) is added with 8-12% of weight and consists of Eudragit LD30-55 aqueous dispersion and triethyl citrate in the weight ratio of 20-25: 1; preferably in a weight ratio of 22.2-22.3: 1.
8. The esomeprazole magnesium enteric pellet of any one of claims 1-7, wherein:
wherein the weight ratio of the esomeprazole magnesium to all auxiliary materials reaches 0.18-0.6;
preferably, the weight ratio of the esomeprazole magnesium to all auxiliary materials reaches 0.29-0.46;
preferably, the weight ratio of the esomeprazole magnesium to all auxiliary materials is 0.4-0.46.
9. A process for the preparation of esomeprazole magnesium enteric pellets according to any one of claims 1 to 8, characterized by comprising the following steps:
(1) preparing a blank pellet core with a coating: coating the blank pill core with a blank pill core coating layer to obtain a coated blank pill core;
(2) preparing a drug-loaded pill core: coating the drug-loaded layer composition on the blank pill core with the coating to prepare a drug-loaded pill core;
(3) preparing a drug-loaded pill core with an isolation coating layer: coating the drug-loaded pill core with the isolation coating layer composition to prepare the drug-loaded pill core with the isolation coating layer;
(4) preparing enteric pellets (I): coating the drug-loaded pellet core with the isolation coating layer with the enteric coating layer (I) composition to prepare an enteric pellet (I);
preferably, in preparing coated, empty cores, the fluid bed operating parameters are as follows: the air volume is 30-40 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 35-40 ℃, the maximum liquid spraying speed is 5ml/min, and the liquid spraying stirring speed is 50-100 rpm;
in the process of preparing the drug-loaded pill core, the operating parameters of the fluidized bed are as follows: the air volume is 30-40 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 32-35 ℃, the maximum liquid spraying speed is 10ml/min, and the liquid spraying stirring speed is 50-100 rpm;
in the process of preparing the drug-loaded pill core with the isolation coating layer, the operating parameters of the fluidized bed are as follows: the air volume is 30-60 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 35-40 ℃, the maximum liquid spraying speed is 12ml/min, and the liquid spraying stirring speed is 50-100 rpm;
in the process of preparing the enteric-coated pellets, the operating parameters of the fluidized bed are as follows: the air volume is 30-60 m3H, atomization pressure 0.18X 106～0.20×106Pa, the air inlet temperature is 40-80 ℃, the material temperature is 35-40 ℃, the maximum liquid spraying speed is 12ml/min, and the liquid spraying stirring speed is 50-100 rpm.
10. An esomeprazole magnesium enteric pellet capsule containing the esomeprazole magnesium enteric pellet of any one of claims 1-8, the specification of which is 20mg per pellet calculated on esomeprazole.
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