CN105434398B - A kind of Rabeprazole enteric-coated micro-pill and preparation method thereof - Google Patents
A kind of Rabeprazole enteric-coated micro-pill and preparation method thereof Download PDFInfo
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- CN105434398B CN105434398B CN201510957689.1A CN201510957689A CN105434398B CN 105434398 B CN105434398 B CN 105434398B CN 201510957689 A CN201510957689 A CN 201510957689A CN 105434398 B CN105434398 B CN 105434398B
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- enteric
- rabeprazole
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- 239000006187 pill Substances 0.000 title claims abstract description 91
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960004157 rabeprazole Drugs 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000010410 layer Substances 0.000 claims abstract description 174
- 239000003814 drug Substances 0.000 claims abstract description 79
- 229940079593 drug Drugs 0.000 claims abstract description 71
- 239000002775 capsule Substances 0.000 claims abstract description 67
- 230000004888 barrier function Effects 0.000 claims abstract description 58
- 239000002702 enteric coating Substances 0.000 claims abstract description 52
- 238000009505 enteric coating Methods 0.000 claims abstract description 52
- 229960001778 rabeprazole sodium Drugs 0.000 claims abstract description 50
- ZGDLVKWIZHHWIR-UHFFFAOYSA-N 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N2CCOCC2)N=C1 ZGDLVKWIZHHWIR-UHFFFAOYSA-N 0.000 claims abstract description 39
- 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 abstract description 34
- 239000008188 pellet Substances 0.000 claims abstract description 34
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 25
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 25
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 25
- 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 abstract description 22
- 229930006000 Sucrose Natural products 0.000 claims abstract description 20
- 239000005720 sucrose Substances 0.000 claims abstract description 20
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 15
- 229960004793 sucrose Drugs 0.000 claims abstract description 15
- 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 abstract description 14
- 239000004408 titanium dioxide Substances 0.000 claims abstract description 14
- 239000004925 Acrylic resin Substances 0.000 claims abstract description 13
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 claims abstract description 12
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 11
- 229940079827 sodium hydrogen sulfite Drugs 0.000 claims abstract description 11
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 11
- 229920000178 Acrylic resin Polymers 0.000 claims abstract description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960003511 macrogol Drugs 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 26
- 239000000463 material Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 21
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 21
- 235000019441 ethanol Nutrition 0.000 claims description 16
- 239000011248 coating agent Substances 0.000 claims description 12
- 238000000576 coating method Methods 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000007921 spray Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 3
- 239000000084 colloidal system Substances 0.000 claims description 3
- 238000005243 fluidization Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000009423 ventilation Methods 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920002472 Starch Polymers 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
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 238000012360 testing method Methods 0.000 abstract description 8
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 230000031891 intestinal absorption Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 16
- 239000000523 sample Substances 0.000 description 15
- 238000000889 atomisation Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 150000003851 azoles Chemical class 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 6
- 230000001070 adhesive effect Effects 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000003605 opacifier Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 210000001198 duodenum Anatomy 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- KRCQSTCYZUOBHN-UHFFFAOYSA-N rabeprazole sodium Chemical compound [Na+].COCCCOC1=CC=NC(CS(=O)C=2[N-]C3=CC=CC=C3N=2)=C1C KRCQSTCYZUOBHN-UHFFFAOYSA-N 0.000 description 4
- 239000003340 retarding agent Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 208000007107 Stomach Ulcer Diseases 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 239000005030 aluminium foil Substances 0.000 description 3
- 239000011805 ball Substances 0.000 description 3
- 208000000718 duodenal ulcer Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 201000005917 gastric ulcer Diseases 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 235000015170 shellfish Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000006101 laboratory sample Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 159000000011 group IA salts Chemical group 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 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
- 239000004014 plasticizer Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- -1 sodium rabeprazole compound Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 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
- A61K9/5005—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
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Rabeprazole enteric-coated micro-pills and preparation method thereof, the enteric-coated micro-pill includes blank capsule core, drug-loaded layer, barrier layer, enteric coating layer from inside to outside, drug-loaded layer weightening 25% 30%, barrier layer weightening 22% 27%, enteric coating layer weightening 13% 17%, drug-loaded layer is made of Rabeprazole or RABEPRAZOLE SODIUM, sucrose, hydroxypropyl methyl cellulose, sodium hydrogensulfite and lauryl sodium sulfate；Barrier layer is made of hydroxypropyl methyl cellulose, Macrogol 6000, titanium dioxide and disodium hydrogen phosphate；Enteric coating layer is made of acrylic resin c-type, Macrogol 6000 and talcum powder.The rate of release that the present invention passes through suitable control pellet enteric solubility and drug, keep drug release patterns consistent with intestinal absorption drug rate curve, drug is short with the time existing for free state in enteron aisle, less degradation, bioavilability is high, clinical test show obvious effective rate higher, it is more stable, facilitate patient to take medicine.
Description
Technical field
The present invention relates to a kind of Rabeprazole enteric-coated micro-pills and preparation method thereof, belong to pharmaceutical preparations technology field.
Background technology
RABEPRAZOLE SODIUM chemical name is 2- [[[4- (3- methoxy propoxies) -3- methyl -2- pyridyl groups] methyl] Asia sulphurs
Acyl group] -1H- benzimidazole sodium.It is unstable to meet light, heat, acid, easily decomposing makes drug lose activity, therefore oral preparation is made and answers
It avoids contacting with hydrochloric acid in gastric juice.RABEPRAZOLE SODIUM be mainly used for gastric ulcer, duodenal ulcer, marginal ulcer, reflux esophagitis,
Zhuo-Emhorn (Zollinger-Ellison) syndrome (gastrinoma).Auxiliary is used for gastric ulcer or duodenal ulcer patients root
Except helicobacter pylori, belong to disease of digestive system.This product transforms into active form (sub- sulphur in parietal cell under acid condition
Acyl form), by modifying proton pump (H+,K+ATP enzyme) sulfydryl, inhibit H+,K+The activity and gastric acid inhibitory point of ATP enzyme
It secretes.
Patent US2010121068, EP2162449, WO2010006904, WO2010004571, CN101580520 etc., in detail
The thin preparation process for describing sodium rabeprazole compound.Chinese patent CN101143143 provides a kind for the treatment of stomach oesophagus and returns
Flow the drug of disease and functional dyspepsia FD, including the neutral form of Rabeprazole or alkaline salt forms and its optical voidness
Stereoisomer or its active metabolite.
RABEPRAZOLE SODIUM is the new varieties of Japanese Wei Cai companies exploitation, is listed first in Japan in 1997, sheet in 1999
Product list in the U.S., and trade name Pariet, dosage form is enteric coatel tablets.Enteric coated tablet full wafer swallows difficulty, and is easy to be stung by patient
It breaks and the effect of losing activity.Release is uneven in vivo, is also easy to produce burst release.
Rabeprazole is a kind of specific drug for treating hyperhydrochloria, gastric ulcer and duodenal ulcer, common Lei Beila
Release profiles and duodenal absorption speed are inconsistent in vivo for azoles enteric coatel tablets, Rabeprazole capsulae enterosolubilis, lead to thunder after release
Shellfish draws azoles residence time in enteron aisle longer and degrades, and causes bioavilability low, curative effect decreases.Furthermore common enteric
Piece, capsulae enterosolubilis are to enter duodenum after stomach in the form of complete, since volume is larger, in duodenum at one section
Between have uncomfortable sensation.
The enteric coatel tablets or common capsulae enterosolubilis that enteric-coated pellet capsule has listed have significant advantage.China application No. is
201010603181.9,201110051209.7 it, is disclosed in 201310191057.X, the patent applications such as 201510423522.7
A kind of Rabeprazole sodium enterosoluble micro-particles (or pellets) and preparation method thereof.
The shortcomings that above-mentioned patented method, is insufficient as follows：
Number of patent application 201010603181.9, drug-loaded layer is by RABEPRAZOLE SODIUM, hypromellose and talcum powder
Composition, drug-loaded layer component is simple, oxidizable, influences the content and stability of drug.
Number of patent application 201110051209.7, (1) blank capsule core are the innermost layer structure of above-mentioned enteric-coated microsome；(2)
Drug-loaded layer is coated on outside above-mentioned blank capsule core, is made of drug-loaded layer composition, and the composition includes active constituents of medicine thunder shellfish
Draw azoles sodium, adhesive and pH adjusting agent；(3) barrier layer is coated on outside above-mentioned drug-loaded layer, by barrier layer composition system
At the composition includes adhesive, opacifier and antiplastering aid；(4) enteric coating layer is coated on outside above-mentioned barrier layer, by
Enteric coating layer composition is made, and the composition includes enteric-coating material, plasticizer, antiplastering aid and retarding agent.Drug-loaded layer uses
PH adjusting agent, separation layer use opacifier, improve to stability of drug products, but also to be added at anti-oxidant aspect
By force.
Number of patent application 201310191057.X, the pellet core include RABEPRAZOLE SODIUM, filler, adhesive, collapse
Agent and basifier are solved, the separation layer includes retarding agent, adhesive, antiplastering aid and opacifier, and pellet core is adjusted using pH value
Agent, separation layer use opacifier, improve to stability of drug products, but also to be strengthened at anti-oxidant aspect.
Number of patent application 201510423522.7, the medicated layer include RABEPRAZOLE SODIUM, adhesive and pH adjusting agent, every
Absciss layer total amount is 100% meter, and the separation layer of the Rabeprazole sodium enteric-coated micro-pellet includes 10~30% retarding agent, 40~65%
Adhesive and 25~45% antiplastering aid.Medicated layer adjusts pH using basifier, and separation layer contains only retarding agent, stablizing effect
Difference.
Invention content
In order to overcome the above-mentioned deficiencies of the prior art, a kind of Rabeprazole enteric-coated micro-pill of present invention offer, capsule and its system
Preparation Method.The present invention in drug-loaded layer, separation layer by using antioxidant, stabilizer, to ensure that the steady of invention formulation
It is qualitative.Dissolving releases Ф 0.6- to gastric solubility Rabeprazole enteric-coated pellet capsule capsule shells prepared by the present invention in time in stomach
The enteric-coated micro-pill of 1.0mm, the pellet then slowly enter duodenum, and since enteric-coated micro-pill volume is small, human body sensory is comfortable.
And the rate of release of technology the suitable control pellet enteric solubility and drug of this law use, make drug release patterns and enteron aisle
The rate curve to absorb the drug is consistent, and drug is short with the time existing for free state in enteron aisle, and degradation is also relatively fewer, biology
Availability is high, and clinical test shows that obvious effective rate higher, more stable, the term of validity is longer, facilitates patient to take medicine.
Technical solution of the present invention is as follows：
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer,
Middle drug-loaded layer weightening is 25%-30%, and barrier layer weightening is 22%-27%, and enteric coating layer weightening is 13%-17%, wherein
Drug-loaded layer is by Rabeprazole or RABEPRAZOLE SODIUM, sucrose, hydroxypropyl methyl cellulose (E-8), sodium hydrogensulfite and dodecyl
Sodium sulphate forms；Barrier layer is by hydroxypropyl methyl cellulose (E-8), polyethylene glycol-6000, titanium dioxide and disodium hydrogen phosphate group
At；Enteric coating layer is made of acrylic resin c-type (L-30D), polyethylene glycol-6000 and talcum powder.
Above-mentioned Rabeprazole enteric-coated micro-pill, wherein：
Preferably, the granularity of the raw material Rabeprazole or RABEPRAZOLE SODIUM is less than 160 microns, more preferably 100-
130 microns.
Preferably, the ball that the discord inventive compound of this field routine reacts may be used in the blank capsule core
Core, disintegration rate will at least meet this field conventional technique requirement, and the present invention can be according to the product for preparing different size
And select the blank capsule core of corresponding different-grain diameter.Currently preferred blank capsule core is starch blank capsule core, microcrystalline cellulose sky
White capsule core or sucrose blank capsule core；More preferably sucrose blank capsule core.The grain size of the blank capsule core is preferably 0.3-0.9mm,
More preferably 0.4-0.7mm；Still more preferably it is the sucrose blank capsule core of grain size Ф 0.4-0.7mm.
Preferably, the solvent used in the Rabeprazole enteric-coated micro-pill preparation process is ethyl alcohol or water, or both
Any proportion mixes.
Preferably, the Rabeprazole enteric-coated micro-pill grain size is Ф 0.6-1.0mm.
Preferably, for the Rabeprazole enteric-coated micro-pill to be made in terms of 1000 finished products, prescription is as follows：
| The name of an article | Prescription | Optimizing prescriptions |
| Blank capsule core | 52g-208g | 104g |
Drug-loaded layer：
Barrier layer：
| The name of an article | Prescription | Optimizing prescriptions |
| Hydroxypropyl methyl cellulose (E-8) | 21g-84g | 42g |
| Polyethylene glycol-6000 | 2.0g-8.0g | 4.0g |
| Titanium dioxide | 4.2g-16.8g | 8.4g |
| Disodium hydrogen phosphate | 0.8g-3.2g | 1.6g |
| Ethyl alcohol (95%) | In right amount | In right amount |
| Purified water | In right amount | In right amount |
Enteric coating layer：
| The name of an article | Prescription | Optimizing prescriptions |
| Acrylic resin c-type (L-30D) | 84g-336g | 168g |
| Polyethylene glycol-6000 | 2.2g-8.8g | 4.4g |
| Talcum powder | 6g-24g | 12g |
The prescription of the above-mentioned Rabeprazole enteric-coated micro-pill of the present invention is by 1000 (20mg/) or 2000 (10mg/ are made
Grain) Rabeprazole enteric-coated micro-pill capsule designs, the side of clicking here in proportion reduces 0.5 times at least 1000000 times of amplification
Production prescription range still falls within the range that the present invention is covered.
The present invention also provides the preparation methods of above-mentioned Rabeprazole enteric-coated micro-pill, it is preferable that the Rabeprazole enteric is micro-
The solvent used in ball preparation process mixes for ethyl alcohol or water, or both any proportion.
The preparation method of above-mentioned Rabeprazole enteric-coated micro-pill, includes the following steps：
Drug-loaded layer composition is coated in blank capsule core, is made and carries pill core；
Load pill core barrier layer composition is coated, the load pill core with barrier layer is made；
The load pill core with barrier layer enteric coating layer composition is coated, enteric-coated micro-pill is made.
Above-mentioned preparation method further comprises the steps：By the filling capsule of the enteric-coated micro-pill；Or it is the enteric is micro-
Ball mixes with pharmaceutically acceptable auxiliary material and prepares Rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets.Such as by above-mentioned prescription
1000 (20mg/) or 2000 (10mg/) Rabeprazole enteric-coated pellet capsules are made.Such as select II capsules.
Specifically, the preparation method of above-mentioned Rabeprazole enteric-coated micro-pill, includes the following steps：
S1 prepares drug-loaded layer:
11) with the sucrose, sodium hydrogensulfite, lauryl sodium sulfate of purifying water dissolution recipe quantity；
12) with the hydroxypropyl methyl cellulose (E-8) for purifying water-swellable recipe quantity, the ethyl alcohol of recipe quantity, which is added, makes it fully
Dissolving；
13) by step 11) and 12) made of two kinds of solution mix, the Rabeprazole or RABEPRAZOLE SODIUM of recipe quantity is added,
It is sufficiently mixed uniformly；
14) blank capsule core of recipe quantity (preferably sucrose capsule core) is placed in the jet flow seed-coating machine of bottom and is preheating to 30 DEG C, it will
Packet is uniformly sprayed in blank capsule core (preferably sucrose capsule core) containing drug solns made of step 3)；
15) dry after liquid medicine jet is complete, cross 20 mesh sieve, be made and carry pill core；
S2 prepares barrier layer:
21) with the hydroxypropyl methyl cellulose (E-8) of purifying water dissolution recipe quantity；
22) with Macrogol 6000, titanium dioxide, the disodium hydrogen phosphate of purifying water dissolution recipe quantity；
23) by step 21) and 22), two kinds of solution mixings, addition ethyl alcohol are mixed, and cross colloid mill, barrier layer material is made；
24) load pill core prepared by step S1 is again placed in bottom spray fluidisation machine, ventilation is preheating to 30 DEG C；
25) barrier layer material spray packet is made in capsule core in step 23), is finished coating material；
26) dry after being coated, sieving removes fine powder, and the load pill core with barrier layer is made；
S3 prepares enteric coating layer:
31) polyethylene glycol-6000, the talcum powder of water dissolution recipe quantity are used；
32) the acrylic resin c-type of recipe quantity is added in solution made from step 31), stirs (preferably 20
Minute), enteric coating layer material is made；
33) the load pill core with barrier layer prepared by step S2 is again placed in the jet flow seed-coating machine of bottom, passes through bottom
Spray enteric coating layer material on fluidized coating；
34) after having wrapped enteric coating layer material, dry, sieving removes fine powder, obtains complete enteric-coated micro-pill.
The preparation method of above-mentioned Rabeprazole enteric-coated micro-pill, wherein：
Preferably, it is as follows to prepare step 14) operating parameter in drug-loaded layer by step S1：
Preferably, step S2 prepares step 24) in barrier layer and 25) operating parameter is as follows：
| Operation item | Parameter | Preferred parameter |
| Absorbing quantity | 12.5-50HZ | 25HZ |
| Inlet air temperature | 17.5℃-70℃ | 35℃ |
| Temperature of charge | 15℃-60℃ | 30℃ |
| Wriggling revolution speed | 1pm-4pm | 2pm |
| Atomisation pressure | 0.12mpa-0.48mpa | 0.24mpa |
Preferably, it is as follows to prepare step 33) operating parameter in enteric coating layer by step S3：
| Operation item | Parameter | Preferred parameter |
| Absorbing quantity | 14-56HZ | 28HZ |
| Inlet air temperature | 19℃-76℃ | 38℃ |
| Temperature of charge | 16.5℃-66℃ | 33℃ |
| Atomisation pressure | 0.115mpa-0.46mpa | 0.23mpa |
| Wriggling revolution speed | 0.75pm-3pm | 1.5pm |
Prescription of the present invention is by 1000 (20mg/) or 2000 (10mg/) Rabeprazole enteric-coated micro-pill glue are made
Capsule designs, and the production prescription range that the side of clicking here reduces 0.5 times of extremely 1000000 times of amplification in proportion still falls within of the invention asked
Protection domain.
The present invention also provides a kind of Rabeprazole enteric-coated pellet capsules, contain above-mentioned Rabeprazole enteric-coated micro-pill.The thunder
It is 20mg/ or 10mg/ that shellfish, which draws azoles or Rabeprazole sodium enteric-coated micro-pellet capsule, specification,.
The present invention also provides a kind of Rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets, micro- containing above-mentioned Rabeprazole enteric
Ball and pharmaceutically acceptable auxiliary material.
The Rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets can be prepared by art methods.
Dissolving releases Ф to gastric solubility Rabeprazole enteric-coated pellet capsule capsule shells prepared by the present invention in time in stomach
The enteric-coated micro-pill of 0.6-1.0mm, the pellet then slowly enter duodenum, since enteric-coated micro-pill volume is small, human body sensory
Comfortably.And the rate of release of technology the suitable control pellet enteric solubility and drug of this law use, make drug release patterns
Consistent with the rate curve of intestinal absorption drug, drug is short with the time existing for free state in enteron aisle, degrades also relatively
Few, bioavilability is high, and clinical test shows that obvious effective rate higher, more stable, the term of validity is longer, facilitates patient to take medicine.
Rabeprazole enteric-coated micro-pill of the present invention selects the components such as niter cake, disodium hydrogen phosphate, titanium dioxide, passes through collaboration
Effect increases the stability of drug.
The drug-loaded layer of Rabeprazole sodium enteric-coated micro-pellet of the present invention contain RABEPRAZOLE SODIUM, hydroxypropyl cellulose (E-8),
Lauryl sodium sulfate etc., these ingredients be effectively guaranteed RABEPRAZOLE SODIUM human body quick release and efficient absorption.With
Separation layer by alkalinity RABEPRAZOLE SODIUM medicine layer in acidity enteric material keep apart, be effectively protected pharmaceutical activity at
Point, while antioxidant and opacifier being added in the isolation layer as protective ingredient, drug is significantly enhanced by coordinative role
Stability.
According to Rabeprazole sodium enteric-coated micro-pellet capsule prepared by patent of invention, in 40 ± 2 DEG C, relative humidity 75 ± 5%
Accelerate to investigate 6 months in climatic chamber, the appearance of Rabeprazole sodium enteric-coated micro-pellet capsule, character, related substance, release with
And content has no significant change compared with 0 day.
Rabeprazole sodium enteric-coated micro-pellet capsule prepared by the present invention, with acid solution (take hydrochloric acid 7.0ml, add sodium chloride 2.0g,
Be dissolved in water and be diluted to 1000ml, pH 1.2) 500ml be dissolution medium, using dissolution method (Chinese Pharmacopoeia 2010
Two the first methods of annex XC of year version) device, rotating speed is 100 turns per minute, through 2 hours, is not found bright on this formulation aesthetics
Aobvious variation, it is acidproof sharp up to 90% or more；Dissolution test：According to two drug release determination methods of Chinese Pharmacopoeia version in 2010, (two attached
Record the second methods of XD), rotating speed is 100 turns per minute, (takes hydrochloric acid 7.0ml in 37 scholar, 0.5 DEG C of acid solution, adds sodium chloride 2.0g, add water
Dissolve and be diluted to 1000ml, pH 1.2) in 500ml after 2 hours, acid solution is discarded, addition is preheated to 37 DEG C
0.235mol/L disodium phosphate solns 400ml and ethyl alcohol 100ml, when through 45 minutes, sampling measures release up to 80% or more.
Description of the drawings
Fig. 1-6 is respectively the HPLC collection of illustrative plates of laboratory sample in experimental example 4.
Specific implementation mode
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Embodiment 1
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer,
Middle drug-loaded layer weightening is 25%, and barrier layer weightening is 25%, and enteric coating layer weightening is 15%, wherein drug-loaded layer is by Lei Beila
Azoles or RABEPRAZOLE SODIUM, hydroxypropyl methyl cellulose (E-8), sodium hydrogensulfite and lauryl sodium sulfate composition；Barrier layer
It is made of hydroxypropyl methyl cellulose (E-8), polyethylene glycol-6000, titanium dioxide and disodium hydrogen phosphate；Enteric coating layer is by acrylic acid
Resin c-type (L-30D), polyethylene glycol-6000 and talcum powder composition.
Embodiment 2
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer,
Middle drug-loaded layer weightening is 27%, and barrier layer weightening is 23%, and enteric coating layer weightening is 15%, wherein drug-loaded layer is by Lei Beila
Azoles or RABEPRAZOLE SODIUM, hydroxypropyl methyl cellulose (E-8), sodium hydrogensulfite and lauryl sodium sulfate composition；Barrier layer
It is made of hydroxypropyl methyl cellulose (E-8), polyethylene glycol-6000, titanium dioxide and disodium hydrogen phosphate；Enteric coating layer is by acrylic acid
Resin c-type (L-30D), polyethylene glycol-6000 and talcum powder composition.
Embodiment 3
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer,
Middle drug-loaded layer weightening is 30%, and barrier layer weightening is 22%, and enteric coating layer weightening is 13%, wherein drug-loaded layer is by Lei Beila
Azoles or RABEPRAZOLE SODIUM, hydroxypropyl methyl cellulose (E-8), sodium hydrogensulfite and lauryl sodium sulfate composition；Barrier layer
It is made of hydroxypropyl methyl cellulose (E-8), polyethylene glycol-6000, titanium dioxide and disodium hydrogen phosphate；Enteric coating layer is by acrylic acid
Resin c-type (L-30D), polyethylene glycol-6000 and talcum powder composition.
Embodiment 4
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer, with
1000 finished product meters are made, prescription is as follows：
For the Rabeprazole enteric-coated micro-pill to be made in terms of 1000 finished products, prescription is as follows：
| The name of an article | Prescription |
| Sucrose blank capsule core Ф 0.4mm | 104g |
Drug-loaded layer：
Barrier layer：
| The name of an article | Prescription |
| Hydroxypropyl methyl cellulose (E-8) | 42g |
| Polyethylene glycol-6000 | 4.0g |
| Titanium dioxide | 8.4g |
| Disodium hydrogen phosphate | 1.6g |
| Ethyl alcohol (95%) | In right amount |
| Purified water | In right amount |
Enteric coating layer：
| The name of an article | Prescription |
| Acrylic resin c-type (L-30D) | 168g |
| Polyethylene glycol-6000 | 4.4g |
| Talcum powder | 12g |
Embodiment 5
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer, with
1000 finished product meters are made, prescription is as follows：
For the Rabeprazole enteric-coated micro-pill to be made in terms of 1000 finished products, prescription is as follows：
| The name of an article | Prescription |
| Sucrose blank capsule core Ф 0.7mm | 208g |
Drug-loaded layer：
| The name of an article | Prescription |
| Rabeprazole or RABEPRAZOLE SODIUM | 50g |
| Sucrose | 16.8g |
| Hydroxypropyl methyl cellulose (E-8) | 20g |
| Sodium hydrogensulfite | 2.6g |
| Lauryl sodium sulfate | 2.5g |
| Ethyl alcohol (95%) | 334g |
| Purified water | -- |
Barrier layer：
| The name of an article | Prescription |
| Hydroxypropyl methyl cellulose (E-8) | 84g |
| Polyethylene glycol-6000 | 8.0g |
| Titanium dioxide | 16.8g |
| Disodium hydrogen phosphate | 3.2g |
| Ethyl alcohol (95%) | 170ml |
| Purified water | In right amount |
Enteric coating layer：
| The name of an article | Prescription |
| Acrylic resin c-type (L-30D) | 336g |
| Polyethylene glycol-6000 | 8.8g |
| Talcum powder | 24g |
Embodiment 6
A kind of Rabeprazole enteric-coated micro-pill, from inside to outside include blank capsule core, drug-loaded layer, barrier layer, enteric coating layer, with
1000 finished product meters are made, prescription is as follows：
For the Rabeprazole enteric-coated micro-pill to be made in terms of 1000 finished products, prescription is as follows：
| The name of an article | Prescription |
| Sucrose blank capsule core Ф 0.5mm | 52g |
Drug-loaded layer：
| The name of an article | Prescription |
| Rabeprazole or RABEPRAZOLE SODIUM | 12.5g |
| Sucrose | 4.2g |
| Hydroxypropyl methyl cellulose (E-8) | 5g |
| Sodium hydrogensulfite | 0.65g |
| Lauryl sodium sulfate | 0.625g |
| Ethyl alcohol (95%) | 83.5g |
| Purified water | -- |
Barrier layer：
| The name of an article | Prescription |
| Hydroxypropyl methyl cellulose (E-8) | 21g |
| Polyethylene glycol-6000 | 2.0g |
| Titanium dioxide | 4.2g |
| Disodium hydrogen phosphate | 0.8g |
| Ethyl alcohol (95%) | 170ml |
| Purified water | In right amount |
Enteric coating layer：
| The name of an article | Prescription |
| Acrylic resin c-type (L-30D) | 84g |
| Polyethylene glycol-6000 | 2.2g |
| Talcum powder | 6g |
Embodiment 7
The present embodiment provides the preparation methods of Rabeprazole enteric-coated micro-pill described in embodiment 4, include the following steps：
S1 prepares drug-loaded layer:
11) purify the sucrose of water dissolution recipe quantity, sodium hydrogensulfite, lauryl sodium sulfate with 62ml；
12) purify the hydroxypropyl methyl cellulose (E-8) of water-swellable recipe quantity with 42ml, the ethyl alcohol of recipe quantity, which is added, makes it
Fully dissolving；
13) by step 11) and 12) made of two kinds of solution mix, the Rabeprazole or RABEPRAZOLE SODIUM of recipe quantity is added,
It is sufficiently mixed uniformly；
14) cane sugar core of recipe quantity is placed in the jet flow seed-coating machine of bottom and is preheating to 30 DEG C, will contained made of step 3)
Drug solns uniformly spray packet in cane sugar core；
15) dry after liquid medicine jet is complete, cross 20 mesh sieve, be made and carry pill core；
S2 prepares barrier layer:
21) purify the hydroxypropyl methyl cellulose (E-8) of water dissolution recipe quantity with 125ml；
22) purify Macrogol 6000, titanium dioxide, the disodium hydrogen phosphate of water dissolution recipe quantity with 84ml；
23) by step 21) and 22) two kinds of solution mixings, 625ml ethyl alcohol (95%) is added and is mixed, crosses colloid mill, be made every
From clothing layer material；
24) load pill core prepared by step S1 is again placed in bottom spray fluidisation machine, ventilation is preheating to 30 DEG C；
25) barrier layer material spray packet is made in capsule core in step 23), is finished coating material；
26) dry after being coated, sieving removes fine powder, and the load pill core with barrier layer is made；
S3 prepares enteric coating layer:
31) polyethylene glycol-6000, the talcum powder of 42ml water dissolution recipe quantities are used；
32) the acrylic resin c-type of recipe quantity is added in solution made from step 31), is sufficiently stirred at least 20 minutes,
To stirring evenly, enteric coating layer material is made；
33) the load pill core with barrier layer prepared by step S2 is again placed in the jet flow seed-coating machine of bottom, passes through bottom
Spray enteric coating layer material on fluidized coating；
34) after having wrapped enteric coating layer material, dry, sieving removes fine powder, obtains complete enteric-coated micro-pill.
The preparation method of above-mentioned Rabeprazole enteric-coated micro-pill, wherein：
It is as follows that step S1 prepares step 14) operating parameter in drug-loaded layer：
| Operation item | Parameter |
| Absorbing quantity | 25HZ |
| Atomisation pressure | 0.25mpa |
| Inlet air temperature | 30℃ |
| Wriggling revolution speed | 1pm |
Step S2 prepares step 24) in barrier layer and 25) operating parameter is as follows：
| Operation item | Parameter |
| Absorbing quantity | 25HZ |
| Inlet air temperature | 35℃ |
| Temperature of charge | 30℃ |
| Wriggling revolution speed | 2pm |
| Atomisation pressure | 0.24mpa |
It is as follows that step S3 prepares step 33) operating parameter in enteric coating layer：
| Operation item | Parameter |
| Absorbing quantity | 28HZ |
| Inlet air temperature | 38℃ |
| Temperature of charge | 33℃ |
| Atomisation pressure | 0.23mpa |
| Wriggling revolution speed | 1.5pm |
Embodiment 8
The present embodiment provides the preparation methods of Rabeprazole enteric-coated micro-pill described in embodiment 5, and the difference with embodiment 7 only exists
In：
The preparation method of above-mentioned Rabeprazole enteric-coated micro-pill, wherein：
It is as follows that step S1 prepares step 14) operating parameter in drug-loaded layer：
| Operation item | Parameter |
| Absorbing quantity | 50HZ |
| Atomisation pressure | 0.50mpa |
| Inlet air temperature | 60℃ |
| Wriggling revolution speed | 2pm |
Step S2 prepares step 24) in barrier layer and 25) operating parameter is as follows：
It is as follows that step S3 prepares step 33) operating parameter in enteric coating layer：
| Operation item | Parameter |
| Absorbing quantity | 56HZ |
| Inlet air temperature | 76℃ |
| Temperature of charge | 66℃ |
| Atomisation pressure | 0.46mpa |
| Wriggling revolution speed | 3pm |
Embodiment 9
The present embodiment provides the preparation methods of Rabeprazole enteric-coated micro-pill described in embodiment 6, and the difference with embodiment 7 only exists
In：
The preparation method of above-mentioned Rabeprazole enteric-coated micro-pill, wherein：
It is as follows that step S1 prepares step 14) operating parameter in drug-loaded layer：
| Operation item | Parameter |
| Absorbing quantity | 12.5HZ |
| Atomisation pressure | 0.125mpa |
| Inlet air temperature | 15℃ |
| Wriggling revolution speed | 0.5pm |
Step S2 prepares step 24) in barrier layer and 25) operating parameter is as follows：
| Operation item | Parameter |
| Absorbing quantity | 12.5HZ |
| Inlet air temperature | 17.5℃ |
| Temperature of charge | 15℃ |
| Wriggling revolution speed | 1pm |
| Atomisation pressure | 0.12mpa |
It is as follows that step S3 prepares step 33) operating parameter in enteric coating layer：
| Operation item | Parameter |
| Absorbing quantity | 14HZ |
| Inlet air temperature | 19℃ |
| Temperature of charge | 16.5℃ |
| Atomisation pressure | 0.115mpa |
| Wriggling revolution speed | 0.75pm |
Embodiment 10
A kind of Rabeprazole enteric-coated pellet capsule contains any Rabeprazole enteric-coated micro-pills of embodiment 4-6 or implementation
Rabeprazole enteric-coated micro-pill made from any one of example 7-9 the methods.
The Rabeprazole enteric-coated pellet capsule, specification are 20mg/ or 10mg/.
Embodiment 11
A kind of Rabeprazole enteric orally disintegrating tablet contains any Rabeprazole enteric-coated micro-pills of embodiment 4-6 or embodiment
Rabeprazole enteric-coated micro-pill made from any the methods of 7-9 also contains pharmaceutically acceptable auxiliary material.
Comparative example 1
Rabeprazole sodium enteric-coated micro-pellet disclosed in CN201010603181.9.
Comparative example 2
Rabeprazole sodium enteric-coated micro-pellet disclosed in CN201110051209.7.
1 release of experimental example is evaluated
It is experiment sample with above-mentioned 4-6 according to embodiments of the present invention and comparative example the 1-2 Rabeprazole sodium enteric-coated micro-pellet prepared
Product are controlled according to 2010 editions enteric coated preparations quality standards of Chinese Pharmacopoeia.As a result it see the table below：
| Release | 1 | 2 | 3 | 4 | 5 | 6 |
| Embodiment 4 | 96.5 | 95.4 | 97.7 | 97.2 | 97.1 | 94.5 |
| Embodiment 5 | 94.6 | 95.5 | 95.7 | 96.8 | 97.3 | 94.4 |
| Embodiment 6 | 95.3 | 96.2 | 94.8 | 96.7 | 95.3 | 94.1 |
| Comparative example 1 | 92.2 | 93.6 | 94.7 | 91.5 | 92.2 | 93.6 |
| Comparative example 2 | 91.8 | 92.4 | 93.2 | 90.8 | 92.5 | 94.9 |
Release the result shows that, the release of Rabeprazole sodium enteric-coated micro-pellet capsule is 90% or more, and reproducibility is preferable.
2 accelerated test of embodiment
It is experiment sample with above-mentioned 4-6 according to embodiments of the present invention and comparative example the 1-2 Rabeprazole sodium enteric-coated micro-pellet prepared
Product, internal layer plastic-aluminum, housing aluminium foil bag, the inside add drier, in 40 ± 2 DEG C, the climatic chamber of relative humidity 75 ± 5%
Accelerated test is investigated 6 months, is investigated result and be see the table below：
The result shows that：Rabeprazole sodium enteric-coated micro-pellet capsule prepared by 4-6 of the embodiment of the present invention places 6 in accelerated test
A month, sample pellet color was off-white color, and content is increased slightly without significant change, impurity but all in limits, total miscellaneous equal
Less than 1.0%；Comparative example 1-2 sample pellet colors are off-white color, and acid resistance, release, content slightly reduce, and impurity slightly increases
Add, total impurities are more than 2.0%.The sample that at present prepared by the present invention is still in the experiment of long-term reserved sample observing.It can be with by accelerated test
Prove that embodiment sample is substantially better than comparative example.According to expiration date of drug criterion, the effective of invention formulation is fixed tentatively
Phase is 2 years.
3 long-term stable experiment of experimental example
It is experiment sample with above-mentioned 4-6 according to embodiments of the present invention and comparative example the 1-2 Rabeprazole sodium enteric-coated micro-pellet prepared
Product, internal layer plastic-aluminum, housing aluminium foil bag, the inside add drier, in 25 ± 2 DEG C, the climatic chamber of relative humidity 60 ± 5%
Long term test is investigated 24 months, is investigated result and be see the table below：
It can be found by long-time stability data, the stability of Rabeprazole sodium enteric-coated micro-pellet of the invention will be significantly larger than
The stabilization data of comparative example 1 and comparative example 2.
Experimental example 4
The Rabeprazole sodium enteric-coated micro-pellet prepared using above-mentioned according to embodiments of the present invention 4 and comparative example 1 is interior as laboratory sample
Layer plastic-aluminum, housing aluminium foil bag, the inside add drier, long-term in 25 ± 2 DEG C, the climatic chamber of relative humidity 60 ± 5%
24 months, related substance detection, HPLC are carried out to embodiment 4 and 1 sample of comparative example respectively by 2010 editions methods of Chinese Pharmacopoeia
Collection of illustrative plates is shown in Fig. 1-6.
Fig. 1-3 is respectively 4 sample of embodiment 0 month, the HPLC collection of illustrative plates in December, 24 months.Fig. 4-6 is respectively 1 sample 0 of comparative example
The moon, December, 24 months HPLC collection of illustrative plates.
The result shows that：Impurity content is apparently higher than in 4 sample of embodiment in 1 sample of comparative example within the placement same time
Impurity content.Therefore the stability of 4 sample of embodiment is more than 1 sample of comparative example.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (16)
1. a kind of Rabeprazole enteric-coated micro-pill, from inside to outside including blank capsule core, drug-loaded layer, barrier layer, enteric coating layer, wherein
Drug-loaded layer weightening is 25%-30%, and barrier layer weightening is 22%-27%, and enteric coating layer weightening is 13%-17%, wherein is carried
Medicine layer is by Rabeprazole or RABEPRAZOLE SODIUM, sucrose, hydroxypropyl methyl cellulose, sodium hydrogensulfite and lauryl sodium sulfate group
At；Barrier layer is made of hydroxypropyl methyl cellulose, polyethylene glycol-6000, titanium dioxide and disodium hydrogen phosphate；Enteric coating layer by
Acrylic resin c-type, polyethylene glycol-6000 and talcum powder composition；
For the Rabeprazole enteric-coated micro-pill to be made in terms of 1000 finished products, prescription is as follows：
Name of an article prescription
Blank capsule core 52g-208g；
Drug-loaded layer：
Barrier layer：
Enteric coating layer：
2. Rabeprazole enteric-coated micro-pill according to claim 1, which is characterized in that the Rabeprazole or RABEPRAZOLE SODIUM
Granularity be less than 160 microns.
3. Rabeprazole enteric-coated micro-pill according to claim 1, which is characterized in that the Rabeprazole or RABEPRAZOLE SODIUM
Granularity be 100-130 microns.
4. Rabeprazole enteric-coated micro-pill according to claim 1 or 2, which is characterized in that the blank capsule core is starch sky
White capsule core, microcrystalline cellulose blank pellet or sucrose blank capsule core.
5. Rabeprazole enteric-coated micro-pill according to claim 4, which is characterized in that the grain size of the blank capsule core is 0.3-
0.9mm。
6. Rabeprazole enteric-coated micro-pill according to claim 5, which is characterized in that the grain size of the blank capsule core is 0.4-
0.7mm。
7. Rabeprazole enteric-coated micro-pill according to claim 4, which is characterized in that the blank capsule core is grain size Ф 0.4-
The sucrose blank capsule core of 0.7mm.
8. according to claim 1-3,5-7 any one of them Rabeprazole enteric-coated micro-pill, which is characterized in that the Rabeprazole
Enteric-coated micro-pill grain size is Ф 0.6-1.0mm.
9. Rabeprazole enteric-coated micro-pill according to claim 1, which is characterized in that the Rabeprazole enteric-coated micro-pill is to make
At 1000 finished product meters, prescription is as follows：
Name of an article prescription
Blank capsule core 104g；
Drug-loaded layer：
Barrier layer：
Enteric coating layer：
10. Rabeprazole enteric-coated micro-pill according to claim 1, which is characterized in that the Rabeprazole enteric-coated micro-pill with
1000 finished product meters are made, prescription is as follows：
Name of an article prescription
Sucrose blank capsule core Ф 0.7mm 208g
Drug-loaded layer：
Barrier layer：
Enteric coating layer：
11. Rabeprazole enteric-coated micro-pill according to claim 1, which is characterized in that the Rabeprazole enteric-coated micro-pill with
1000 finished product meters are made, prescription is as follows：
Name of an article prescription
Sucrose blank capsule core Ф 0.5mm 52g
Drug-loaded layer：
Barrier layer：
Enteric coating layer：
12. the preparation method of any one of the claim 1-11 Rabeprazole enteric-coated micro-pills, which is characterized in that including following step
Suddenly：
Drug-loaded layer composition is coated in blank capsule core, is made and carries pill core；
Load pill core barrier layer composition is coated, the load pill core with barrier layer is made；
The load pill core with barrier layer enteric coating layer composition is coated, enteric-coated micro-pill is made；
The solvent used in the Rabeprazole enteric-coated micro-pill preparation process is mixed for ethyl alcohol or water, or both any proportion
It closes.
13. preparation method according to claim 12, which is characterized in that include the following steps：
S1 prepares drug-loaded layer:
11) with the sucrose, sodium hydrogensulfite, lauryl sodium sulfate of purifying water dissolution recipe quantity；
12) with the hydroxypropyl methyl cellulose for purifying water-swellable recipe quantity, the ethyl alcohol of recipe quantity, which is added, makes it fully dissolve；
13) by step 11) and 12) made of two kinds of solution mix, the Rabeprazole or RABEPRAZOLE SODIUM of recipe quantity is added, fully
It is uniformly mixed；
14) blank capsule core of recipe quantity is placed in the jet flow seed-coating machine of bottom and is preheating to 30 DEG C, drug containing made of step 13) is molten
Liquid uniformly sprays packet in blank capsule core；
15) dry after liquid medicine jet is complete, cross 20 mesh sieve, be made and carry pill core；
S2 prepares barrier layer:
21) with the hydroxypropyl methyl cellulose of purifying water dissolution recipe quantity；
22) with Macrogol 6000, titanium dioxide, the disodium hydrogen phosphate of purifying water dissolution recipe quantity；
23) by step 21) and 22), two kinds of solution mixings, addition ethyl alcohol are mixed, and cross colloid mill, barrier layer material is made；
24) load pill core prepared by step S1 is again placed in bottom spray fluidisation machine, ventilation is preheating to 30 DEG C；
25) barrier layer material spray packet is made in capsule core in step 23), is finished coating material；
26) dry after being coated, sieving removes fine powder, and the load pill core with barrier layer is made；
S3 prepares enteric coating layer:
31) polyethylene glycol-6000, the talcum powder of water dissolution recipe quantity are used；
32) the acrylic resin c-type of recipe quantity is added in solution made from step 31), is stirred, enteric coating is made
Layer material；
33) the load pill core with barrier layer prepared by step S2 is again placed in the jet flow seed-coating machine of bottom, passes through bottom jet flow
Change the upper enteric coating layer material of coating；
34) after having wrapped enteric coating layer material, dry, sieving removes fine powder, obtains complete enteric-coated micro-pill；
It is as follows that step S1 prepares step 14) operating parameter in drug-loaded layer：
And/or step S2 prepares step 24) in barrier layer and 25) operating parameter is as follows：
And/or step 33) operating parameter is as follows in step S3 preparation enteric coating layers：
14. preparation method according to claim 13, which is characterized in that step S1 prepares step 14) in drug-loaded layer and operates
Parameter is as follows：
And/or step S2 prepares step 24) in barrier layer and 25) operating parameter is as follows：
And/or step 33) operating parameter is as follows in step S3 preparation enteric coating layers：
15. a kind of Rabeprazole enteric-coated pellet capsule, containing any one of the claim 1-11 Rabeprazole enteric-coated micro-pills or
Rabeprazole enteric-coated micro-pill prepared by any one of claim 12-14 the methods.
16. a kind of Rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets contain any one of the claim 1-11 Rabeprazoles
Rabeprazole enteric-coated micro-pill prepared by any one of enteric-coated micro-pill or claim 12-14 the method, and contain and pharmaceutically may be used
The auxiliary material of receiving.
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| KR102227486B1 (en) * | 2017-06-30 | 2021-03-12 | 롯데정밀화학 주식회사 | Oral solid formulation composition comprising proton pump inhibitor, oral solid formulation comprising the same and manufacturing method thereof |
| CN112168800B (en) * | 2020-09-28 | 2023-03-28 | 南京长澳医药科技有限公司 | Rabeprazole sodium enteric-coated orally disintegrating tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004075881A1 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Stable pharmaceutical composition of rabeprazole and processes for their preparation |
| CN103340829A (en) * | 2013-07-26 | 2013-10-09 | 珠海润都制药股份有限公司 | Enteric coating pellet of proton pump inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004075881A1 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Stable pharmaceutical composition of rabeprazole and processes for their preparation |
| CN103340829A (en) * | 2013-07-26 | 2013-10-09 | 珠海润都制药股份有限公司 | Enteric coating pellet of proton pump inhibitor |
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