CN105434398A - Rabeprazole enteric-coated micro pellet, and preparation method thereof - Google Patents
Rabeprazole enteric-coated micro pellet, and preparation method thereof Download PDFInfo
- Publication number
- CN105434398A CN105434398A CN201510957689.1A CN201510957689A CN105434398A CN 105434398 A CN105434398 A CN 105434398A CN 201510957689 A CN201510957689 A CN 201510957689A CN 105434398 A CN105434398 A CN 105434398A
- Authority
- CN
- China
- Prior art keywords
- rabeprazole
- enteric
- layer
- drug
- coating layer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 91
- 229960004157 rabeprazole Drugs 0.000 title claims abstract description 86
- 239000008188 pellet Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000010410 layer Substances 0.000 claims abstract description 154
- 239000003814 drug Substances 0.000 claims abstract description 68
- 229940079593 drug Drugs 0.000 claims abstract description 51
- 239000002702 enteric coating Substances 0.000 claims abstract description 49
- 238000009505 enteric coating Methods 0.000 claims abstract description 49
- 229960001778 rabeprazole sodium Drugs 0.000 claims abstract description 48
- 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 38
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 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 21
- 229930006000 Sucrose Natural products 0.000 claims abstract description 21
- 239000005720 sucrose Substances 0.000 claims abstract description 21
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 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
- 229920000178 Acrylic resin Polymers 0.000 claims abstract description 13
- 239000000843 powder Substances 0.000 claims abstract description 7
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims abstract description 5
- 229960004793 sucrose Drugs 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000002775 capsule Substances 0.000 claims description 24
- -1 hydroxypropyl Chemical group 0.000 claims description 23
- 239000006187 pill Substances 0.000 claims description 22
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 20
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 20
- 239000011248 coating agent Substances 0.000 claims description 19
- 238000000576 coating method Methods 0.000 claims description 19
- 239000008213 purified water Substances 0.000 claims description 18
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 14
- 235000019800 disodium phosphate Nutrition 0.000 claims description 14
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 11
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 235000010265 sodium sulphite Nutrition 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000084 colloidal system Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 235000010603 pastilles Nutrition 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 230000008961 swelling Effects 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
- 239000002994 raw material Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 238000002474 experimental method Methods 0.000 abstract description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract description 3
- 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 abstract description 3
- 230000031891 intestinal absorption Effects 0.000 abstract description 3
- 239000011247 coating layer Substances 0.000 abstract 3
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 abstract 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 abstract 1
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 abstract 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 16
- 239000000523 sample Substances 0.000 description 12
- 238000000889 atomisation Methods 0.000 description 10
- 230000002572 peristaltic effect Effects 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000007789 sealing Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000011230 binding agent Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 239000006101 laboratory sample Substances 0.000 description 5
- 239000003605 opacifier Substances 0.000 description 5
- 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 5
- 238000012360 testing method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000001198 duodenum Anatomy 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 208000007107 Stomach Ulcer Diseases 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 239000005030 aluminium foil Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 208000000718 duodenal ulcer Diseases 0.000 description 3
- 201000005917 gastric ulcer Diseases 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000126 substance 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
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 238000011835 investigation Methods 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
- 230000001953 sensory effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020601 Hyperchlorhydria Diseases 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
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 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
- 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
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 159000000011 group IA salts Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000001727 in vivo Methods 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
- 239000004531 microgranule 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
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 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)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a rabeprazole enteric-coated micro pellet, and a preparation method thereof. The rabeprazole enteric-coated micro pellet comprises a core pellet, a drug-carrying layer, an insulating coating layer, and an enteric coating layer from inside to outside; the weight of the drug-carrying layer accounts for 25 to 30%, the weight of the insolating coating layer accounts for 22 to 27%, and the weight of the enteric coating layer accounts for 13 to 17%; the drug-carrying layer is composed of rabeprazole or rabeprazole sodium, sucrose, hydroxypropyl methyl cellulose, sodium hydrogen sulfite, and lauryl sodium sulfate; the insulating coating layer is composed of hydroxypropyl methyl cellulose, polyethylene glycol 6000, titanium dioxide powder, and disodium hydrogen phosphate; and the enteric coating layer is composed of C-type acrylic resin, polyethylene glycol 6000, and talcum powder. A drug release curve and a drug intestinal absorption rate curve which are coincident with each other are obtained via appropriate controlling on enteric solubility and drug release rate of the rabeprazole enteric-coated micro pellet; existing time of drugs in intestinal tract in free states is shorter; less degradation is caused; bioavailability is high; and it is shown by clinical experiments that obvious effective rate is higher, stability is higher, and the rabeprazole enteric-coated micro pellet is convenient for patients to eat.
Description
Technical field
The present invention relates to a kind of rabeprazole enteric coated micropill and preparation method thereof, belong to pharmaceutical preparations technology field.
Background technology
RABEPRAZOLE SODIUM chemical name is 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole sodium.Meet light, heat, acid all unstable, easily decompose and medicine is lost activity, therefore make oral formulations and should avoid contacting with gastric acid.RABEPRAZOLE SODIUM is mainly used in gastric ulcer, duodenal ulcer, stoma ulcer, reflux esophagitis, Zhuo-Emhorn (Zollinger-Ellison) syndrome (gastrinoma).Assist for gastric ulcer or duodenal ulcer patients eliminating pylorus, belong to digestive system disease.This product transforms into activity form (sulfinyl form) in parietal cell under acid condition, by modifying proton pump (H
+, K
+-ATP enzyme) sulfydryl, suppress H
+,k
+the active also gastric acid secretion inhibiting of-ATP enzyme.
Patent US2010121068, EP2162449, WO2010006904, WO2010004571, CN101580520 etc., describe the preparation process of sodium rabeprazole compound in detail.Chinese patent CN101143143 provides class treatment gastroesophageal reflux disease and the medicine of functional dyspepsia, comprises neutral form or the alkaline salt forms of rabeprazole, and its optical voidness stereoisomer or its active metabolite.
RABEPRAZOLE SODIUM is the new varieties of Japanese Wei Cai company exploitation, and in 1997 first in Japan's listing, within 1999, this product is gone on the market in the U.S., and commodity are called Pariet, and dosage form is enteric coatel tablets.Enteric coated tablet full wafer is swallowed difficulty, and is easily broken by the teeth and the effect of losing activity by patient.In body, release is uneven, easily produces prominent releasing.
Rabeprazole is a kind of specific drug for the treatment of hyperchlorhydria, gastric ulcer and duodenal ulcer, common rabeprazole enteric coatel tablets, rabeprazole enteric coated capsule in vivo release profiles and duodenal absorption speed inconsistent, it is longer and degrade to cause discharging rear rabeprazole time of staying in intestinal, cause bioavailability low, curative effect decreases.Moreover common enteric coatel tablets, enteric coated capsule enter duodenum with complete form after stomach, because volume is comparatively large, in duodenum, there is uncomfortable sensation a period of time.
The enteric coatel tablets that enteric-coated pellet capsule has gone on the market more or common enteric coated capsule have significant advantage.China's application number is 201010603181.9,201110051209.7,201310191057.X, all disclose a kind of sodium rabeprazole enteric-coated microgranule (or micropill) and preparation method thereof in the patent applications such as 201510423522.7.
The shortcoming or not enough as follows of above-mentioned patented method:
Number of patent application 201010603181.9, its drug-loaded layer is made up of RABEPRAZOLE SODIUM, hydroxypropyl methylcellulose and Pulvis Talci, and drug-loaded layer component is simple, oxidizable, affects content and the stability of medicine.
Number of patent application 201110051209.7, (1) celphere, it is the innermost layer structure of above-mentioned enteric-coated microsome; (2) drug-loaded layer, it is coated on outside above-mentioned celphere, is made up of drug-loaded layer compositions, and said composition comprises active constituents of medicine RABEPRAZOLE SODIUM, binding agent and pH value regulator; (3) contagion gown layer, it is coated on outside above-mentioned drug-loaded layer, is made up of contagion gown layer composition, and said composition comprises binding agent, opacifier and antiplastering aid; (4) enteric coating layer, it is coated on outside above-mentioned contagion gown layer, is made up of enteric coating layer compositions, and said composition comprises enteric-coating material, plasticizer, antiplastering aid and blocker.Drug-loaded layer uses pH value regulator, and sealing coat uses opacifier, improves to stability of drug products, but need to strengthen in antioxidation.
Number of patent application 201310191057.X, the described pill core that contains comprises RABEPRAZOLE SODIUM, filler, binding agent, disintegrating agent and basifier, described sealing coat comprises blocker, binding agent, antiplastering aid and opacifier, pH value regulator is used containing pill core, sealing coat uses opacifier, stability of drug products is improved, but need to strengthen in antioxidation.
Number of patent application 201510423522.7, described medicated layer comprises RABEPRAZOLE SODIUM, binding agent and pH adjusting agent, sealing coat total amount is 100%, the sealing coat of described Rabeprazole sodium enteric-coated micro-pellet comprise the blocker of 10 ~ 30%, the binding agent of 40 ~ 65% and 25 ~ 45% antiplastering aid.Medicated layer utilizes basifier to regulate pH, and sealing coat is only containing blocker, and stablizing effect is poor.
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of rabeprazole enteric coated micropill, capsule and preparation method thereof.The present invention is by using antioxidant, stabilizing agent at drug-loaded layer, sealing coat, thus ensure that the stability of invention formulation.Gastric solubility rabeprazole enteric-coated pellet capsule capsule shells prepared by the present invention dissolves the enteric coated micropill discharging Ф 0.6-1.0mm in time at gastric, this micropill slowly enters duodenum subsequently, and because enteric coated micropill volume is small, human body sensory is comfortable.And the Technology of this law employing suitably controls the rate of release of micropill enteric solubility and medicine, make drug release patterns consistent with the rate curve of intestinal absorption medicine, the time that medicine exists with free state in intestinal is short, degrade also relatively less, bioavailability is high, clinical trial shows that obvious effective rate is higher, more stable, effect duration is longer, facilitates patient consumes.
Technical solution of the present invention is as follows:
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, wherein drug-loaded layer weightening finish is 25%-30%, the weightening finish of contagion gown layer is 22%-27%, enteric coating layer weightening finish is 13%-17%, wherein, drug-loaded layer is made up of rabeprazole or RABEPRAZOLE SODIUM, sucrose, hydroxypropyl emthylcellulose (E-8), sodium sulfite and sodium lauryl sulphate; Contagion gown layer is made up of hydroxypropyl emthylcellulose (E-8), PEG-4000, titanium dioxide and sodium hydrogen phosphate; Enteric coating layer is made up of acrylic resin C type (L-30D), PEG-4000 and Pulvis Talci.
Above-mentioned rabeprazole enteric coated micropill, wherein:
Preferably, the granularity of described raw material rabeprazole or RABEPRAZOLE SODIUM, for being less than 160 microns, is more preferably 100-130 micron.
Preferably, the ball core that described celphere can adopt the discord inventive compound of this area routine to react, its disintegration rate at least will meet the technical requirement of this area routine, and the present invention can select the celphere of corresponding different-grain diameter according to the product preparing different size.The preferred celphere of the present invention is starch celphere, microcrystalline Cellulose celphere or sucrose celphere; Be more preferably sucrose celphere.The particle diameter of described celphere is preferably 0.3-0.9mm, is more preferably 0.4-0.7mm; Further be preferably the sucrose celphere of particle diameter Ф 0.4-0.7mm.
Preferably, the solvent used in described rabeprazole enteric coated micropill preparation process is ethanol or water, or both arbitrary ratio mixing.
Preferably, described rabeprazole enteric coated micropill particle diameter is Ф 0.6-1.0mm.
Preferably, described rabeprazole enteric coated micropill is to make 1000 finished products, and its prescription is as follows:
| The name of an article | Prescription | Optimizing prescriptions |
| Celphere | 52g-208g | 104g |
Drug-loaded layer:
Contagion gown layer:
| The name of an article | Prescription | Optimizing prescriptions |
| Hydroxypropyl emthylcellulose (E-8) | 21g-84g | 42g |
| PEG-4000 | 2.0g-8.0g | 4.0g |
| Titanium dioxide | 4.2g-16.8g | 8.4g |
| Sodium hydrogen phosphate | 0.8g-3.2g | 1.6g |
| Ethanol (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 |
| PEG-4000 | 2.2g-8.8g | 4.4g |
| Pulvis Talci | 6g-24g | 12g |
The prescription of the above-mentioned rabeprazole enteric coated micropill of the present invention is by the capsule designs making 1000 (20mg/ grains) or 2000 (10mg/ grain) rabeprazole enteric coated micropills, and the side of clicking here reduces 0.5 times in proportion and still belongs to the production prescription scope of at least amplifying 1000000 times the scope that the present invention contains.
The present invention also provides the preparation method of above-mentioned rabeprazole enteric coated micropill, and preferably, the solvent used in described rabeprazole enteric coated micropill preparation process is ethanol or water, or both arbitrary ratio mixing.
The preparation method of above-mentioned rabeprazole enteric coated micropill, comprises the following steps:
Drug-loaded layer compositions is coated on celphere, obtained year pill core;
By described year pill core contagion gown layer composition coating, year pill core of obtained band contagion gown layer;
By year pill core enteric coating layer compositions coating of described band contagion gown layer, obtained enteric coated micropill.
Above-mentioned preparation method is further comprising the steps: by described enteric coated micropill fill capsule; Or described enteric coated micropill is mixed with pharmaceutically acceptable adjuvant and prepares rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets.Such as make 1000 (20mg/ grains) or 2000 (10mg/ grain) rabeprazole enteric-coated pellet capsules by above-mentioned prescription.Such as select II capsule.
Particularly, the preparation method of above-mentioned rabeprazole enteric coated micropill, comprises the following steps:
S1 prepares drug-loaded layer:
11) sucrose, sodium sulfite, the sodium lauryl sulphate of recipe quantity is dissolved by purified water;
12) with the hydroxypropyl emthylcellulose (E-8) of the swelling recipe quantity of purified water, the ethanol adding recipe quantity makes it fully dissolve;
13) by step 11) and 12) two kinds of solution mixing of making, add rabeprazole or the RABEPRAZOLE SODIUM of recipe quantity, abundant mix homogeneously;
14) celphere (preferably sucrose ball core) of recipe quantity being placed in end jet flow seed-coating machine and being preheating to 30 DEG C, by step 3) spray of the pastille dissolution homogeneity made wraps on celphere (preferably sucrose ball core);
15) the complete rear drying of liquid medicine jet, excessively 20 mesh sieves, an obtained year pill core;
S2 prepares contagion gown layer:
21) hydroxypropyl emthylcellulose (E-8) of recipe quantity is dissolved by purified water;
22) polyethylene glycol 6000, titanium dioxide, the sodium hydrogen phosphate of recipe quantity is dissolved by purified water;
23) by step 21) and 22) two kinds of solution mixings, add ethanol and be mixed, cross colloid mill, obtained contagion gown layer material;
24) pill core that carries prepared by step S1 is placed in end jet flow machine again, ventilates and is preheating to 30 DEG C;
25) by step 23) obtained contagion gown layer material spraying wraps on ball core, is finished coating material;
26) dry after coating, sieve removing fine powder, year pill core of obtained band contagion gown layer;
S3 prepares enteric coating layer:
31) with PEG-4000, the Pulvis Talci of water dissolution recipe quantity;
32) the acrylic resin C type of recipe quantity is added step 31) in obtained solution, stir (preferably 20 minutes), obtained enteric coating layer material;
33) pill core that carries of the band contagion gown layer prepared by step S2 is placed in end jet flow seed-coating machine again, by enteric coating layer material on end spray fluidized coating;
34) after having wrapped enteric coating layer material, dry, sieve removing fine powder, obtains complete enteric coated micropill.
The preparation method of above-mentioned rabeprazole enteric coated micropill, wherein:
Preferably, step S1 prepares step 14 in drug-loaded layer) operating parameter is as follows:
Preferably, step S2 prepares step 24 in contagion gown layer) and 25) operating parameter is as follows:
| Operation item | Parameter | Preferred parameter |
| Absorbing quantity | 12.5-50HZ | 25HZ |
| Inlet temperature | 17.5℃-70℃ | 35℃ |
| Temperature of charge | 15℃-60℃ | 30℃ |
| Peristaltic pump rotating speed | 1pm-4pm | 2pm |
| Atomisation pressure | 0.12mpa-0.48mpa | 0.24mpa |
Preferably, step S3 prepares step 33 in enteric coating layer) operating parameter is as follows:
| Operation item | Parameter | Preferred parameter |
| Absorbing quantity | 14-56HZ | 28HZ |
| Inlet temperature | 19℃-76℃ | 38℃ |
| Temperature of charge | 16.5℃-66℃ | 33℃ |
| Atomisation pressure | 0.115mpa-0.46mpa | 0.23mpa |
| Peristaltic pump rotating speed | 0.75pm-3pm | 1.5pm |
Prescription of the present invention is that the side of clicking here reduces 0.5 times in proportion and still belongs to the claimed scope of the present invention to the production prescription scope of amplifying 1000000 times by making 1000 (20mg/ grains) or 2000 (10mg/ grain) rabeprazole enteric-coated pellet capsule designs.
The present invention also provides a kind of rabeprazole enteric-coated pellet capsule, containing above-mentioned rabeprazole enteric coated micropill.Described rabeprazole or Rabeprazole sodium enteric-coated micro-pellet capsule, its specification is 20mg/ grain or 10mg/ grain.
The present invention also provides a kind of rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets, containing above-mentioned rabeprazole enteric coated micropill and pharmaceutically acceptable adjuvant.
Described rabeprazole or sodium rabeprazole enteric-coated orally disintegrating tablets can be prepared by art methods.
Gastric solubility rabeprazole enteric-coated pellet capsule capsule shells prepared by the present invention dissolves the enteric coated micropill discharging Ф 0.6-1.0mm in time at gastric, this micropill slowly enters duodenum subsequently, and because enteric coated micropill volume is small, human body sensory is comfortable.And the Technology of this law employing suitably controls the rate of release of micropill enteric solubility and medicine, make drug release patterns consistent with the rate curve of intestinal absorption medicine, the time that medicine exists with free state in intestinal is short, degrade also relatively less, bioavailability is high, clinical trial shows that obvious effective rate is higher, more stable, effect duration is longer, facilitates patient consumes.
Rabeprazole enteric coated micropill of the present invention, selects the components such as sodium bisulfate, sodium hydrogen phosphate, titanium dioxide, is increased the stability of medicine by synergism.
The drug-loaded layer of Rabeprazole sodium enteric-coated micro-pellet of the present invention contains RABEPRAZOLE SODIUM, hydroxypropyl cellulose (E-8), sodium lauryl sulphate etc., and these compositions effectively ensure that RABEPRAZOLE SODIUM is in the quick release of human body and efficient absorption.With sealing coat, the RABEPRAZOLE SODIUM medicine layer of alkalescence is kept apart with in acid enteric material; effectively protect active constituents of medicine; add antioxidant and opacifier in the isolation layer as protection composition simultaneously, significantly enhanced the stability of medicine by coordinative role.
According to Rabeprazole sodium enteric-coated micro-pellet capsule prepared by patent of invention, in 40 ± 2 DEG C, accelerate investigation 6 months in the climatic chamber of relative humidity 75 ± 5%, the outward appearance of Rabeprazole sodium enteric-coated micro-pellet capsule, character, related substance, release and content compared with 0 day and have no significant change.
Rabeprazole sodium enteric-coated micro-pellet capsule prepared by the present invention, (hydrochloric acid 7.0ml is got with acid solution, add sodium chloride 2.0g, be dissolved in water and be diluted to 1000ml, pH is 1.2) 500ml is dissolution medium, adopts the device of dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC first methods), rotating speed is 100 turns per minute, through 2 hours, do not find the significant change on this formulation aesthetics, acidproof profit reaches more than 90%; Dissolution test: according to Chinese Pharmacopoeia version in 2010 two drug release determination methods (two annex XD second methods), rotating speed is 100 turns per minute, (hydrochloric acid 7.0ml is got at 37 scholar, 0.5 DEG C of acid solution, add sodium chloride 2.0g, be dissolved in water and be diluted to 1000ml, pH is 1.2) in 500ml after 2 hours, acid solution is discarded, add the 0.235mol/L disodium phosphate soln 400ml and ethanol 100ml that are preheated to 37 DEG C, through 45 minutes time, sampling records release and reaches more than 80%.
Accompanying drawing explanation
Fig. 1-6 is respectively the HPLC collection of illustrative plates of laboratory sample in experimental example 4.
Detailed description of the invention
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, wherein drug-loaded layer weightening finish is 25%, the weightening finish of contagion gown layer is 25%, enteric coating layer weightening finish is 15%, wherein, drug-loaded layer is made up of rabeprazole or RABEPRAZOLE SODIUM, hydroxypropyl emthylcellulose (E-8), sodium sulfite and sodium lauryl sulphate; Contagion gown layer is made up of hydroxypropyl emthylcellulose (E-8), PEG-4000, titanium dioxide and sodium hydrogen phosphate; Enteric coating layer is made up of acrylic resin C type (L-30D), PEG-4000 and Pulvis Talci.
Embodiment 2
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, wherein drug-loaded layer weightening finish is 27%, the weightening finish of contagion gown layer is 23%, enteric coating layer weightening finish is 15%, wherein, drug-loaded layer is made up of rabeprazole or RABEPRAZOLE SODIUM, hydroxypropyl emthylcellulose (E-8), sodium sulfite and sodium lauryl sulphate; Contagion gown layer is made up of hydroxypropyl emthylcellulose (E-8), PEG-4000, titanium dioxide and sodium hydrogen phosphate; Enteric coating layer is made up of acrylic resin C type (L-30D), PEG-4000 and Pulvis Talci.
Embodiment 3
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, wherein drug-loaded layer weightening finish is 30%, the weightening finish of contagion gown layer is 22%, enteric coating layer weightening finish is 13%, wherein, drug-loaded layer is made up of rabeprazole or RABEPRAZOLE SODIUM, hydroxypropyl emthylcellulose (E-8), sodium sulfite and sodium lauryl sulphate; Contagion gown layer is made up of hydroxypropyl emthylcellulose (E-8), PEG-4000, titanium dioxide and sodium hydrogen phosphate; Enteric coating layer is made up of acrylic resin C type (L-30D), PEG-4000 and Pulvis Talci.
Embodiment 4
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, to make 1000 finished products, its prescription is as follows:
Described rabeprazole enteric coated micropill is to make 1000 finished products, and its prescription is as follows:
| The name of an article | Prescription |
| Sucrose celphere Ф 0.4mm | 104g |
Drug-loaded layer:
Contagion gown layer:
| The name of an article | Prescription |
| Hydroxypropyl emthylcellulose (E-8) | 42g |
| PEG-4000 | 4.0g |
| Titanium dioxide | 8.4g |
| Sodium hydrogen phosphate | 1.6g |
| Ethanol (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 |
| PEG-4000 | 4.4g |
| Pulvis Talci | 12g |
Embodiment 5
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, to make 1000 finished products, its prescription is as follows:
Described rabeprazole enteric coated micropill is to make 1000 finished products, and its prescription is as follows:
| The name of an article | Prescription |
| Sucrose celphere Ф 0.7mm | 208g |
Drug-loaded layer:
| The name of an article | Prescription |
| Rabeprazole or RABEPRAZOLE SODIUM | 50g |
| Sucrose | 16.8g |
| Hydroxypropyl emthylcellulose (E-8) | 20g |
| Sodium sulfite | 2.6g 7 --> |
| Sodium lauryl sulphate | 2.5g |
| Ethanol (95%) | 334g |
| Purified water | -- |
Contagion gown layer:
| The name of an article | Prescription |
| Hydroxypropyl emthylcellulose (E-8) | 84g |
| PEG-4000 | 8.0g |
| Titanium dioxide | 16.8g |
| Sodium hydrogen phosphate | 3.2g |
| Ethanol (95%) | 170ml |
| Purified water | In right amount |
Enteric coating layer:
| The name of an article | Prescription |
| Acrylic resin C type (L-30D) | 336g |
| PEG-4000 | 8.8g |
| Pulvis Talci | 24g |
Embodiment 6
A kind of rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, to make 1000 finished products, its prescription is as follows:
Described rabeprazole enteric coated micropill is to make 1000 finished products, and its prescription is as follows:
| The name of an article | Prescription |
| Sucrose celphere Ф 0.5mm | 52g |
Drug-loaded layer:
| The name of an article | Prescription |
| Rabeprazole or RABEPRAZOLE SODIUM | 12.5g |
| Sucrose | 4.2g |
| Hydroxypropyl emthylcellulose (E-8) | 5g |
| Sodium sulfite | 0.65g |
| Sodium lauryl sulphate | 0.625g |
| Ethanol (95%) | 83.5g |
| Purified water | -- |
Contagion gown layer:
| The name of an article | Prescription |
| Hydroxypropyl emthylcellulose (E-8) | 21g 8 --> |
| PEG-4000 | 2.0g |
| Titanium dioxide | 4.2g |
| Sodium hydrogen phosphate | 0.8g |
| Ethanol (95%) | 170ml |
| Purified water | In right amount |
Enteric coating layer:
| The name of an article | Prescription |
| Acrylic resin C type (L-30D) | 84g |
| PEG-4000 | 2.2g |
| Pulvis Talci | 6g |
Embodiment 7
The present embodiment provides the preparation method of rabeprazole enteric coated micropill described in embodiment 4, comprises the following steps:
S1 prepares drug-loaded layer:
11) sucrose, sodium sulfite, the sodium lauryl sulphate of recipe quantity is dissolved by 62ml purified water;
12) with the hydroxypropyl emthylcellulose (E-8) of the swelling recipe quantity of 42ml purified water, the ethanol adding recipe quantity makes it fully dissolve;
13) by step 11) and 12) two kinds of solution mixing of making, add rabeprazole or the RABEPRAZOLE SODIUM of recipe quantity, abundant mix homogeneously;
14) the sucrose ball core of recipe quantity being placed in end jet flow seed-coating machine and being preheating to 30 DEG C, by step 3) spray of the pastille dissolution homogeneity made wraps on sucrose ball core;
15) the complete rear drying of liquid medicine jet, excessively 20 mesh sieves, an obtained year pill core;
S2 prepares contagion gown layer:
21) hydroxypropyl emthylcellulose (E-8) of recipe quantity is dissolved by 125ml purified water;
22) polyethylene glycol 6000, titanium dioxide, the sodium hydrogen phosphate of recipe quantity is dissolved by 84ml purified water;
23) by step 21) and 22) two kinds of solution mixings, add 625ml ethanol (95%) and be mixed, cross colloid mill, obtained contagion gown layer material;
24) pill core that carries prepared by step S1 is placed in end jet flow machine again, ventilates and is preheating to 30 DEG C;
25) by step 23) obtained contagion gown layer material spraying wraps on ball core, is finished coating material;
26) dry after coating, sieve removing fine powder, year pill core of obtained band contagion gown layer;
S3 prepares enteric coating layer:
31) with PEG-4000, the Pulvis Talci of 42ml water dissolution recipe quantity;
32) the acrylic resin C type of recipe quantity is added step 31) in obtained solution, be stirred well to few 20 minutes, to stirring, obtained enteric coating layer material;
33) pill core that carries of the band contagion gown layer prepared by step S2 is placed in end jet flow seed-coating machine again, by enteric coating layer material on end spray fluidized coating;
34) after having wrapped enteric coating layer material, dry, sieve removing fine powder, obtains complete enteric coated micropill.
The preparation method of above-mentioned rabeprazole enteric coated micropill, wherein:
Step S1 prepares step 14 in drug-loaded layer) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 25HZ |
| Atomisation pressure | 0.25mpa |
| Inlet temperature | 30℃ |
| Peristaltic pump rotating speed | 1pm |
Step S2 prepares step 24 in contagion gown layer) and 25) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 25HZ |
| Inlet temperature | 35℃ |
| Temperature of charge | 30℃ |
| Peristaltic pump rotating speed | 2pm |
| Atomisation pressure | 0.24mpa |
Step S3 prepares step 33 in enteric coating layer) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 28HZ |
| Inlet temperature | 38℃ |
| Temperature of charge | 33℃ |
| Atomisation pressure | 0.23mpa |
| Peristaltic pump rotating speed | 1.5pm |
Embodiment 8
The present embodiment provides the preparation method of rabeprazole enteric coated micropill described in embodiment 5, is only with the difference of embodiment 7:
The preparation method of above-mentioned rabeprazole enteric coated micropill, wherein:
Step S1 prepares step 14 in drug-loaded layer) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 50HZ |
| Atomisation pressure | 0.50mpa |
| Inlet temperature | 60℃ |
| Peristaltic pump rotating speed | 2pm |
Step S2 prepares step 24 in contagion gown layer) and 25) operating parameter is as follows:
Step S3 prepares step 33 in enteric coating layer) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 56HZ |
| Inlet temperature | 76℃ |
| Temperature of charge | 66℃ |
| Atomisation pressure | 0.46mpa |
| Peristaltic pump rotating speed | 3pm |
Embodiment 9
The present embodiment provides the preparation method of rabeprazole enteric coated micropill described in embodiment 6, is only with the difference of embodiment 7:
The preparation method of above-mentioned rabeprazole enteric coated micropill, wherein:
Step S1 prepares step 14 in drug-loaded layer) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 12.5HZ |
| Atomisation pressure | 0.125mpa |
| Inlet temperature | 15℃ |
| Peristaltic pump rotating speed | 0.5pm |
Step S2 prepares step 24 in contagion gown layer) and 25) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 12.5HZ |
| Inlet temperature | 17.5℃ |
| Temperature of charge | 15℃ |
| Peristaltic pump rotating speed | 1pm |
| Atomisation pressure | 0.12mpa |
Step S3 prepares step 33 in enteric coating layer) operating parameter is as follows:
| Operation item | Parameter |
| Absorbing quantity | 14HZ |
| Inlet temperature | 19℃ |
| Temperature of charge | 16.5℃ |
| Atomisation pressure | 0.115mpa 11 --> |
| Peristaltic pump rotating speed | 0.75pm |
Embodiment 10
A kind of rabeprazole enteric-coated pellet capsule, containing the rabeprazole enteric coated micropill that method described in the arbitrary described rabeprazole enteric coated micropill of embodiment 4-6 or any one of embodiment 7-9 is obtained.
Described rabeprazole enteric-coated pellet capsule, its specification is 20mg/ grain or 10mg/ grain.
Embodiment 11
A kind of rabeprazole enteric-coated orally disintegrating tablets, containing the rabeprazole enteric coated micropill that the arbitrary described rabeprazole enteric coated micropill of embodiment 4-6 or the arbitrary described method of embodiment 7-9 obtain, also containing pharmaceutically acceptable adjuvant.
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.
The evaluation of experimental example 1 release
With the above-mentioned Rabeprazole sodium enteric-coated micro-pellet prepared according to embodiment of the present invention 4-6 and comparative example 1-2 for laboratory sample, control according to the described enteric coated preparation quality standard of Chinese Pharmacopoeia 2010 editions.The results are shown in following table:
| 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 result shows, the release of Rabeprazole sodium enteric-coated micro-pellet capsule is more than 90%, and repeatability is better.
Embodiment 2 accelerated test
With the above-mentioned Rabeprazole sodium enteric-coated micro-pellet prepared according to embodiment of the present invention 4-6 and comparative example 1-2 for laboratory sample, internal layer plastic-aluminum, overcoat aluminium foil bag, the inside adds desiccant, in 40 ± 2 DEG C, accelerated test investigates 6 months in the climatic chamber of relative humidity 75 ± 5%, investigate and the results are shown in following table:
Result shows: Rabeprazole sodium enteric-coated micro-pellet capsule prepared by embodiment of the present invention 4-6, places 6 months in accelerated test, and sample micropill color is off-white color, and content is without significant change, and impurity slightly increases but all in limits, total mixing all is less than 1.0%; Comparative example 1-2 sample micropill color is off-white color, and acid resistance, release, content slightly reduce, and impurity slightly increases, and total impurities is more than 2.0%.Sample prepared by current the present invention is still in long-term reserved sample observing test.Can prove that embodiment sample is obviously better than comparative example by accelerated test.According to expiration date of drug criterion, the effect duration of tentative invention formulation is 2 years.
Experimental example 3 long-term stable experiment
With the above-mentioned Rabeprazole sodium enteric-coated micro-pellet prepared according to embodiment of the present invention 4-6 and comparative example 1-2 for laboratory sample, internal layer plastic-aluminum, overcoat aluminium foil bag, the inside adds desiccant, in 25 ± 2 DEG C, the medium-term and long-term experiment investigation of climatic chamber of relative humidity 60 ± 5% 24 months, investigate and the results are shown in following table:
Can be found by long-time stability data, the stability of Rabeprazole sodium enteric-coated micro-pellet of the present invention will far away higher than the stable data of comparative example 1 and comparative example 2.
Experimental example 4
With the above-mentioned Rabeprazole sodium enteric-coated micro-pellet prepared according to the embodiment of the present invention 4 and comparative example 1 for laboratory sample, internal layer plastic-aluminum, overcoat aluminium foil bag, the inside adds desiccant, in 25 ± 2 DEG C, medium-term and long-term 24 months of the climatic chamber of relative humidity 60 ± 5%, carry out related substance detection to embodiment 4 and comparative example 1 sample respectively by Chinese Pharmacopoeia 2010 editions methods, Fig. 1-6 is shown in by its HPLC collection of illustrative plates.
Fig. 1-3 be respectively embodiment 4 sample 0 month, December, the HPLC collection of illustrative plates of 24 months.Fig. 4-6 be respectively comparative example 1 sample 0 month, December, the HPLC collection of illustrative plates of 24 months.
Result shows: in comparative example 1 sample in the time that placement is same, impurity content is apparently higher than the impurity content in embodiment 4 sample.Therefore the stability of embodiment 4 sample is greater than comparative example 1 sample.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. a rabeprazole enteric coated micropill, comprise celphere, drug-loaded layer, contagion gown layer, enteric coating layer from inside to outside, wherein drug-loaded layer weightening finish is 25%-30%, the weightening finish of contagion gown layer is 22%-27%, enteric coating layer weightening finish is 13%-17%, wherein, drug-loaded layer is made up of rabeprazole or RABEPRAZOLE SODIUM, sucrose, hydroxypropyl emthylcellulose, sodium sulfite and sodium lauryl sulphate; Contagion gown layer is made up of hydroxypropyl emthylcellulose, PEG-4000, titanium dioxide and sodium hydrogen phosphate; Enteric coating layer is made up of acrylic resin C type, PEG-4000 and Pulvis Talci.
2. rabeprazole enteric coated micropill according to claim 1, is characterized in that, the granularity of described raw material rabeprazole or RABEPRAZOLE SODIUM, for being less than 160 microns, is preferably 100-130 micron.
3. rabeprazole enteric coated micropill according to claim 1 and 2, is characterized in that, described celphere is starch celphere, microcrystalline Cellulose celphere or sucrose celphere; Be preferably sucrose celphere;
Preferably, the particle diameter of described celphere is 0.3-0.9mm, is more preferably 0.4-0.7mm; Further be preferably the sucrose celphere of particle diameter Ф 0.4-0.7mm.
4. the rabeprazole enteric coated micropill according to any one of claim 1-3, is characterized in that, the solvent used in described rabeprazole enteric coated micropill preparation process is ethanol or water, or both arbitrary ratio mixing.
5. the rabeprazole enteric coated micropill according to any one of claim 1-4, is characterized in that, described rabeprazole enteric coated micropill particle diameter is Ф 0.6-1.0mm.
6. rabeprazole enteric coated micropill according to claim 1, is characterized in that, described rabeprazole enteric coated micropill is to make 1000 finished products, and its prescription is as follows:
Name of an article prescription
Celphere 52g-208g;
Drug-loaded layer:
Contagion gown layer:
Enteric coating layer:
Preferably, described rabeprazole enteric coated micropill is to make 1000 finished products, and its prescription is as follows:
Name of an article prescription
Celphere 104g;
Drug-loaded layer:
Contagion gown layer:
Enteric coating layer:
7. the preparation method of rabeprazole enteric coated micropill described in any one of claim 1-6, is characterized in that, comprise the following steps:
Drug-loaded layer compositions is coated on celphere, obtained year pill core;
By described year pill core contagion gown layer composition coating, year pill core of obtained band contagion gown layer;
By year pill core enteric coating layer compositions coating of described band contagion gown layer, obtained enteric coated micropill;
Preferably, the solvent used in described rabeprazole enteric coated micropill preparation process is ethanol or water, or both arbitrary ratio mixing.
8. preparation method according to claim 7, is characterized in that, comprises the following steps:
S1 prepares drug-loaded layer:
11) sucrose, sodium sulfite, the sodium lauryl sulphate of recipe quantity is dissolved by purified water;
12) with the hydroxypropyl emthylcellulose of the swelling recipe quantity of purified water, the ethanol adding recipe quantity makes it fully dissolve;
13) by step 11) and 12) two kinds of solution mixing of making, add rabeprazole or the RABEPRAZOLE SODIUM of recipe quantity, abundant mix homogeneously;
14) celphere of recipe quantity being placed in end jet flow seed-coating machine and being preheating to 30 DEG C, by step 3) spray of the pastille dissolution homogeneity made wraps on celphere;
15) the complete rear drying of liquid medicine jet, excessively 20 mesh sieves, an obtained year pill core;
S2 prepares contagion gown layer:
21) hydroxypropyl emthylcellulose of recipe quantity is dissolved by purified water;
22) polyethylene glycol 6000, titanium dioxide, the sodium hydrogen phosphate of recipe quantity is dissolved by purified water;
23) by step 21) and 22) two kinds of solution mixings, add ethanol and be mixed, cross colloid mill, obtained contagion gown layer material;
24) pill core that carries prepared by step S1 is placed in end jet flow machine again, ventilates and is preheating to 30 DEG C;
25) by step 23) obtained contagion gown layer material spraying wraps on ball core, is finished coating material;
26) dry after coating, sieve removing fine powder, year pill core of obtained band contagion gown layer;
S3 prepares enteric coating layer:
31) with PEG-4000, the Pulvis Talci of water dissolution recipe quantity;
32) the acrylic resin C type of recipe quantity is added step 31) in obtained solution, stir, obtained enteric coating layer material;
33) pill core that carries of the band contagion gown layer prepared by step S2 is placed in end jet flow seed-coating machine again, by enteric coating layer material on end spray fluidized coating;
34) after having wrapped enteric coating layer material, dry, sieve removing fine powder, obtains complete enteric coated micropill;
Preferably, step S1 prepares step 14 in drug-loaded layer) operating parameter is as follows:
And/or step S2 prepares step 24 in contagion gown layer) and 25) operating parameter is as follows:
And/or step S3 prepares step 33 in enteric coating layer) operating parameter is as follows:
9. a rabeprazole enteric-coated pellet capsule, containing rabeprazole enteric coated micropill prepared by method described in rabeprazole enteric coated micropill described in any one of claim 1-6 or any one of claim 7-8.
10. rabeprazole or a sodium rabeprazole enteric-coated orally disintegrating tablets, containing rabeprazole enteric coated micropill prepared by method described in rabeprazole enteric coated micropill described in any one of claim 1-6 or any one of claim 7-8, and containing pharmaceutically acceptable adjuvant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510957689.1A CN105434398B (en) | 2015-12-18 | 2015-12-18 | A kind of Rabeprazole enteric-coated micro-pill and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510957689.1A CN105434398B (en) | 2015-12-18 | 2015-12-18 | A kind of Rabeprazole enteric-coated micro-pill and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105434398A true CN105434398A (en) | 2016-03-30 |
| CN105434398B CN105434398B (en) | 2018-09-18 |
Family
ID=55545335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510957689.1A Active CN105434398B (en) | 2015-12-18 | 2015-12-18 | A kind of Rabeprazole enteric-coated micro-pill and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105434398B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107550908A (en) * | 2016-06-30 | 2018-01-09 | 康普药业股份有限公司 | A kind of pharmaceutical composition for treating lower intestinal tract ulcer |
| CN110785164A (en) * | 2017-06-30 | 2020-02-11 | 乐天精密化学株式会社 | Solid preparation composition for oral administration comprising proton pump inhibitor, solid preparation for oral administration comprising the same, and method for producing the same |
| CN112168800A (en) * | 2020-09-28 | 2021-01-05 | 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 |
|---|---|---|---|---|
| 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 |
-
2015
- 2015-12-18 CN CN201510957689.1A patent/CN105434398B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107550908A (en) * | 2016-06-30 | 2018-01-09 | 康普药业股份有限公司 | A kind of pharmaceutical composition for treating lower intestinal tract ulcer |
| CN110785164A (en) * | 2017-06-30 | 2020-02-11 | 乐天精密化学株式会社 | Solid preparation composition for oral administration comprising proton pump inhibitor, solid preparation for oral administration comprising the same, and method for producing the same |
| CN112168800A (en) * | 2020-09-28 | 2021-01-05 | 南京长澳医药科技有限公司 | Rabeprazole sodium enteric-coated orally disintegrating tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105434398B (en) | 2018-09-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102552159A (en) | Rabeprazole sodium enteric-coated micro-pellet and preparation method thereof | |
| CN101816641A (en) | Omeprazole quick-release solid preparation and preparation method thereof | |
| CN102836137A (en) | Pramipexole dihydrochloride slow-release tablet with high content uniformity and preparation method thereof | |
| CN104414978A (en) | Enteric-coated micropellet containing esomeprazole magnesium | |
| CN105030725A (en) | Vonoprazan fumarate enteric-coated composition and preparation method thereof | |
| CN105434398A (en) | Rabeprazole enteric-coated micro pellet, and preparation method thereof | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| CN101596162B (en) | Doxycycline hyclate enteric-coated pellet | |
| CN102764243A (en) | Aspirin pulsed release pellets, its preparation and preparation method thereof | |
| CN105816436B (en) | A kind of Pantoprazole enteric-coated micro-pill, Pantoprazole enteric slow-release tablet agent and preparation method thereof | |
| CN102188388B (en) | Diclofenac sodium sustained-release pellet preparation and preparation method thereof | |
| CN101658507B (en) | Glyceryl guaiacolate and pseudoephedrine compound sustained release preparation | |
| CN203677566U (en) | Double-layer tablet for treating helicobacter pylori | |
| CN103006611B (en) | Omeprazole enteric bilayer slow-release tablet | |
| CN112402392A (en) | Dabigatran etexilate mesylate sustained release preparation and preparation method thereof | |
| CN102247326A (en) | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts | |
| CN101756981A (en) | Brufen loratadine pseudoephedrine release preparation and preparation method thereof | |
| CN106806353A (en) | Ailamode spansule and preparation method thereof | |
| CN107072956A (en) | A kind of Pharmaceutical composition containing dabigatran etcxilate, its preparation method, solid pharmaceutical preparation and purposes | |
| CN107648231B (en) | Dexlansoprazole medicinal preparation | |
| CN204072820U (en) | A kind of compound recipe three-layer tablet being used for the treatment of helicobacter pylori | |
| CN114432257B (en) | Bluprofen sustained-release tablet and preparation method thereof | |
| CN110711184B (en) | Tamsulosin hydrochloride sustained-release particles and preparation method thereof | |
| CN108057029A (en) | A kind of Zaltoprofen fast release micropill preparation, preparation method | |
| CN108379237A (en) | A kind of medicament microcapsule preparation for the treatment of of urinary tract infections and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Rabeprazole enteric coated pellets and preparation method thereof Effective date of registration: 20210730 Granted publication date: 20180918 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20211014 Granted publication date: 20180918 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: No.8 Kangpu Avenue, high tech Industrial Park, Hanshou County, Changde City, Hunan Province, 415900 Patentee after: KAMP PHARMACEUTICALS Co.,Ltd. Address before: 12 / F, building B, Lugu information port, 658 Lugu Avenue, high tech Zone, Changsha City, Hunan Province, 410205 Patentee before: KAMP PHARMACEUTICALS Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Rabeprazole enteric coated pellets and preparation method thereof Effective date of registration: 20211028 Granted publication date: 20180918 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021980011259 |