CN103356489A - Proton pump inhibitor enteric coated pellet and preparation and preparation method thereof - Google Patents
Proton pump inhibitor enteric coated pellet and preparation and preparation method thereof Download PDFInfo
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- CN103356489A CN103356489A CN2013103370364A CN201310337036A CN103356489A CN 103356489 A CN103356489 A CN 103356489A CN 2013103370364 A CN2013103370364 A CN 2013103370364A CN 201310337036 A CN201310337036 A CN 201310337036A CN 103356489 A CN103356489 A CN 103356489A
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- CN
- China
- Prior art keywords
- enteric
- proton pump
- pump inhibitor
- micropill
- coated
- 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.)
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Links
- 229940126409 proton pump inhibitor Drugs 0.000 title claims abstract description 117
- 239000000612 proton pump inhibitor Substances 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 82
- 239000008188 pellet Substances 0.000 title abstract description 38
- 239000010410 layer Substances 0.000 claims abstract description 179
- 239000003814 drug Substances 0.000 claims abstract description 143
- 229940079593 drug Drugs 0.000 claims abstract description 93
- 239000011241 protective layer Substances 0.000 claims abstract description 81
- 239000011248 coating agent Substances 0.000 claims abstract description 47
- 238000000576 coating method Methods 0.000 claims abstract description 47
- 239000000463 material Substances 0.000 claims abstract description 47
- 239000011230 binding agent Substances 0.000 claims abstract description 44
- 239000003381 stabilizer Substances 0.000 claims abstract description 44
- 239000003605 opacifier Substances 0.000 claims abstract description 30
- 239000004014 plasticizer Substances 0.000 claims abstract description 28
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 27
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- 239000002904 solvent Substances 0.000 claims abstract description 20
- 229920002494 Zein Polymers 0.000 claims abstract description 16
- 239000005019 zein Substances 0.000 claims abstract description 16
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 142
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- 239000012055 enteric layer Substances 0.000 claims description 69
- 238000007789 sealing Methods 0.000 claims description 61
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 60
- 229960000381 omeprazole Drugs 0.000 claims description 60
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- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 28
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- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 26
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- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 14
- 239000013530 defoamer Substances 0.000 claims description 13
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- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims description 6
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- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 claims description 5
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 claims description 5
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 24
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 238000000034 method Methods 0.000 description 18
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 15
- 239000003826 tablet Substances 0.000 description 14
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- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical group O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 8
- 239000002662 enteric coated tablet Substances 0.000 description 8
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 8
- 239000008101 lactose Substances 0.000 description 8
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Abstract
The invention relates to the field of medicines, especially to a proton pump inhibitor enteric coated pellet and a preparation and a preparation method thereof. The proton pump inhibitor enteric coated pellet is composed of a blank pellet core, a drug loaded layer, a protective layer, a separating layer, a waterproof layer and an enteric coating, wherein the waterproof layer is made from zein, the drug loaded layer is composed of a proton pump inhibitor, a first binder, a first stabilizing agent, a first antiadherent and a solubilizer or of the proton pump inhibitor, the first binder, the first stabilizing agent, a filler, a disintegrating agent and a first opacifier, the protective layer is composed of a second binder, a second stabilizing agent, a plasticizer, a second opacifier and an antifoaming agent, the separating layer is made of a coating material, and the enteric coating is composed of an enteric material, a plasticiser and a second antiadherent. The proton pump inhibitor enteric coated pellet and the preparation thereof in the invention have stable properties, reliable quality and high bioavailability and can avoid burst effects and moisture absorption.
Description
Technical field
The present invention relates to drug world, particularly a kind of proton pump inhibitor enteric coated micropill and preparation thereof, preparation method.
Background technology
Peptic ulcer mainly refers to occur in the duodenal chronic ulcer of harmonization of the stomach, also can betide around the distal esophagus, stomach intestinal anastomosis mouth and contain the Mei Keer diverticulum of ectopic gastric mucosa, the formation of these ulcer is relevant with pepsic Digestion with gastric acid, so the title peptic ulcer mainly comprises gastric ulcer and duodenal ulcer.Research in recent years finds that the formation of peptic ulcer is relevant with the existence of helicobacter pylori, show as when participating in the cintest chronic, periodically, epigastrium pain in the rhythmicity, gastric ulcer is everlasting under the xiphoid-process or is taken back, and outbreak in 1～2 hour after having meal continues to alleviate behind the stomach row in 1～2 hour; Duodenal ulcer is many to take under xiphoid-process, more than occuring on an empty stomach, alleviates after the feed.Characteristic of pain is dull pain, causalgia or hungry sample pain, often with return acid, belch, sialorrhea, feel sick, vomiting etc., the patient shows as insomnia and waits the neurosis symptom, sharp ache and the patient who has influence on feed show as the symptom of becoming thin with anemia.
Proton pump inhibitor is benzimidazoles compound, can effectively treat peptic ulcer, also can be used for the treatment of esophageal reflux disease, gastrinoma syndrome and helicobacter pylori infections.Up to now, the proton pump inhibitor that has gone on the market both at home and abroad have omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, dextral-rabeprazole, Dexlansoprazole with and acceptable salt etc. pharmaceutically, wherein, omeprazole is the earliest the benzimidazole proton pump inhibitors of going on the market in listing in 1988.
Research is found, when the water content of proton pump inhibitor micropill surpasses certain limit, as surpassing 4.0%, the stability of proton pump inhibitor can significantly descend, main manifestations is the increase of related substance, particularly accelerate experiment after 6 months, related substance increases more than 1%, the related substance such as medicine that some stability is bad such as rabeprazole even above 1.5%.Therefore, the content of control medicine moisture and/or prevent that the moisture absorption from being the important means that guarantees proton pump inhibitor drug quality and stability.Yet the coating material that existing proton pump inhibitor medicine such as omeprazole enteric-coated capsules (micro-pill type) use is hydrophilic material, and only is surrounded by 3 layers at the skin of the blank pill heart, is respectively drug-loaded layer, sealing coat and enteric layer.What wherein sealing coat used is the phosphate-buffered ion pair, and pH value is about 9 to 10, is alkalescence; Core material in the enteric coating is polyacrylic resin such as EUDRAGIT L30D-55, and the molecular surface of this material contains ester group and free carboxyl, and pH value is about 3 to 5, is acid.When the omeprazole enteric-coated micro-pill moisture absorption or when being placed in the water (dissolution medium), because omeprazole enteric-coated micro-pill does not have material water-proof material, cause hydrone to penetrate into sealing coat by enteric layer, become free ion after phosphate-buffered ion pair in the sealing coat is water-soluble, this ion combines with the carboxylic ions of polyacrylic resin, produce ion and move the effect of drawing, the enteric material cracking finally causes the omeprazole drug release.Detect in the test at dissolution, during as dissolution medium, the release in the time of 2 hours surpasses 50%, that is to say to be easy to produce " burst effect " in this dissolution medium of water with water.If omeprazole enteric-coated capsules (micro-pill type) is in the comparatively moist environment for a long time, will cause the degraded of the medicine moisture absorption, related substance increases, and has directly affected quality and the stability of medicine.Therefore provide a kind of and avoid the proton pump inhibitor enteric coated micropill of " burst effect " and moisture absorption effect and preparation thereof, preparation method to have important practical significance.
Summary of the invention
In view of this, the invention provides a kind of proton pump inhibitor enteric coated micropill and preparation thereof, preparation method.This proton pump inhibitor enteric coated micropill comprises celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer, wherein water blocking layer has used corn protein to be material water-proof material, can effectively avoid medicine moisture absorption problem and problem of in water (dissolution medium), producing " burst effect " in storage, improve quality and the stability of product; This preparation method is simple to operate, is suitable for suitability for industrialized production.
In order to realize the foregoing invention purpose, the invention provides following technical scheme:
The invention provides a kind of proton pump inhibitor enteric coated micropill, formed by celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer;
The material of water blocking layer is zein;
Drug-loaded layer is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid and solubilizing agent, perhaps is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent and the first opacifier;
Protective layer is comprised of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier and defoamer;
The material of sealing coat is coating material;
Enteric layer is comprised of enteric material, plasticiser and the second antiplastering aid.
Unstability is a common feature of proton pump inhibitor, such as all easily degradeds under the conditions such as illumination, heating, acid, oxidation, causes medicine to lose drug effect.For patients with gastric disease, after taking the common proton pump inhibitor medicine without water blocking layer, within 2 hours of gastric emptying, proton pump inhibitor discharges fully substantially, and proton pump inhibitor is very unstable under acid condition, extremely easily degraded, cause proton pump inhibitor not by before the intestinal absorption in most of destroyed and degraded of gastric, the patient occurs and take without the proton pump inhibitor capsule weak effect of water blocking layer or invalid situation.Proton pump inhibitor enteric coated micropill provided by the invention is comprised of celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer; by between the sealing coat of proton pump inhibitor enteric coated micropill and enteric layer or the enteric layer outside be surrounded by one deck water blocking layer; it is very slow and steady to have guaranteed that the proton pump inhibitor enteric coated micropill discharges in water; avoided " burst effect "; for patients with gastric disease; have the high characteristics of bioavailability; can play good therapeutical effect; and in storage process, avoided moisture absorption effect, guaranteed the quality of medicine.
As preferably, the quality percentage composition that zein accounts for the proton pump inhibitor enteric coated micropill is 0.1%～2%.
As preferably, the mass ratio of celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer is (700～900): (268～282): (194～213): (60～75): (3.0～45.2): (1335～1545).
Preferably, the mass ratio of celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer is (375～800): (275～827): (194～218): (63～71): (6.6～28.8): (1369～1536).
In embodiment more provided by the invention, enteric layer is at the skin of water blocking layer, and the structure of proton pump inhibitor enteric coated micropill is celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer from inside to outside.
In other embodiment provided by the invention, water blocking layer is at the skin of enteric layer, and the structure of proton pump inhibitor enteric coated micropill is celphere, drug-loaded layer, protective layer, sealing coat, enteric layer and water blocking layer from inside to outside.
In embodiment more provided by the invention, proton pump inhibitor is benzimidazoles compound.
In embodiment more provided by the invention, proton pump inhibitor comprises omeprazole and pharmaceutically acceptable salt, esomeprazole and pharmaceutically acceptable salt thereof, pantoprazole and pharmaceutically acceptable salt thereof, rabeprazole and pharmaceutically acceptable salt thereof, dextral-rabeprazole and pharmaceutically acceptable salt thereof, lansoprazole and pharmaceutically acceptable salt thereof, Dexlansoprazole and pharmaceutically acceptable salt thereof.
In embodiment more provided by the invention, pharmaceutically acceptable salt is sodium salt or magnesium salt.
In embodiment more provided by the invention, celphere is sucrose-spherex.
As preferably, the particle diameter of sucrose-spherex is 0.6～0.8mm.
In embodiment more provided by the invention, drug-loaded layer is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid and solubilizing agent.
As preferably, in drug-loaded layer, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid and solubilizing agent is (162～179): (55～61): (23～26): (13～14): (8～9).
Preferably, in drug-loaded layer, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid and solubilizing agent is 170:58.4:24.4:13.5:8.5.
In other embodiment provided by the invention, drug-loaded layer is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent and the first opacifier.
In embodiment more provided by the invention, in drug-loaded layer, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent and the first opacifier is (285～315): (8.5～10): (100～110): (257～284): (89～99): (46～51).
As preferably, in drug-loaded layer, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent and the first opacifier is 300:9:105:270:94:49.
As preferably, the first binding agent in the drug-loaded layer is hypromellose or hydroxypropyl cellulose.
As preferably, the first stabilizing agent in the drug-loaded layer is the mixture of sodium hydrogen phosphate and sodium phosphate, perhaps is magnesium carbonate.
In embodiment more provided by the invention, the mass ratio of sodium hydrogen phosphate and sodium phosphate is 1:1.
As preferably, the first antiplastering aid in the drug-loaded layer is silicon dioxide.
As preferably, the solubilizing agent in the drug-loaded layer is polyoxyethylene sorbitan monoleate.
As preferably, the filler in the drug-loaded layer is sucrose.
In embodiment more provided by the invention, sucrose is selected purification sucrose.
As preferably, the disintegrating agent in the drug-loaded layer is hydroxypropyl cellulose.
In embodiment more provided by the invention, hydroxypropyl cellulose is selected low-substituted hydroxypropyl cellulose.
As preferably, the first opacifier in the drug-loaded layer is titanium dioxide.
In embodiment more provided by the invention, protective layer is comprised of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier and defoamer.
As preferably, in protective layer, the mass ratio of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier and defoamer is (120～150): (24～32): (11～15): (23～30): (0.8～1.2).
Preferably, in protective layer, the mass ratio of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier and defoamer is (129～145): (27～30): (13～14): (25～28): (0.9～1.1).
In embodiment more provided by the invention, the second binding agent in the protective layer can be identical with the first binding agent in the drug-loaded layer, also can be different.
As preferably, the second binding agent in the protective layer is hypromellose.
In embodiment more provided by the invention, the second stabilizing agent in the protective layer can be identical with the first stabilizing agent in the drug-loaded layer, also can be different.
As preferably, the second stabilizing agent in the protective layer is the mixture of sodium hydrogen phosphate and sodium phosphate.
In embodiment more provided by the invention, the plasticizer in the protective layer is PEG6000.
In embodiment more provided by the invention, the second opacifier in the protective layer is titanium dioxide, and is identical with the opacifier that uses in the drug-loaded layer.
In embodiment more provided by the invention, the defoamer in the protective layer is simethicone.
In embodiment more provided by the invention, the material of sealing coat is coating material.
As preferably, coating material is Opadry.
In embodiment more provided by the invention, Opadry is selected Opadry YS-7027.
In embodiment more provided by the invention, enteric layer is comprised of enteric material, plasticiser and the second antiplastering aid.
As preferably, in enteric layer, the mass ratio of enteric material, plasticiser and the second antiplastering aid is (1200～1400): (35～45): (90～110).
Preferably, in enteric layer, the mass ratio of enteric material, plasticiser and the second antiplastering aid is (1239～1390): (37～42): (93～104).
As preferably, the enteric material in the enteric layer is methacrylic resin.
In embodiment more provided by the invention, methacrylic resin is selected EUDRAGIT L30D-55.
As preferably, the plasticiser in the enteric layer is triethyl citrate.
In embodiment more provided by the invention, the second antiplastering aid in the enteric layer can be identical with the first antiplastering aid in the drug-loaded layer, also can be different.
As preferably, the second antiplastering aid in the enteric layer is Pulvis Talci.
The present invention also provides a kind of preparation method of proton pump inhibitor enteric coated micropill, comprises the steps:
Obtain drug-loaded layer solution;
Get the second binding agent, the second stabilizing agent, plasticizer, the second opacifier, defoamer, water and ethanol water and mix, obtain protective layer solution;
Get coating material and mix with ethanol water, obtain sealing coat solution;
Get zein and mix with ethanol water, obtain water blocking layer solution;
Get enteric material, plasticiser, the second antiplastering aid and water and mix, obtain enteric layer solution;
Get successively coated celphere of drug-loaded layer solution, protective layer solution and sealing coat solution, obtain the medicine carrying micropill, get the coated medicine carrying micropill of water blocking layer solution and enteric layer solution, drying namely gets the proton pump inhibitor enteric coated micropill;
Drug-loaded layer solution is the mixture of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid, solubilizing agent and water, perhaps is the mixture of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent, the first opacifier and water.
As preferably, the quality percentage composition that zein accounts for the proton pump inhibitor enteric coated micropill is 0.1%～2%.
As preferably, the mass ratio of celphere, drug-loaded layer solution, protective layer solution, sealing coat solution, water blocking layer solution and enteric layer solution is (700～900): (268～282): (194～213): (60～75): (3.0～45.2): (1335～1545).
Preferably, the mass ratio of celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer is (375～800): (275～827): (194～218): (63～71): (6.6～28.8): (1369～1536).
In embodiment more provided by the invention, proton pump inhibitor is benzimidazoles compound.
In embodiment more provided by the invention, proton pump inhibitor comprises omeprazole and pharmaceutically acceptable salt, esomeprazole and pharmaceutically acceptable salt thereof, pantoprazole and pharmaceutically acceptable salt thereof, rabeprazole and pharmaceutically acceptable salt thereof, dextral-rabeprazole and pharmaceutically acceptable salt thereof, lansoprazole and pharmaceutically acceptable salt thereof, Dexlansoprazole and pharmaceutically acceptable salt thereof.
In embodiment more provided by the invention, pharmaceutically acceptable salt is sodium salt or magnesium salt.
As preferably, the coated temperature of water blocking layer solution is 35 ℃～50 ℃.
As preferably, when preparation water blocking layer solution, the mass percent concentration of used ethanol water is not more than 95%.
In embodiment more provided by the invention, when coated water blocking layer solution, coated atomization air pressure is 0.05～0.10MPa.
In embodiment more provided by the invention, enteric layer is at the skin of water blocking layer, and the structure of proton pump inhibitor enteric coated micropill is celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer from inside to outside.
In other embodiment provided by the invention, water blocking layer is at the skin of enteric layer, and the structure of proton pump inhibitor enteric coated micropill is celphere, drug-loaded layer, protective layer, sealing coat, enteric layer and water blocking layer from inside to outside.
In embodiment more provided by the invention, celphere is sucrose-spherex.
As preferably, the particle diameter of sucrose-spherex is 0.6～0.8mm.
In embodiment more provided by the invention, drug-loaded layer solution comprises proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid, solubilizing agent and water.Wherein, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid, solubilizing agent and water is (162～179): (55～61): (23～26): (13～14): (8～9): (923～1021).
Preferably, in drug-loaded layer, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid, solubilizing agent and water is 170:58.4:24.4:13.5:8.5:972.
In other embodiment provided by the invention, drug-loaded layer solution comprises proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent, the first opacifier and water.Wherein, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent, the first opacifier and water is (285～315): (8.5～10): (100～110): (257～284): (89～99): (46～51): (446～492).
As preferably, in drug-loaded layer solution, the mass ratio of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent, the first opacifier and water is 300:9:105:270:94:49:469.
As preferably, the first binding agent in the drug-loaded layer solution is hypromellose or hydroxypropyl cellulose.
As preferably, the first stabilizing agent in the drug-loaded layer solution is the mixture of sodium hydrogen phosphate and sodium phosphate, perhaps is magnesium carbonate.
In embodiment more provided by the invention, the mass ratio of sodium hydrogen phosphate and sodium phosphate is 1:1.
As preferably, the first antiplastering aid in the drug-loaded layer solution is silicon dioxide.
As preferably, the solubilizing agent in the drug-loaded layer solution is polyoxyethylene sorbitan monoleate.
As preferably, the filler in the drug-loaded layer solution is sucrose.
In embodiment more provided by the invention, sucrose is selected purification sucrose.
As preferably, the disintegrating agent in the drug-loaded layer solution is hydroxypropyl cellulose.
In embodiment more provided by the invention, hydroxypropyl cellulose is selected low-substituted hydroxypropyl cellulose.
As preferably, the first opacifier in the drug-loaded layer solution is titanium dioxide.
In embodiment more provided by the invention, protective layer solution is comprised of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier, defoamer, water and ethanol water.Wherein, the mass ratio of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier, defoamer, water and ethanol water is (120～150): (24～32): (11～15): (23～30): (0.8～1.2): (1800～2150).
As preferably; in protective layer solution, the mass ratio of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier, defoamer, water and ethanol water is (129～145): (27～30): (13～14): (25～28): (0.9～1.1): (1855～2093).
In embodiment more provided by the invention, the second binding agent in the protective layer solution can be identical with the first binding agent in the drug-loaded layer solution, also can be different.
As preferably, the second binding agent in the protective layer solution is hypromellose.
In embodiment more provided by the invention, the second stabilizing agent in the protective layer solution can be identical with the first stabilizing agent in the drug-loaded layer solution, also can be different.
As preferably, the second stabilizing agent in the protective layer solution is the mixture of sodium hydrogen phosphate and sodium phosphate.
In embodiment more provided by the invention, the plasticizer in the protective layer solution is PEG6000.
In embodiment more provided by the invention, the second opacifier in the protective layer solution is titanium dioxide, and is identical with the opacifier that uses in the drug-loaded layer solution.
In embodiment more provided by the invention, the defoamer in the protective layer solution is simethicone.
As preferably, the coating material in the sealing coat solution is Opadry.
In embodiment more provided by the invention, sealing coat solution is the mixture of coating material and ethanol water, and as preferably, in sealing coat solution, the mass ratio of coating material and ethanol water is (60～75): (800～950).
Preferably, in sealing coat solution, the mass ratio of coating material and ethanol water is (63～71): (838～945).
In embodiment more provided by the invention, Opadry is selected Opadry YS-7027.
In embodiment more provided by the invention, water blocking layer solution is the mixture of material water-proof material and ethanol water.In water blocking layer solution, the mass ratio of material water-proof material and ethanol water is (3～45): (180～500).
As preferably, in water blocking layer solution, the mass ratio of material water-proof material and ethanol water is (6.6～28.8): (193～400).
In embodiment more provided by the invention, enteric layer solution is comprised of enteric material, plasticiser, the second antiplastering aid and water.Wherein, the mass ratio of enteric material, plasticiser, the second antiplastering aid and water is (1200～1400): (35～45): (90～110): (600～700).
As preferably, in enteric layer solution, the mass ratio of enteric material, plasticiser, the second antiplastering aid and water is (1239～1390): (37～42): (93～104): (606～680).
As preferably, the enteric material in the enteric layer solution is methacrylic resin.
In embodiment more provided by the invention, methacrylic resin is selected EUDRAGIT L30D-55.
As preferably, the plasticiser in the enteric layer solution is triethyl citrate.
In embodiment more provided by the invention, the second antiplastering aid in the enteric layer solution can be identical with the first antiplastering aid in the drug-loaded layer solution, also can be different.
As preferably, the second antiplastering aid in the enteric layer solution is Pulvis Talci.
The present invention also provides the proton pump inhibitor that is made by preparation method provided by the invention enteric coated micropill.
The present invention also provides a kind of pharmaceutical preparation, comprises that proton pump inhibitor enteric coated micropill provided by the invention and pharmaceutically acceptable adjuvant form.In the present invention, the mass ratio of proton pump inhibitor enteric coated micropill and pharmaceutically acceptable adjuvant is not done restriction at this in the pharmaceutical preparation, and those skilled in the art think that feasible supplementary material mass ratio is all within protection scope of the present invention.
In embodiment more provided by the invention, the dosage form of pharmaceutical preparation is tablet or capsule.
In embodiment more provided by the invention, pharmaceutically acceptable adjuvant is selected from filler, disintegrating agent, fluidizer or lubricant.
In embodiment more provided by the invention; filler is the mixture of lactose and microcrystalline Cellulose; but those skilled in the art think feasible filler all within protection scope of the present invention, and the filler kind is not limited to this, and the present invention does not do restriction at this.
As preferably, lactose is selected from Tablettose80 or Cellactose80.
As preferably, microcrystalline Cellulose is selected from Ceolus PH-102, Ceolus PH-301 or Ceolus PH302.
In embodiment more provided by the invention; disintegrating agent is selected from cross-linked carboxymethyl cellulose sodium or cross-linked pvp; but those skilled in the art think feasible disintegrating agent all within protection scope of the present invention, and the filler kind is not limited to this, and the present invention does not do restriction at this.
In embodiment more provided by the invention, fluidizer is micropowder silica gel, but those skilled in the art think feasible fluidizer all within protection scope of the present invention, and the fluidizer kind is not limited to this, and the present invention does not do restriction at this.
As preferably, micropowder silica gel is the gas phase micropowder silica gel.
In embodiment more provided by the invention; lubricant is selected from Pulvis Talci, magnesium stearate or sodium stearyl fumarate; but those skilled in the art think feasible lubricant all within protection scope of the present invention, and the lubricant kind is not limited to this, and the present invention does not do restriction at this.
As preferably, lubricant is magnesium stearate.
In embodiment more provided by the invention, capsule is comprised of proton pump inhibitor enteric coated micropill and pharmaceutically acceptable adjuvant.
In embodiment more provided by the invention; proton pump inhibitor enteric coated micropill in the capsule and the mass ratio of pharmaceutically acceptable adjuvant are 99.8:0.2; but those skilled in the art think that feasible supplementary material mass ratio is all within protection scope of the present invention; the mass ratio of proton pump inhibitor enteric coated micropill and pharmaceutically acceptable adjuvant is not limited to this, and the present invention does not do restriction at this.
In embodiment more provided by the invention, acceptable adjuvant is comprised of fluidizer and lubricant on the capsule Chinese materia medica.
In embodiment more provided by the invention; the mass ratio of fluidizer and lubricant is 1:1; but those skilled in the art think that the mass ratio of feasible fluidizer and lubricant is all within protection scope of the present invention; the mass ratio of fluidizer and lubricant is not limited to this, and the present invention does not do restriction at this.
In embodiment more provided by the invention, tablet is comprised of proton pump inhibitor enteric coated micropill and pharmaceutically acceptable adjuvant.
In embodiment more provided by the invention; as preferably; proton pump inhibitor enteric coated micropill in the tablet and the mass ratio of pharmaceutically acceptable adjuvant are (1656.8～2261.5): (716.1～3131.4); but those skilled in the art think that feasible supplementary material mass ratio is all within protection scope of the present invention; the mass ratio of proton pump inhibitor enteric coated micropill and pharmaceutically acceptable adjuvant is not limited to this, and the present invention does not do restriction at this.
In embodiment more provided by the invention, acceptable adjuvant is comprised of filler, disintegrating agent, fluidizer and lubricant on the tablet Chinese materia medica.
In embodiment more provided by the invention; the mass ratio of filler, disintegrating agent, fluidizer and lubricant is (660.3～2799.9): (50.8～400.0): (2.5～80.0): (2.5～32.2); but those skilled in the art think that mass ratio between the feasible adjuvant is all within protection scope of the present invention; the mass ratio of filler, disintegrating agent, fluidizer and lubricant is not limited to this, and the present invention does not do restriction at this.
The invention provides a kind of proton pump inhibitor enteric coated micropill and preparation thereof, preparation method.This proton pump inhibitor enteric coated micropill is comprised of celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer; The material of water blocking layer is zein; Drug-loaded layer is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid and solubilizing agent, perhaps is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent and the first opacifier; Protective layer is comprised of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier and defoamer; The material of sealing coat is coating material; Enteric layer is comprised of enteric material, plasticiser and the second antiplastering aid.Test by vitro release, the result shows that proton pump inhibitor enteric coated micropill provided by the invention and the dissolution of preparation in strong acid solution and water thereof are very low, and dissolution is high in the phosphate buffer of pH6.0～6.8, and the dissolution of proton pump inhibitor enteric coated capsule in water without water blocking layer that matched group provides is very high, as seen proton pump inhibitor enteric coated micropill provided by the invention and preparation thereof can not dissolve under one's belt, in small intestinal, can dissolve rapidly, bioavailability is high, can avoid " burst effect " and moisture absorption effect; By Detection of Stability test, the result shows that this proton pump inhibitor enteric coated micropill and preparation nature thereof are stable, reliable in quality; By wettability test, the result shows that this proton pump inhibitor enteric coated micropill and preparation hygroscopicity thereof significantly reduce, and show in storage process and can avoid moisture absorption effect.This shows that proton pump inhibitor enteric coated micropill provided by the invention and preparation nature thereof are stable, reliable in quality, bioavailability is high, can avoid " burst effect " and moisture absorption effect.
Description of drawings
Fig. 1 shows the structural representation of the omeprazole enteric-coated micro-pill that embodiment 1 provides; Wherein, 1 shows celphere, and 2 show drug-loaded layer, and 3 show protective layer, and 4 show sealing coat, and 5 show water blocking layer, and 6 show enteric layer;
Fig. 2 shows the structural representation of the Lansoprazole enteric pellet that embodiment 2 provides; Wherein, 1 shows celphere, and 2 show drug-loaded layer, and 3 show protective layer, and 4 show sealing coat, and 6 show enteric layer, and 5 show water blocking layer.
The specific embodiment
The invention discloses a kind of proton pump inhibitor enteric coated micropill and preparation thereof, preparation method, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described within not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
Raw materials used medicine or adjuvant all can be buied by market in proton pump inhibitor enteric coated micropill provided by the invention and preparation thereof, the preparation method; Wherein sucrose-spherex is available from Gaocheng Biologic Nutrition Technology Co Ltd, Hangzhou; The fluidized bed granulation seed-coating machine is available from Chongqing Seiko pharmaceutical machine Co., Ltd, and model is DPL-1.
Below in conjunction with embodiment, further set forth the present invention:
The preparation of embodiment 1 omeprazole enteric-coated micro-pill
Get in the purified water of 500g25 ℃ of 58.4g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 12.2g sodium hydrogen phosphate and 12.2g sodium phosphate respectively with the purified water dissolving of 50g, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring the Tween 80 of 8.5g and the silicon dioxide of 13.5g; Add the omeprazole of 170.0g, stir, obtain suspension.Above-mentioned suspension is crossed 80 mesh sieves, and rinse well with the 100g purified water, add again the 272.0g purified water, stir, obtain drug-loaded layer solution.(particle diameter 0.6～0.8mm) is inserted in the fluidized bed granulation seed-coating machine with 800g sucrose-spherex, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations (being coated with) of adding medicine to of hydrojet pump speed are until drug-loaded layer solution has sprayed.Set 40 ℃ of temperature of charge, with the micropill fluidized drying of coated upper drug-loaded layer solution 30 minutes, dry by the fire to moisture less than 2.5%, collection cut size is at 16～30 purpose micropills, with the encapsulation of PE bag, weighing obtains being coated with the micropill 1065.8g of drug-loaded layer.
Get in the purified water of 1000g50 ℃ of 128.7g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 13.3g sodium hydrogen phosphate and 13.3g sodium phosphate respectively with 18.5g50 ℃ purified water dissolving, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring 12.7g PEG6000,24.6g titanium dioxide and 1.0g simethicone, stir 1h, cross 80 mesh sieves, with 817.5g95% alcoholic solution wash residual, continue stirring until evenly, obtain protective layer solution, gross weight is 2048.1g.The micropill that is coated with drug-loaded layer of above-mentioned 1065.8g is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1256.9g of protective layer.
Get 62.8g Opadry YS-7027 and join in the ethanol water of 837.9g95%, stir at least 2 hours to disperseing fully, cross 80 mesh sieves, obtain sealing coat solution.The micropill that above-mentioned 1256.9g is coated with protective layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer solution, dry by the fire to moisture less than 2.5%.Collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1319.7g of sealing coat.
Get in the ethanol water that the 6.6g zein joins 193.4g75%, be stirred to fully dissolving, obtain water blocking layer solution.The micropill that above-mentioned 1319.7g is coated with sealing coat is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until water blocking layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of water blocking layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1326.3g of sealing coat.
1239.1g methacrylic resin EUDRAGIT L30D-55 and 37.3g triethyl citrate are dissolved in during 606.3g purifies waste water, add again the 92.8g Pulvis Talci and obtain enteric layer solution.The micropill that above-mentioned 1326.3g is coated with water blocking layer is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until enteric layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of enteric layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain omeprazole enteric-coated micro-pill 1975.1g, its structural representation is seen Fig. 1.In preparation process, the inventory of raw material and adjuvant is as shown in table 1.
Table 1 is the supplementary material inventory in preparation omeprazole enteric-coated micro-pill process
Annotate: solvent is removed in preparation process.
The preparation of embodiment 2 Lansoprazole enteric pellets
300.0g lansoprazole, 105.0g magnesium carbonate, 195.0g are purified sucrose and 75.0g LH-21 evenly be mixed to get dusting for the active component layer; 75.0g is purified sucrose, 48.8g titanium dioxide and 18.8g LH-21 evenly be mixed to get dusting for the intermediate layer; Getting the 9.4g hydroxypropyl cellulose is dissolved in the 469.0g purified water and is mixed with hydroxypropyl cellulose solution; 375.0g sucrose-spherex is inserted in the fluidized bed granulation seed-coating machine, in the spraying hydroxypropyl cellulose solution, with sucrose-spherex with above-mentioned dusting for the active component layer be used for the dusting coating in intermediate layer, the micropill that is coated with drug-loaded layer solution that obtains; Set 40 ℃ of temperature of charge, with the micropill fluidized drying of coated upper drug-loaded layer solution 30 minutes, dry by the fire to moisture less than 2.5%, collection cut size with the encapsulation of PE bag, obtains being coated with the micropill 1202.0g of drug-loaded layer at 16～30 purpose micropills.
Get in the purified water of 1000g50 ℃ of 145.1g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 15.0g sodium hydrogen phosphate and 15.0g sodium phosphate and dissolve with 84.75g50 ℃ purified water, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring 14.3g PEG6000,27.7g titanium dioxide and 1.0g simethicone, continue to stir, cross 80 mesh sieves before using, with 923.0g95% alcoholic solution wash residual, continue stirring until evenly, obtain protective layer solution.The micropill that above-mentioned 1202.0g is coated with drug-loaded layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1417.5g of protective layer.
Get in the ethanol water of 70.8g Opadry YS-7027 adding 945.0g95%, stir 2 hours to disperseing fully, continue to stir, cross 80 mesh sieves before the use, obtain sealing coat solution.The micropill that above-mentioned 1488.3g is coated with protective layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until sealing coat solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of sealing coat, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1488.3g of sealing coat.
1390.4g methacrylic resin EUDRAGIT L30D-55 and 41.9g triethyl citrate are dissolved in during 680.4g purifies waste water, add the 104.1g Pulvis Talci, obtain enteric layer solution.The micropill that above-mentioned 1488.3g is coated with sealing coat is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until enteric layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of enteric layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 2216.3g of enteric layer.
Get in the ethanol water of 45.2g zein adding 500g90%, be stirred to fully dissolving, obtain water blocking layer solution.The micropill that above-mentioned 2216.3g is coated with enteric layer is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until water blocking layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of water blocking layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain Lansoprazole enteric pellet 2261.5g, its structural representation is seen Fig. 2.In preparation process, the inventory of raw material and adjuvant is as shown in table 2.
Table 2 is the supplementary material inventory in preparation Lansoprazole enteric pellet process
Annotate: solvent is removed in preparation process.
The preparation of embodiment 3 esomeprazole enteric capsules
Get in the purified water of 500.0g25 ℃ of 61.0g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 11.5g sodium hydrogen phosphate and 11.5g sodium phosphate respectively with the purified water dissolving of 50.0g, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring the Tween 80 of 8.0g and the silicon dioxide of 14.0g; Add the esomeprazole magnesium (being equivalent to the 145.7g esomeprazole) of 162.0g, stir, obtain suspension.Above-mentioned suspension is crossed 80 mesh sieves, and rinse well with the 100.0g purified water, add again the 223.0g purified water, stir, obtain drug-loaded layer solution.(particle diameter 0.6～0.8mm) is inserted in the fluidized bed granulation seed-coating machine with 700.0g sucrose-spherex, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations (being coated with) of adding medicine to of hydrojet pump speed are until drug-loaded layer solution has sprayed.Set the micropill fluidized drying 30 minutes that 40 ℃ of temperature of charge will be coated with drug-loaded layer solution, dry by the fire to moisture less than 2.5%, collection cut size is at 16～30 purpose micropills, with the encapsulation of PE bag, weighing obtains being coated with the micropill 958.0g of drug-loaded layer.
Get in the purified water of 900.0g50 ℃ of 120.0g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 16.0g sodium hydrogen phosphate and 16.0g sodium phosphate respectively with 50.0g50 ℃ purified water dissolving, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring 11.0g PEG6000,30.0g titanium dioxide and 0.8g simethicone, stir 1h, cross 80 mesh sieves, with 800.0g95% alcoholic solution wash residual, continue stirring until evenly, obtain protective layer solution.The above-mentioned micropill that is coated with drug-loaded layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1151.8g of protective layer.
Get 60.0g Opadry YS-7027 and join in the ethanol water of 950.0g95%, stir at least 2 hours to disperseing fully, cross 80 mesh sieves, obtain sealing coat solution.The above-mentioned micropill that is coated with protective layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer solution, dry by the fire to moisture less than 2.5%.Collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1211.8g of sealing coat.
Get in the ethanol water that the 10.0g zein joins 200.0g75%, be stirred to fully dissolving, obtain water blocking layer solution.The above-mentioned micropill that is coated with sealing coat is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until water blocking layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of water blocking layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1221.8g of sealing coat.
1200.0g methacrylic resin EUDRAGIT L30D-55 and 45.0g triethyl citrate are dissolved in during 600g purifies waste water, add again the 90.0g Pulvis Talci and obtain enteric layer solution.The above-mentioned micropill that is coated with water blocking layer is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until enteric layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of enteric layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain esomeprazole enteric capsules 1656.8g.In preparation process, the inventory of raw material and adjuvant is as shown in table 3.
Table 3 is the supplementary material inventory in preparation esomeprazole enteric capsules process
Annotate: solvent is removed in preparation process.
The preparation of embodiment 4 enteric coated mini-pill of pantoprazole sodium
Get in the purified water of 600.0g25 ℃ of 55.0g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 13.0g sodium hydrogen phosphate and 13.0g sodium phosphate respectively with the purified water dissolving of 50.0g, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring the Tween 80 of 9.0g and the silicon dioxide of 13.0g; Add the Pantoprazole Sodium (being equivalent to the 169.3g pantoprazole) of 179.0g, stir, obtain suspension.Above-mentioned suspension is crossed 80 mesh sieves, and rinse well with the 100.0g purified water, add again the 221.0g purified water, stir, obtain drug-loaded layer solution.(particle diameter 0.6～0.8mm) is inserted in the fluidized bed granulation seed-coating machine with 900.0g sucrose-spherex, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations (being coated with) of adding medicine to of hydrojet pump speed are until drug-loaded layer solution has sprayed.Set the micropill fluidized drying 30 minutes that 40 ℃ of temperature of charge will be coated with drug-loaded layer solution, dry by the fire to moisture less than 2.5%, collection cut size is at 16～30 purpose micropills, with the encapsulation of PE bag, weighing obtains being coated with the micropill 1182.0g of drug-loaded layer.
Get in the purified water of 1000.0g50 ℃ of 150.0g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 12.0g sodium hydrogen phosphate and 12.0g sodium phosphate respectively with 100.0g50 ℃ purified water dissolving, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring 15.0g PEG6000,23.0g titanium dioxide and 1.2g simethicone, stir 1h, cross 80 mesh sieves, with 950.0g95% alcoholic solution wash residual, continue stirring until evenly, obtain protective layer solution, gross weight is 2048.1g.The above-mentioned micropill that is coated with drug-loaded layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1395.2g of protective layer.
Get 75.0g Opadry YS-7027 and join in the ethanol water of 800.0g95%, stir at least 2 hours to disperseing fully, cross 80 mesh sieves, obtain sealing coat solution.The above-mentioned micropill that is coated with protective layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer solution, dry by the fire to moisture less than 2.5%.Collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1470.2g of sealing coat.
Get in the ethanol water that the 3.0g zein joins 180.0g75%, be stirred to fully dissolving, obtain water blocking layer solution.The above-mentioned micropill that is coated with sealing coat is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until water blocking layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of water blocking layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1473.2g of sealing coat.
1400.0g methacrylic resin EUDRAGIT L30D-55 and 35.0g triethyl citrate are dissolved in during 700.0g purifies waste water, add again the 110.0g Pulvis Talci and obtain enteric layer solution.The above-mentioned micropill that is coated with water blocking layer is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until enteric layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of enteric layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain enteric coated mini-pill of pantoprazole sodium 1823.2g.In preparation process, the inventory of raw material and adjuvant is as shown in table 4.
Table 4 is the supplementary material inventory in preparation enteric coated mini-pill of pantoprazole sodium process
Annotate: solvent is removed in preparation process.
The preparation of embodiment 5 Rabeprazole sodium enteric-coated micro-pellets
315.0g RABEPRAZOLE SODIUM (being equivalent to the 296.8g rabeprazole), 100.0g magnesium carbonate, 200.0g purification sucrose, 73.0g LH-21 evenly are mixed to get the dusting for the active component layer; 84.0g is purified sucrose, 51.0g titanium dioxide and 16.0g LH-21 evenly be mixed to get dusting for the intermediate layer; Getting the 8.5g hydroxypropyl cellulose is dissolved in the 446.0g purified water and is mixed with hydroxypropyl cellulose solution; 300.0g sucrose-spherex is inserted in the fluidized bed granulation seed-coating machine, in the spraying hydroxypropyl cellulose solution, with sucrose-spherex with above-mentioned dusting for the active component layer be used for the dusting coating in intermediate layer, the micropill that is coated with drug-loaded layer solution that obtains; Set 40 ℃ of temperature of charge, with the micropill fluidized drying of coated upper drug-loaded layer solution 30 minutes, dry by the fire to moisture less than 2.5%, collection cut size with the encapsulation of PE bag, obtains being coated with the micropill 1147.5g of drug-loaded layer at 16～30 purpose micropills.
Get in the purified water of 1000.0g50 ℃ of 130.0g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 14.0g sodium hydrogen phosphate and 14.0g sodium phosphate respectively with 40.0g50 ℃ purified water dissolving, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring 13.0g PEG6000,25.0g titanium dioxide and 1.1g simethicone, continue to stir, cross 80 mesh sieves before using, with 850.0g95% alcoholic solution wash residual, continue stirring until evenly, obtain protective layer solution.The above-mentioned micropill that is coated with drug-loaded layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1344.6g of protective layer.
Get in the ethanol water of 65.0g Opadry YS-7027 adding 900.0g95%, stir 2 hours to disperseing fully, continue to stir, cross 80 mesh sieves before the use, obtain sealing coat solution.The above-mentioned micropill that is coated with protective layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until sealing coat solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of sealing coat, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1409.6g of sealing coat.
1300.0g methacrylic resin EUDRAGIT L30D-55 and 40.0g triethyl citrate are dissolved in during 650.0g purifies waste water, add the 100.0g Pulvis Talci, obtain enteric layer solution.The above-mentioned micropill that is coated with sealing coat is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until enteric layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of enteric layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1734.6g of enteric layer.
Get in the ethanol water of 28.8g zein adding 500.0g90%, be stirred to fully dissolving, obtain water blocking layer solution.The above-mentioned micropill that is coated with enteric layer is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until water blocking layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of water blocking layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain Rabeprazole sodium enteric-coated micro-pellet 1763.4g.In preparation process, the inventory of raw material and adjuvant is as shown in table 5.
Table 5 is the supplementary material inventory in preparation Rabeprazole sodium enteric-coated micro-pellet process
Annotate: solvent is removed in preparation process.
The preparation of embodiment 6 dextral-rabeprazole sodium enteric-coated pellets
285.0g dextral-rabeprazole sodium (being equivalent to the 268.6g dextral-rabeprazole), 110.0g magnesium carbonate, 190.0g purification sucrose, 80.0g LH-21 evenly are mixed to get the dusting for the active component layer; 67.0g is purified sucrose, 46.0g titanium dioxide and 19.0g LH-21 evenly be mixed to get dusting for the intermediate layer; Getting the 10.0g hydroxypropyl cellulose is dissolved in the 492.0g purified water and is mixed with hydroxypropyl cellulose solution; 400.0g sucrose-spherex is inserted in the fluidized bed granulation seed-coating machine, in the spraying hydroxypropyl cellulose solution, with sucrose-spherex with above-mentioned dusting for the active component layer be used for the dusting coating in intermediate layer, the micropill that is coated with drug-loaded layer solution that obtains; Set 40 ℃ of temperature of charge, with the micropill fluidized drying of coated upper drug-loaded layer solution 30 minutes, dry by the fire to moisture less than 2.5%, collection cut size with the encapsulation of PE bag, obtains being coated with the micropill 1207.0g of drug-loaded layer at 16～30 purpose micropills.
Get in the purified water of 1000.0g50 ℃ of 125.0g HPMC adding, it is stand-by that stirring is swelling to clarification; Take by weighing 13.0g sodium hydrogen phosphate and 13.0g sodium phosphate respectively with 50.0g50 ℃ purified water dissolving, when stirring HPMC solution, add successively above-mentioned disodium phosphate soln and sodium radio-phosphate,P-32 solution; Add while stirring 14.0g PEG6000,26.0g titanium dioxide and 0.9g simethicone, continue to stir, cross 80 mesh sieves before using, with 900.0g95% alcoholic solution wash residual, continue stirring until evenly, obtain protective layer solution.The above-mentioned micropill that is coated with drug-loaded layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until protective layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of protective layer, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1398.9g of protective layer.
Get in the ethanol water of 68.0g Opadry YS-7027 adding 850.0g95%, stir 2 hours to disperseing fully, continue to stir, cross 80 mesh sieves before the use, obtain sealing coat solution.The above-mentioned micropill that is coated with protective layer is inserted in the fluidized bed granulation seed-coating machine; blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until sealing coat solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of sealing coat, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1466.9g of sealing coat.
1250.0g methacrylic resin EUDRAGIT L30D-55 and 42.0g triethyl citrate are dissolved in during 630.0g purifies waste water, add the 95.0g Pulvis Talci, obtain enteric layer solution.The above-mentioned micropill that is coated with sealing coat is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until enteric layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of enteric layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain being coated with the micropill 1916.4g of enteric layer.
Get in the ethanol water of 43.5g zein adding 400.0g90%, be stirred to fully dissolving, obtain water blocking layer solution.The above-mentioned micropill that is coated with enteric layer is inserted in the fluidized bed granulation seed-coating machine, blower fan frequency 20～40Hz, 50～70 ℃ of inlet temperature, 35～50 ℃ of temperature of charge, atomization air pressure 0.05～0.10MPa, 10～30 rev/mins of operations of adding medicine to of hydrojet pump speed are until water blocking layer solution has sprayed.Set 40 ℃ of temperature of charge, will be coated with the micropill fluidized drying 30 minutes of water blocking layer solution, dry by the fire to moisture less than 2.5%, collect the micropill of micropill particle diameter between 16～30 orders, with the encapsulation of PE bag, obtain dextral-rabeprazole sodium enteric-coated pellet 1959.9g.In preparation process, the inventory of raw material and adjuvant is as shown in table 6.
Table 6 is the supplementary material inventory in preparation dextral-rabeprazole sodium enteric-coated pellet process
Annotate: solvent is removed in preparation process.
The preparation of embodiment 7 omeprazole enteric-coated capsules
Get the omeprazole enteric-coated micro-pill 1975.1g that embodiment 1 makes, add 2g gas phase micropowder silica gel and 2g Pulvis Talci mix homogeneously, filled capsules is amounted to every capsules content 116.3mg, and every omeprazole enteric-coated capsules contains omeprazole 10mg.Its prescription is as shown in table 7.
Table 7 omeprazole enteric-coated capsules prescription
| Classification | The supplementary material title | Inventory (g) |
| The medicine carrying micropill | The omeprazole enteric-coated micro-pill that |
1975.1 |
| Fluidizer | The gas phase micropowder silica gel | 2.0 |
| Lubricant | Pulvis Talci | 2.0 |
The preparation of embodiment 8 lansoprazole intestine dissolving capsules
Get the Lansoprazole enteric pellet 2261.5g that embodiment 2 makes, add 4.5g gas phase micropowder silica gel and 4.5g Pulvis Talci mix homogeneously, filled capsules is amounted to every capsules content 227.3mg, and every lansoprazole intestine dissolving capsule contains lansoprazole 30mg.Its prescription is as shown in table 8.
Table 8 lansoprazole intestine dissolving capsule prescription
| Classification | The supplementary material title | Inventory (g) |
| The medicine carrying micropill | The Lansoprazole enteric pellet that embodiment 2 makes | 2261.5 |
| Fluidizer | The gas phase micropowder silica gel | 4.5 |
| Lubricant | Pulvis Talci | 4.5 |
The preparation of embodiment 9 esomeprazole magnesium enteric coated capsulees
Get the esomeprazole enteric capsules 1656.8g that embodiment 3 makes, add 3.2g gas phase micropowder silica gel and 3.2g magnesium stearate mix homogeneously, filled capsules is amounted to every capsules content 228.3mg, and every esomeprazole magnesium enteric coated capsule contains esomeprazole 20mg.Its prescription is as shown in table 9.
Table 9 esomeprazole magnesium enteric coated capsule prescription
| Classification | The supplementary material title | Inventory (g) |
| The medicine carrying micropill | The esomeprazole enteric capsules that |
1656.8 |
| Fluidizer | The gas phase micropowder silica gel | 3.2 |
| Lubricant | Magnesium stearate | 3.2 |
The preparation of embodiment 10 Pantoprazole Sodium Enteric-Coated Capsules
Get the enteric coated mini-pill of pantoprazole sodium 1823.2g that embodiment 4 makes, add 3.6g gas phase micropowder silica gel and 3.6g sodium stearyl fumarate mix homogeneously, filled capsules is amounted to every capsules content 216.2mg, and every Pantoprazole Sodium Enteric-Coated Capsules contains pantoprazole 20mg.Its prescription is as shown in table 10.
Table 10 Pantoprazole Sodium Enteric-Coated Capsules prescription
| Classification | The supplementary material title | Inventory (g) |
| The medicine carrying micropill | The enteric coated mini-pill of pantoprazole sodium that |
1823.2 |
| Fluidizer | The gas phase micropowder silica gel | 3.6 |
| Lubricant | Sodium stearyl fumarate | 3.6 |
The preparation of embodiment 11 sodium rabeprazole enteric-coated capsules
Get the Rabeprazole sodium enteric-coated micro-pellet 1763.4g that embodiment 5 makes, add 3.5g gas phase micropowder silica gel and 3.5g magnesium stearate mix homogeneously, filled capsules is amounted to every capsules content 59.7mg, and every sodium rabeprazole enteric-coated capsule contains rabeprazole 10mg.Its prescription is as shown in table 11.
The sodium rabeprazole enteric-coated capsule prescription of table 11
| Classification | The supplementary material title | Inventory (g) |
| The medicine carrying micropill | The Rabeprazole sodium enteric-coated micro-pellet that |
1763.4 |
| Fluidizer | The gas phase micropowder silica gel | 3.5 |
| Lubricant | Magnesium stearate | 3.5 |
The preparation of embodiment 12 dextral-rabeprazole sodium enteric coated capsulees
Get the dextral-rabeprazole sodium enteric-coated pellet 1959.9g that embodiment 6 makes, add 3.9g gas phase micropowder silica gel and 3.9g sodium stearyl fumarate mix homogeneously, filled capsules is amounted to every capsules content 73.3mg, and every dextral-rabeprazole sodium enteric coated capsule contains dextral-rabeprazole 10mg.Its prescription is as shown in table 12.
Table 12 dextral-rabeprazole sodium enteric coated capsule prescription
| Classification | The supplementary material title | Inventory (g) |
| The medicine carrying micropill | The dextral-rabeprazole sodium enteric-coated pellet that |
1959.9 |
| Fluidizer | The gas phase micropowder silica gel | 3.9 |
| Lubricant | Sodium stearyl fumarate | 3.9 |
The preparation of embodiment 13 Omeprazole Enteric-coated Tablets agent
Get omeprazole enteric-coated micro-pill 1975.1g, lactose (Tablettose80) 1866.6g, Celluloasun Microcrystallisatum (Ceolus PH-102) 933.3g, cross-linked carboxymethyl cellulose sodium 255.0g, micropowder silica gel 51.0g, magnesium stearate 25.5g mixing that embodiment 1 makes, tabletting on powder vertical compression type tablet machine, namely get the Omeprazole Enteric-coated Tablets agent, sheet heavily is 300.0mg, and every contains omeprazole 10mg.
The preparation of embodiment 14 Lansoprazole enteric coated tablets
Get Lansoprazole enteric pellet 2261.5g, lactose (Cellactose80) 832.0g, Celluloasun Microcrystallisatum Ceolus PH-301416.0g, cross-linked pvp 400.0g, micropowder silica gel 80.0g, sodium stearyl fumarate 8.0g mixing that embodiment 2 makes, tabletting on powder vertical compression type tablet machine, namely get Lansoprazole enteric coated tablet, sheet heavily is 400.0mg, and every contains lansoprazole 30mg.
The preparation of embodiment 15 esomeprazole magnesium enteric coated tablets
Get esomeprazole enteric capsules 1656.8g, lactose (Tablettose80) 170.1g, Celluloasun Microcrystallisatum (Ceolus PH302) 507.9g, cross-linked carboxymethyl cellulose sodium 72.9g, micropowder silica gel 12.2g, magnesium stearate 12.2g mixing that embodiment 3 makes, tabletting on powder vertical compression type tablet machine, namely get the esomeprazole magnesium enteric coated tablet, sheet heavily is 333.6mg, and every contains esomeprazole 20mg.
The preparation of embodiment 16 pantoprazole sodium enteric tablet agent
Get enteric coated mini-pill of pantoprazole sodium 1823.2g, lactose (Cellactose80) 165.1g, Celluloasun Microcrystallisatum (Ceolus PH-102) 495.2g, cross-linked pvp 50.8g, micropowder silica gel 2.5g, sodium stearyl fumarate 2.5g mixing that embodiment 4 makes, tabletting on powder vertical compression type tablet machine, namely get the pantoprazole sodium enteric tablet agent, sheet heavily is 300.0mg, and every contains pantoprazole 20mg.
The preparation of embodiment 17 sodium rabeprazole enteric-coated tablets
Get Rabeprazole sodium enteric-coated micro-pellet 1763.4g, lactose (Tablettose80) 273.1g, Celluloasun Microcrystallisatum (Ceolus PH-301) 816.2g, cross-linked carboxymethyl cellulose sodium 59.4g, micropowder silica gel 29.7g, magnesium stearate 29.7g mixing that embodiment 5 makes, tabletting on powder vertical compression type tablet machine, namely get sodium rabeprazole enteric-coated tablet, sheet heavily is 100.0mg, and every contains rabeprazole 10mg.
The preparation of embodiment 18 dextral-rabeprazole sodium enteric tablet agent
Get dextral-rabeprazole sodium enteric-coated pellet 1959.9g, lactose (Cellactose80) 670.4g, Celluloasun Microcrystallisatum (Ceolus PH302) 335.2g, cross-linked pvp 161.2g, micropowder silica gel 64.5g, sodium stearyl fumarate 32.2g mixing that embodiment 6 makes, tabletting on powder vertical compression type tablet machine, namely get the agent of dextral-rabeprazole sodium enteric tablet, sheet heavily is 120.0mg, and every contains dextral-rabeprazole 10mg.
The vitro release test of embodiment 19 proton pump inhibitor enteric coated pellets formulations
Get the omeprazole enteric-coated capsules of embodiment 7 preparations as the test group object, place respectively the hydrochloric acid solution of pH1.2, the water of pH7.0, the phosphate buffered solution of pH6.0, in the phosphate buffered solution of pH6.8, getting the commercially available omeprazole enteric-coated capsules without water blocking layer organizes in contrast, place the water of pH7.0, according to dissolution method (" two appendix X of Chinese pharmacopoeia version in 2010 C the second method, add the sedimentation basket) operate: measure the 900mL dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, through 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min, 120min, 3h, 4h, 5h, during 6h, respectively get solution 10mL, and replenish simultaneously the dissolution medium of uniform temp and volume, filter, it is an amount of that precision is measured subsequent filtrate, add the stripping medium quantitatively dilution make the solution of certain density omeprazole, ultraviolet visible spectrophotometry (" two appendix IV of Chinese pharmacopoeia version in 2010 A) is measured the absorbance at 302nm wavelength place; Precision takes by weighing omeprazole reference substance (Chinese food drug inspection institute in addition, lot number: 100367-200702, purity is 99.9%), make the solution that contains approximately certain density omeprazole among every 1mL with dissolution medium dissolving and quantitative dilution, measure with method, obtain every omeprazole enteric-coated capsules at the stripping quantity of different time points, calculate vitro release, measurement result sees Table 13.
Get the lansoprazole intestine dissolving capsule of embodiment 8 preparations, according to the method described above, obtain every lansoprazole intestine dissolving capsule at the stripping quantity of different time points, calculate vitro release, measurement result sees Table 14.
The average accumulated dissolution determination result (n=12) of table 13 omeprazole enteric-coated capsules
The average accumulated dissolution determination result (n=12) of table 14 lansoprazole intestine dissolving capsule
Can be got by table 13 result, the release of the omeprazole enteric-coated capsules that the embodiment of the invention 7 makes under four kinds of different pH environment has different characteristics: do not discharge in 2 hours in the hydrochloric acid solution at pH1.2; Dissolution rate is very slow in the water of pH7.0, and the dissolution when 6h only is 8.3%; The 60min vitro release surpasses 80% in the phosphate buffered solution of pH6.0; The 45min vitro release surpasses 80% in the phosphate buffered solution of pH6.8.And surpassed 50% without the vitro release of omeprazole enteric-coated capsules 30min in dissolution medium water of water blocking layer, 2 hours basic releases fully, it is very fast to show that the commercially available omeprazole enteric-coated capsules without water blocking layer discharges in water, has significantly " burst effect ".This shows that the omeprazole enteric-coated capsules that water blocking layer is arranged that embodiment 7 provides can be avoided " burst effect " and moisture absorption effect, bioavailability is high.Know by inference thus, the omeprazole enteric-coated micro-pill that water blocking layer is arranged that embodiment 1 provides can be avoided " burst effect " and moisture absorption effect, and bioavailability is high.
Can be got by table 14 result, the release of the lansoprazole intestine dissolving capsule that the embodiment of the invention 8 makes under four kinds of different pH environment has different characteristics: do not discharge in 2 hours in the hydrochloric acid solution at pH1.2; Dissolution rate is very slow in the water of pH7.0, and the dissolution when 6h only is 5.9%; The 60min vitro release surpasses 50% in the phosphate buffered solution of pH6.0; The 45min vitro release surpasses 75% in the phosphate buffered solution of pH6.8.And reached 89.7% without the vitro release of lansoprazole intestine dissolving capsule 90min in dissolution medium water of water blocking layer, 2 hours basic releases fully, it is very fast to show that the commercially available lansoprazole intestine dissolving capsule without water blocking layer discharges in water, has significantly " burst effect ".This shows that the lansoprazole intestine dissolving capsule that water blocking layer is arranged that embodiment 8 provides can be avoided " burst effect " and moisture absorption effect, bioavailability is high.Know by inference thus, the Lansoprazole enteric pellet that water blocking layer is arranged that embodiment 2 provides can be avoided " burst effect " and moisture absorption effect, and bioavailability is high.
Get proton pump inhibitor enteric coated pellets formulation that embodiment 9～18 makes according to the dissolution of above-mentioned each medicine of determination of test method, the result of the test of the omeprazole enteric-coated capsules that result and embodiment 7 provide is close, show that the proton pump inhibitor enteric coated pellets formulation that water blocking layer is arranged that embodiment 9～18 provides also can avoid " burst effect " and moisture absorption effect, bioavailability is high.Know by inference thus, the proton pump inhibitor enteric coated pellets formulation that water blocking layer is arranged that embodiment 3～6 provides can be avoided " burst effect " and moisture absorption effect, and bioavailability is high.
This shows that proton pump inhibitor enteric coated micropill provided by the invention and the dissolution of preparation in strong acid solution and water thereof are very low, and dissolution is high in the phosphate buffer of pH6.0～6.8.Can know by inference thus, proton pump inhibitor enteric coated micropill provided by the invention and pharmaceutical preparation can not dissolved under one's belt, can dissolve rapidly in small intestinal, and bioavailability is high, can avoid " burst effect " and moisture absorption effect.
Influence factor's test of embodiment 20 proton pump inhibitor enteric coated pellets formulations
Get the omeprazole enteric-coated capsules of embodiment 7 preparations, after it is carried out aluminium-plastic bubble plate packing, (check its content, vitro release and related substance after placing respectively 10 days under the condition of 4500lx ± 500lx), the result is as shown in Table 15 in high temperature (40 ± 2 ℃), high humidity (RH75% ± 5%), high light.The vitro release assay method is consistent with the method that embodiment 18 provides, and be 45min sample time.
Content assaying method: according to high performance liquid chromatography (" two appendix V of Chinese pharmacopoeia version in 2010 D), be filler with octadecylsilane chemically bonded silica, measure take potassium dihydrogen phosphate aqueous solution-methanol as mobile phase.It is an amount of that precision takes by weighing sample, with diluted to 0.05mg/mL, as need testing solution; It is an amount of that other gets the omeprazole reference substance, accurately weighed, with diluted to 0.05mg/mL, product solution in contrast.The accurate 20 μ L mentioned solution injection liquid chromatographies of drawing record chromatogram and calculate by the external standard method peak area respectively.
Determination of related substances method: according to high performance liquid chromatography (" two appendix V of Chinese pharmacopoeia version in 2010 D), be filler with octadecylsilane chemically bonded silica, measure take potassium dihydrogen phosphate aqueous solution-methanol as mobile phase.It is an amount of that precision takes by weighing sample, with diluted to 0.5mg/mL, as need testing solution; The accurate absorption in need testing solution 1mL to the 100mL measuring bottle used the diluent standardize solution, in contrast solution.The accurate 20 μ L mentioned solution injection liquid chromatographies of drawing, the record chromatogram also calculates.
Influence factor's result of the test of table 15 omeprazole enteric-coated capsules
By table 15 result as can be known, the omeprazole enteric-coated capsules that the embodiment of the invention 7 makes was placed 10 days under high temperature, high humidity and high light condition, its character, related substance, dissolution and assay are showed no significant change, the omeprazole enteric-coated capsules stable in properties that the embodiment of the invention 7 makes is described, reliable in quality.Can know thus the omeprazole enteric-coated micro-pill stable in properties that the embodiment of the invention 1 makes by inference, reliable in quality.
Get proton pump inhibitor enteric coated pellets formulation that embodiment 8～18 makes according to related substance, dissolution and the content of above-mentioned each medicine of determination of test method, observe its character, the result of the test of the omeprazole enteric-coated capsules that result and embodiment 7 provide is close, show the proton pump inhibitor enteric coated pellets formulation stable in properties that embodiment 8～18 provides, reliable in quality.Can know thus the proton pump inhibitor enteric coated micropill stable in properties that the embodiment of the invention 2～6 makes by inference, reliable in quality.
This shows that proton pump inhibitor enteric coated micropill provided by the invention and preparation nature thereof are stable, reliable in quality.
The accelerated test of embodiment 21 proton pump inhibitor enteric coated pellets formulations
Get the omeprazole enteric-coated capsules of embodiment 7 preparations, after it is carried out aluminium-plastic bubble plate packing, it is 40 ± 2 ℃ in temperature, place in the climatic chamber of humidity RH75% ± 5%, take a sample respectively once 0 month, 1 month, 2 months, 3 months, 6 the end of month, check its character, content, dissolution and related substance, content, dissolution and determination of related substances method are identical with the method that embodiment 19 provides.Result of the test is shown in table 16.
The accelerated test result of table 16 omeprazole enteric-coated capsules
By table 7 result as can be known, the omeprazole enteric-coated capsules that the embodiment of the invention 7 makes is 40 ± 2 ℃ in temperature, placed 6 months in the climatic chamber of humidity RH75% ± 5%, its related substance, dissolution and assay are showed no significant change, the omeprazole enteric-coated capsules stable in properties that the embodiment of the invention 7 makes is described, reliable in quality.
Get proton pump inhibitor enteric coated pellets formulation that embodiment 8～18 makes according to related substance, dissolution and the content of above-mentioned each medicine of determination of test method, the result of the test of the omeprazole enteric-coated capsules that result and embodiment 7 provide is close, show the proton pump inhibitor enteric coated pellets formulation stable in properties that embodiment 8～18 provides, reliable in quality.Can know thus the proton pump inhibitor enteric coated micropill stable in properties that the embodiment of the invention 2～6 makes by inference, reliable in quality.
This shows that proton pump inhibitor enteric coated micropill provided by the invention and preparation nature thereof are stable, reliable in quality.
The wettability test of embodiment 22 proton pump inhibitor enteric coated pellets formulations
Get the omeprazole enteric-coated capsules of embodiment 7 preparations as test group, organize in contrast with the commercially available omeprazole enteric-coated capsules without water blocking layer.Precision takes by weighing each 5 parts of the above-mentioned two kinds of omeprazole enteric-coated capsules of 100g respectively, place T=40 ℃, under the RH=75% environment, measured moisture content after taking out during respectively at 0th month, the 1st month, the 2nd month, the 3rd month and 6th month, compare with 0th month water content, average moisture content to two groups of omeprazole enteric-coated capsules carries out the paired t-test analysis, and the result is shown in table 17.
Show the hygroscopicity comparative test of omeprazole enteric-coated capsules under 17T=40 ℃, RH=75% environment
By table 17 result as can be known, at T=40 ℃, under the RH=75% high humidity environment, when placing January, March and 6th month, the water content of the omeprazole enteric-coated capsules of test group all is lower than matched group, and the omeprazole enteric-coated capsules of test group and matched group all has statistical significance (P＜0.05) in the difference of 3rd month, the 6th month water content.The result shows, compares with the commercially available omeprazole enteric-coated capsules without water blocking layer, and the omeprazole enteric-coated capsules hygroscopicity of the embodiment of the invention 7 preparations significantly reduces.Can know thus the omeprazole enteric-coated micro-pill hygroscopicity that the embodiment of the invention 1 makes by inference significantly reduces.
Get proton pump inhibitor enteric coated pellets formulation that embodiment 8～18 makes according to the water content of above-mentioned each preparation of determination of test method, the result of the test of the omeprazole enteric-coated capsules that result and embodiment 7 provide is close, shows that the proton pump inhibitor enteric coated pellets formulation hygroscopicity that embodiment 8～18 provides significantly reduces.Can know thus the proton pump inhibitor enteric coated micropill hygroscopicity that the embodiment of the invention 2～6 makes by inference significantly reduces.
This shows that proton pump inhibitor enteric coated micropill provided by the invention and preparation hygroscopicity thereof significantly reduce, and can avoid moisture absorption effect.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (15)
1. a proton pump inhibitor enteric coated micropill is characterized in that, is comprised of celphere, drug-loaded layer, protective layer, sealing coat, water blocking layer and enteric layer;
The material of described water blocking layer is zein;
Described drug-loaded layer is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid and solubilizing agent, perhaps is comprised of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent and the first opacifier;
Described protective layer is comprised of the second binding agent, the second stabilizing agent, plasticizer, the second opacifier and defoamer;
The material of described sealing coat is coating material;
Described enteric layer is comprised of enteric material, plasticiser and the second antiplastering aid.
2. proton pump inhibitor enteric coated micropill according to claim 1 is characterized in that, the quality percentage composition that described zein accounts for described proton pump inhibitor enteric coated micropill is 0.1%～2%.
3. proton pump inhibitor enteric coated micropill according to claim 1; it is characterized in that the mass ratio of described celphere, described drug-loaded layer, described protective layer, described sealing coat, described water blocking layer and described enteric layer is (700～900): (268～282): (194～213): (60～75): (3.0～45.2): (1335～1545).
4. proton pump inhibitor enteric coated micropill according to claim 1 is characterized in that, described proton pump inhibitor is benzimidazoles compound.
5. proton pump inhibitor enteric coated micropill according to claim 1, it is characterized in that described proton pump inhibitor is omeprazole, esomeprazole, pantoprazole, rabeprazole, dextral-rabeprazole, lansoprazole, Dexlansoprazole or its pharmaceutically acceptable salt.
6. the preparation method of a proton pump inhibitor enteric coated micropill is characterized in that, comprises the steps:
Obtain drug-loaded layer solution;
Get the second binding agent, the second stabilizing agent, plasticizer, the second opacifier, defoamer, water and ethanol water and mix, obtain protective layer solution;
Get coating material and mix with ethanol water, obtain sealing coat solution;
Get zein and mix with ethanol water, obtain water blocking layer solution;
Get enteric material, plasticiser, the second antiplastering aid and water and mix, obtain enteric layer solution;
Get successively coated celphere of described drug-loaded layer solution, described protective layer solution and described sealing coat solution, obtain the medicine carrying micropill, get the coated described medicine carrying micropill of described water blocking layer solution and described enteric layer solution, drying namely gets the proton pump inhibitor enteric coated micropill;
Described drug-loaded layer solution is the mixture of proton pump inhibitor, the first binding agent, the first stabilizing agent, the first antiplastering aid, solubilizing agent and water, perhaps is the mixture of proton pump inhibitor, the first binding agent, the first stabilizing agent, filler, disintegrating agent, the first opacifier and water.
7. preparation method according to claim 6 is characterized in that, the quality percentage composition that described zein accounts for described proton pump inhibitor enteric coated micropill is 0.1%～2%.
8. preparation method according to claim 6; it is characterized in that the mass ratio of described celphere, described drug-loaded layer solution, described protective layer solution, described sealing coat solution, described water blocking layer solution and described enteric layer solution is (700～900): (268～282): (194～213): (60～75): (3.0～45.2): (1335～1545).
9. preparation method according to claim 6 is characterized in that, described proton pump inhibitor is benzimidazoles compound.
10. preparation method according to claim 6, it is characterized in that described proton pump inhibitor is omeprazole, esomeprazole, pantoprazole, rabeprazole, dextral-rabeprazole, lansoprazole, Dexlansoprazole or its pharmaceutically acceptable salt.
11. preparation method according to claim 6 is characterized in that, the coated temperature of described water blocking layer solution is 35 ℃～50 ℃.
12. the proton pump inhibitor enteric coated micropill that makes such as each described preparation method in the claim 6 to 11.
13. a pharmaceutical preparation is characterized in that, comprises in the claim 1 to 5 that each or the described proton pump inhibitor enteric coated micropill of claim 12 and pharmaceutically acceptable adjuvant form.
14. pharmaceutical preparation according to claim 13 is characterized in that, the dosage form of described pharmaceutical preparation is tablet or capsule.
15. pharmaceutical preparation according to claim 13 is characterized in that, described pharmaceutically acceptable adjuvant is selected from filler, disintegrating agent, fluidizer or lubricant.
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| CN105193767A (en) * | 2015-08-25 | 2015-12-30 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium enteric-coated pellets |
| CN106176669A (en) * | 2016-08-26 | 2016-12-07 | 湖北唯森制药有限公司 | A kind of pantoprazole sodium enteric-pellets capsules and preparation method |
| CN109125282A (en) * | 2018-09-05 | 2019-01-04 | 珠海润都制药股份有限公司 | A kind of omeprazole enteric-coated capsules and preparation method thereof |
| WO2020139203A1 (en) * | 2018-12-28 | 2020-07-02 | Neutec Ar-Ge Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | A formulation comprising dexrabeprazole |
| CN112137990A (en) * | 2020-11-04 | 2020-12-29 | 南京康川济医药科技有限公司 | Epalrestat sustained-release preparation and preparation method thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104586792A (en) * | 2014-12-25 | 2015-05-06 | 北京华禧联合科技发展有限公司 | Lansoprazole enteric-coated preparation |
| CN105193767A (en) * | 2015-08-25 | 2015-12-30 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium enteric-coated pellets |
| CN106176669A (en) * | 2016-08-26 | 2016-12-07 | 湖北唯森制药有限公司 | A kind of pantoprazole sodium enteric-pellets capsules and preparation method |
| CN106176669B (en) * | 2016-08-26 | 2017-11-07 | 湖北唯森制药有限公司 | A kind of pantoprazole sodium enteric-pellets capsules and preparation method |
| CN109125282A (en) * | 2018-09-05 | 2019-01-04 | 珠海润都制药股份有限公司 | A kind of omeprazole enteric-coated capsules and preparation method thereof |
| CN109125282B (en) * | 2018-09-05 | 2020-07-14 | 珠海润都制药股份有限公司 | Omeprazole enteric capsule and preparation method thereof |
| WO2020139203A1 (en) * | 2018-12-28 | 2020-07-02 | Neutec Ar-Ge Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | A formulation comprising dexrabeprazole |
| CN112137990A (en) * | 2020-11-04 | 2020-12-29 | 南京康川济医药科技有限公司 | Epalrestat sustained-release preparation and preparation method thereof |
| CN112697688A (en) * | 2020-12-18 | 2021-04-23 | 正大制药（青岛）有限公司 | Acid resistance measuring method of omeprazole chewable tablets |
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Effective date of registration: 20201209 Address after: No.85, Zhenxing Road, Tai'an County, Anshan City, Liaoning Province, 114100 Patentee after: LIAONING KANGBOSHI PHARMACEUTICAL Co.,Ltd. Address before: 430050 2-3-503, Dushi Lanting, Zhongjia village, No.98 Hanyang Avenue, Hanyang District, Wuhan City, Hubei Province Patentee before: Xie Bin |