CN103479653B - Aspirin-esomeprazole compound enteric coated pellet preparation and preparation method - Google Patents
Aspirin-esomeprazole compound enteric coated pellet preparation and preparation method Download PDFInfo
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- CN103479653B CN103479653B CN201310467088.3A CN201310467088A CN103479653B CN 103479653 B CN103479653 B CN 103479653B CN 201310467088 A CN201310467088 A CN 201310467088A CN 103479653 B CN103479653 B CN 103479653B
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- aspirin
- esomeprazole
- preparation
- coating
- sealing coat
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- 229960004770 esomeprazole Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000008188 pellet Substances 0.000 title claims abstract description 33
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 68
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 23
- 239000010410 layer Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000002702 enteric coating Substances 0.000 claims abstract description 6
- 238000009505 enteric coating Methods 0.000 claims abstract description 6
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 3
- 239000011248 coating agent Substances 0.000 claims description 68
- 238000000576 coating method Methods 0.000 claims description 68
- 238000007789 sealing Methods 0.000 claims description 44
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 27
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 27
- 239000012530 fluid Substances 0.000 claims description 24
- 239000006187 pill Substances 0.000 claims description 22
- 239000012055 enteric layer Substances 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 18
- 229960000197 esomeprazole magnesium Drugs 0.000 claims description 17
- 239000003381 stabilizer Substances 0.000 claims description 16
- 239000007779 soft material Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 claims description 12
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 12
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 239000004014 plasticizer Substances 0.000 claims description 9
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- 235000012239 silicon dioxide Nutrition 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- 239000004408 titanium dioxide Substances 0.000 claims description 6
- 229920003163 Eudragit® NE 30 D Polymers 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 238000000227 grinding Methods 0.000 claims description 3
- 230000008676 import Effects 0.000 claims description 3
- 238000005550 wet granulation Methods 0.000 claims description 3
- MQEUGMWHWPYFDD-JIDHJSLPSA-N magnesium;6-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical group [Mg].C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C MQEUGMWHWPYFDD-JIDHJSLPSA-N 0.000 claims description 2
- 230000002572 peristaltic effect Effects 0.000 claims description 2
- -1 sealing coat II Substances 0.000 claims description 2
- KWORUUGOSLYAGD-WLHYKHABSA-N magnesium;5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-WLHYKHABSA-N 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 11
- 230000007774 longterm Effects 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 2
- 210000004369 blood Anatomy 0.000 abstract description 2
- 230000006378 damage Effects 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 238000002955 isolation Methods 0.000 abstract 2
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 abstract 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 abstract 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 229910052749 magnesium Inorganic materials 0.000 abstract 1
- 239000011777 magnesium Substances 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 description 17
- 239000012153 distilled water Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 4
- 229960000502 poloxamer Drugs 0.000 description 4
- 229920001983 poloxamer Polymers 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000008118 PEG 6000 Substances 0.000 description 3
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 229960003893 phenacetin Drugs 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 238000005563 spheronization Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 2
- 108010083204 Proton Pumps Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
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- 238000004132 cross linking Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
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- 239000011259 mixed solution Substances 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- ASTWEMOBIXQPPV-UHFFFAOYSA-K trisodium;phosphate;dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O ASTWEMOBIXQPPV-UHFFFAOYSA-K 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
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- 108091022875 Microtubule Proteins 0.000 description 1
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- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical compound CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 description 1
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- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000011203 antimicrobial therapy Methods 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 229940085334 aspirin 81 mg Drugs 0.000 description 1
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- MIMDHDXOBDPUQW-UHFFFAOYSA-N dioctyl decanedioate Chemical compound CCCCCCCCOC(=O)CCCCCCCCC(=O)OCCCCCCCC MIMDHDXOBDPUQW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an aspirin-esomeprazole compound enteric coated pellet preparation and a preparation method. The preparation is composed of active pharmaceutical ingredients aspirin and esomeprazole and other pharmaceutically acceptable auxiliary materials. The aspirin and the esomeprazole are in a mass ratio of 3-6:1. The compound enteric coated pellet has two forms. For one form of enteric coated pellet, aspirin pellet is adopted as a drug-containing pellet core, which is externally coated by an isolation layer I, an ensomeprazole magnesium drug layer, an isolation layer II, and an enteric coating layer; and for the other form of enteric coated pellet, an aspirin enteric coated pellet and an esomeprazole enteric coated pellet are prepared respectively, and they are mixed to obtain the compound enteric coated pellet. According to the invention, the drugs are released in the intestinal tract, thus avoiding destruction of the drugs in an acidic environment of the stomach; the compound preparation can resist the side effects of aspirin on gastrointestinal irritation so as to facilitate long-term medication of aspirin and bring the platelet aggregation inhibition effect of aspirin into play; and by adopting pellet form release drugs, the bioavailability is high, the blood concentration fluctuation is small, and the side effects are smaller.
Description
Technical field
The present invention relates to the compound enteric-coated pellet preparations of a kind of aspirin-esomeprazole and preparation method, belong to medical art.
Background technology
Aspirin
English by name: Aspirin;
Chemistry is by name: Aspirin;
Molecular weight is: 180.16;
Chemical formula:
Physicochemical property: white needles or plate crystal or powder.Fusing point 135 ~ 140 DEG C.Odorlessness, micro-band tart flavour.Stable in dry air, in humid air, be slowly hydrolyzed into salicylic acid and acetic acid.Easily molten in ethanol, dissolve at EC, be slightly soluble in water, can dissolve in sodium hydroxide solution or sodium carbonate liquor, but decompose simultaneously.These product 1g can be dissolved in 300mL water, 5mL alcohol, 10-15mL ether or 17mL chloroform.
On March 6th, 1899 is born in by aspirin, is apply the earliest, the widest and the most common antipyretic analgesic antirheumatic.Have many-sided pharmacological actions such as antipyretic, analgesia, antiinflammatory, rheumatism and antiplatelet aggregation, drug effect plays rapidly and stable, and overdose is easy to diagnosis and management, seldom anaphylaxis occurs.It has antithrombotic effect in vivo simultaneously, and it can suppress hematoblastic release reaction, suppresses hematoblastic gathering, and this is relevant with the minimizing that TXA2 generates, clinically for preventing the outbreak of cardiovascular and cerebrovascular disease.The main untoward reaction of aspirin is that it directly can irritate gastric mucosa and cause epigastric discomfort and nausea and vomiting to gastrointestinal infringement.Life-time service easily causes mucosal lesion, causes gastric ulcer and gastrorrhagia.
Esomeprazole magnesium trihydrate
English name: Esomeprazole magnesium trihydrate;
Chemical name: two (5-methoxyl group-2-[(S)-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-base) magnesium salt trihydrate;
Physicochemical property: it degrades rapidly in acid medium, but it is stablized in the basic conditions.In the buffer solution of pH=6.8, stable in 19 hours when 25 DEG C, within when 37 DEG C 8 hours, stablize.
Molecular weight: 767.15;
Chemical structural formula:
Esomeprazole is the S-isomer of omeprazole, by the selectively targeted parietal cell higher in acidity, and concentrate under this comparatively peracidity environment, activate and covalency suppress proton pump.Esomeprazole has higher and consistent bioavailability compared with omeprazole, AUC area under curve is larger.Its mechanism of action is esomeprazole is a weak base, secretes in the high acid environment of sour microtubule and concentrates and be converted into activity form, thus suppress the H at this position parietal cell
+/ K
+-ATP enzyme (proton pump), all produces suppression to the gastric acid secretion of basal gastric acid secretion and stimulation.It is applicable to control and the treatment of gastro oesophageal reflux disease (GORD) (GERD); The treatment of erosive reflux esophagitis; The esophagitis patient cured prevents the long term maintenance therapy recurred; Treat the relevant peptic ulcer of helicobacter pylori to suitable antimicrobial therapy drug combination and prevent from recurring.Its clinical advantage is day by day obvious.
Summary of the invention
The object of this invention is to provide the compound enteric-coated pellet preparations of a kind of aspirin-esomeprazole and preparation method, the side effect of the specificity antiulcer action antagonism aspirin gastrointestinal side effect of application esomeprazole magnesium, is beneficial to the long-term prescription of aspirin.
The technical scheme that the present invention takes is:
The compound enteric-coated pellet preparations of aspirin-esomeprazole, be made up of active pharmaceutical ingredient aspirin and esomeprazole and other pharmaceutically acceptable adjuvants, the mass ratio of aspirin and esomeprazole is at 3-6:1.The preferred 4-4.5:1 of mass ratio of aspirin and esomeprazole.
The compound enteric-coated pellet preparations of aspirin-esomeprazole, is made up of aspirin Intestine-soluble micro-pill and Esomeprazole enteric pellet, and the mass ratio of aspirin and esomeprazole is at 3-6:1.
Both, for first to prepare aspirin Intestine-soluble micro-pill, Esomeprazole enteric pellet, then mix by the preparation method of this kind of compound enteric-coated pellet preparations of aspirin-esomeprazole; Aspirin Intestine-soluble micro-pill is do containing pill core with the agglomerated particles and micropellets of Aspirin, its outer bag sealing coat I successively, and bag enteric layer is made; Esomeprazole enteric pellet does ball core its outer bag esomeprazole medicine layer, sealing coat II successively with Blank Pellets, and enteric layer is made.
The wherein preparation of aspirin Intestine-soluble micro-pill:
(1) after by aspirin grinding, 80 mesh sieves are mixed homogeneously with filler, disintegrating agent, binding agent and stabilizing agent excessively afterwards, wet granulation is adopted to prepare soft material, the humidity that made soft material should require than tablet is slightly high, soft material is poured in extruder and extrudes, to extrude bar imports in spheronizator round as a ball, finally by gained the agglomerated particles and micropellets of Aspirin dry 3-4h in 50 DEG C of baking ovens; Wherein weight part ratio is: aspirin 30 ~ 60 parts, filler 40 ~ 70 parts, disintegrating agent 1 ~ 5 part, stabilizing agent 0.5 ~ 5 part; Filler is selected from one or more in starch, dextrin, microcrystalline Cellulose, lactose, sucrose; Disintegrating agent is selected from one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose; Described binding agent is selected from one or more in low concentration HPMC aqueous solution, distilled water, PVP aqueous solution, ethanol-water solution; Tartaric acid selected by stabilizing agent;
(2) sealing coat I is coated: the HPMC solution of preparation 1wt% ~ 3wt%, the silicon dioxide or the Pulvis Talci that add HPMC amount 1wt% ~ 10wt% obtain sealing coat I coating solution, made to (1) aspirin is placed in fluid bed containing pill core, sealing coat I coating solution fluidized coating is also dry;
(3) enteric layer is coated: enteric layer select in Eudragit L30D-55, Eudragit L30D-55/NE30D, CAP one or more do coating material, and add plasticizer and antiplastering aid is mixed in coating solvent, also dry to step (3) product fluidized coating, wherein weight part ratio is: coating material 70 ~ 95 parts, plasticizer 5 ~ 30 parts, antiplastering aid 2 ~ 8 parts.
The wherein preparation of Esomeprazole enteric pellet:
A. the preparation of esomeprazole medicine layer: get esomeprazole magnesium drug powder and be dissolved in or be suspended in binder solution, and add stabilizing agent, solubilizing agent, under Keep agitation, fluidized bed coating medicine-feeding is carried out to celphere, carry out fluid bed drying after coating completes; Its weight part ratio is: esomeprazole magnesium 80 ~ 95 parts, stabilizing agent 0.5 ~ 5 part, solubilizing agent 5 ~ 20 parts; Wherein binding agent is selected from one or more in HPMC, PVP, MC, EC; Dissolved adhesive solvent for use is selected from water, ethanol or the two mixed solution; Stabilizing agent is selected from one or more in sodium phosphate dodecahydrate, sodium hydrogen phosphate, sodium bicarbonate, anhydrous sodium sulfite, sodium phosphate, tertiary sodium phosphate, magnesium carbonate; Solubilizing agent is selected from one or more in sodium lauryl sulphate, Tween-80, poloxamer;
B. sealing coat II is coated: the HPMC solution of preparation 1wt% ~ 3wt%, and the silicon dioxide or the Pulvis Talci that add HPMC amount 1wt% ~ 10wt% do antiplastering aid, also need to add the titanium dioxide of HPMC amount 0.5% ~ 1.5%, obtain sealing coat II coating solution; The ball core that step a is obtained is placed in fluid bed, and sealing coat II coating solution fluidized coating is also dry;
C. the preparation of enteric layer coating solution and coated: enteric layer select in Eudragit L30D-55, Eudragit L30D-55/NE30D, CAP one or more do coating material, and add plasticizer and antiplastering aid is mixed in coating solvent, its weight part ratio is: coating material 70 ~ 95 parts, plasticizer 5 ~ 30 parts, antiplastering aid 2 ~ 8 parts, also dry to step B product fluidized coating.
The compound enteric-coated pellet preparations of aspirin-esomeprazole of another kind of more excellent structure, do containing pill core with the agglomerated particles and micropellets of Aspirin, its outer bag sealing coat I, esomeprazole medicine layer, sealing coat II, enteric coating layer successively, the mass ratio of aspirin and esomeprazole is at 3-6:1.The preferred 4-4.5:1 of mass ratio of aspirin and esomeprazole.Enteric coated micropill single dose is containing aspirin 60-90mg, esomeprazole 15-30mg; Preferred aspirin 81mg, esomeprazole magnesium 20mg.
Namely the agglomerated particles and micropellets of Aspirin adds ball core filler, disintegrating agent, binding agent and stabilizing agent extrusion spheronization method containing pill core by aspirin and obtains.Its weight part ratio consists of: aspirin 30 ~ 60 parts, filler 40 ~ 70 parts, disintegrating agent 1 ~ 5 part, stabilizing agent 0.5 ~ 5 part, binding agent 0.5 ~ 10 part.Ball core filler is selected from one or more in starch, dextrin, microcrystalline Cellulose, lactose, sucrose; Disintegrating agent is selected from one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose; Described binding agent is selected from one or more in low concentration HPMC aqueous solution, distilled water, PVP aqueous solution, ethanol-water solution; Tartaric acid selected by stabilizing agent.
Esomeprazole medicine layer is obtained by esomeprazole magnesium, stabilizing agent, the drying of solubilizing agent coating.Its weight part ratio consists of: esomeprazole magnesium 80 ~ 95 parts, stabilizing agent 0.5 ~ 5 part, solubilizing agent 5 ~ 20 parts.Wherein stabilizing agent is selected from one or more in sodium phosphate dodecahydrate, sodium hydrogen phosphate, sodium bicarbonate, anhydrous sodium sulfite, sodium phosphate, tertiary sodium phosphate, magnesium carbonate; Solubilizing agent is selected from one or more in sodium lauryl sulphate, Tween-80, poloxamer; Solvent for use is selected from water, ethanol or the two mixed solution.
Enteric coating layer select in Eudragit L30D-55, Eudragit L30D-55/NE30D, CAP one or more do coating material, and add plasticizer and antiplastering aid, PEG selected by plasticizer, triethyl citrate TEC, dibutyl phthalate (DBP), dioctyl phthalate (DOP), epoxy soybean oil, tricresyl phosphate, triphenyl phosphate, di-n-octyl sebacate, chlorinated paraffin wax one or more; Antiplastering aid select in silicon dioxide, Pulvis Talci one or both; Its weight part ratio forms: coating material 70 ~ 95 parts, plasticizer 5 ~ 30 parts, antiplastering aid 2 ~ 8 parts.Sealing coat selects HPMC to do coating material, and adds antiplastering aid, 5 ~ 30% opacifiers of coating material quality 1 ~ 10%, the preferred silicon dioxide of antiplastering aid or Pulvis Talci, the preferred titanium dioxide of opacifier.
Above-mentioned esomeprazole is Esomeprazole magnesium salt.
The preparation method of the aspirin phenacetin caffeine-Esomeprazole enteric pellet of this kind of preferred structure, comprises step as follows:
(1) preparation of the agglomerated particles and micropellets of Aspirin: after 80 mesh sieves are mixed homogeneously with filler, disintegrating agent, binding agent and stabilizing agent excessively afterwards by aspirin grinding, wet granulation is adopted to prepare soft material, the humidity that made soft material should require than tablet is slightly high, soft material is poured in extruder and extrudes, to extrude bar imports in spheronizator round as a ball, finally by gained the agglomerated particles and micropellets of Aspirin dry 3-4h in 50 DEG C of baking ovens;
(2) sealing coat I is coated: the HPMC solution of preparation 1wt% ~ 3wt%, the silicon dioxide or the Pulvis Talci that add HPMC amount 1wt% ~ 10wt% obtain sealing coat I coating solution, made aspirin is placed in fluid bed containing pill core, sealing coat I coating solution fluidized coating is also dry;
(3) preparation of esomeprazole medicine layer: get esomeprazole magnesium drug powder and be dissolved in or be suspended in solution, and add stabilizing agent, solubilizing agent, under Keep agitation, fluidized bed coating medicine-feeding is carried out to the obtained ball heart of step (2), after coating completes, carry out fluid bed drying;
(4) sealing coat II is coated: the HPMC solution of preparation 1wt% ~ 3wt%, and the silicon dioxide or the Pulvis Talci that add HPMC amount 1wt% ~ 10wt% do antiplastering aid, also need to add the titanium dioxide of HPMC amount 0.5% ~ 1.5%, obtain sealing coat II coating solution; The ball core that step (3) is obtained is placed in fluid bed, and sealing coat II coating solution fluidized coating is also dry;
(5) preparation of enteric layer coating solution and coated: enteric layer select in Eudragit L30D-55, EudragitL30D-55/NE30D, CAP one or more do coating material, and add plasticizer and antiplastering aid is mixed in coating solvent, dry to step (4) product fluidized coating.
In above-mentioned preparation method, soft material is poured in extruder by step (1), extrudes under 16-22Hz, and described round as a ball parameter is 18-25Hz, finds time as 3-5min.
Fluidized coating parameter described in step (2) is: control temperature is at 40 ± 3 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 20 ~ 35Hz; Hydrojet speed is 2.0mL/min.
Fluidized coating parameter described in step (3) is: control temperature 35 ~ 39 DEG C; Atomizing pressure 0.08 ~ 0.2MPa; Air blast frequency 25 ~ 35Hz; Peristaltic pump 0.5 ~ 2.5mL/min.
Step (4) fluidized coating parameter is: control temperature is at 40 ± 3 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 20 ~ 35Hz; Hydrojet speed is 2.0mL/min.
Step (5) fluidized coating parameter is: control temperature is at 35 ~ 40 DEG C; Atomizing pressure is 0.08 ~ 0.11MPa; Air blast frequency is 20 ~ 35Hz; Hydrojet speed is 1.0mL/min.
Adopt enteric coating, in intestinal, enteric coating film dissolves, and the effect of protection intestinal mucosa is played in esomeprazole magnesium release, and aspirin drug release plays its antipyretic-antalgic, the effect of the treating cardiovascular diseases such as antiplatelet aggregation.The present invention adopts this multiple-unit medicine-releasing system of micropill form administration, it belongs to dosage decentralized preparation, and dose is often made up of, compared with single-dose tablet the multiple unit disperseed, tool has the following advantages: medicine is distributed more widely on the gastrointestinal tract, and bioavailability is high; The release behavior of medicine is the combination of multiple release piller, and release is more steady, fluctuates little.
The invention has the advantages that medicine discharges in intestinal, avoid the destruction of medicine sour environment under one's belt; The side effect of compound preparation antagonism aspirin, is beneficial to the long-term prescription of aspirin, plays the effect of its anticoagulant;
Adopt micropill dosage form release medicine, bioavailability is high, and blood concentration fluctuation is little, and side effect is lower.
Accompanying drawing explanation
Fig. 1 is embodiment 1 product structure figure;
Fig. 2 is embodiment 4 product aspirin Intestine-soluble micro-pill structure chart;
Fig. 3 is embodiment 4 product Esomeprazole enteric pellet structure chart;
Wherein, 1. aspirin contains pill core, 2. esomeprazole medicated layer, 3. sealing coat I, 4. sealing coat II, 5. enteric layer, 6. celphere.
Detailed description of the invention
Further illustrate below in conjunction with preferred embodiment.
Embodiment 1
Aspirin is containing the preparation of pill core:
Aspirin and adjuvant crossed 80 mesh sieves and mixs homogeneously, doing binding agent with distilled water and prepare soft material.Made soft material is placed in extrusion spheronization machine, and extruded velocity is 18Hz, and round as a ball speed is 21Hz, and the round as a ball time is 3min.By made micropill dry 3h in 50 DEG C.
Bag sealing coat I:
Prescription: HPMC E5 5g
Pulvis Talci 0.06g
Distilled water 100mL
HPMC E5 slowly to be joined under stirring in hot distilled water, after letting cool dissolving, add Pulvis Talci, stand-by.Made aspirin is placed in fluid bed, by sealing coat fluidized coating containing pill core.Control temperature is at about 40 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 27Hz; Hydrojet speed is 2.0mL/min; Dry 30min in fluid bed after coating.
Bag esomeprazole magnesium medicated layer
The sodium bicarbonate of recipe quantity, esomeprazole magnesium, poloxamer are slowly joined successively in the 3%HPMCE5 solution under stirring, after being uniformly dispersed, carry out fluidized bed coating medicine-feeding.Control temperature 37 ~ 40 DEG C; Atomizing pressure 0.15 ~ 0.2MPa; Air blast frequency 28.5Hz; Hydrojet flow velocity 0.5 ~ 1mL/min.Made pill is in 40 DEG C of fluidized drying 30min.
Bag sealing coat II:
HPMC E5 slowly to be joined under stirring in hot distilled water, after letting cool dissolving, add Pulvis Talci and titanium dioxide, stand-by.The made esomeprazole magnesium of bag medicated layer micropill is placed in fluid bed, by sealing coat fluidized coating.Control temperature is at about 40 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 27Hz; Hydrojet speed is 2.0mL/min; Dry 30min in fluid bed after coating.
Bag enteric layer
The Eudragit L30D-55 of recipe quantity is joined in the water of stirring, adds PEG6000, the Pulvis Talci of recipe quantity under continuing stirring, until disperse completely.The first micropill is enteric coated for the agglomerated particles and micropellets of Aspirin and esomeprazole micropill that have wrapped sealing coat I and sealing coat II are placed in fluid bed respectively, with identical prescription bag enteric layer.Control temperature is at about 30 ~ 35 DEG C; Atomizing pressure is 0.08 ~ 0.11MPa; Air blast frequency is 29.5Hz; Hydrojet speed is 1.0mL/min; Dry 30min in fluid bed after coating.Obtain aspirin Intestine-soluble micro-pill and Esomeprazole enteric pellet, then carry out combination fill in capsule by predetermined close.The second micropill is that the aspirin having wrapped sealing coat II-esomeprazole micropill is placed in fluid bed, and bag enteric layer, coating parameter is the same.Gained micropill is described aspirin phenacetin caffeine-Esomeprazole enteric pellet.
Embodiment 2
Aspirin is containing the preparation of pill core:
Detailed description of the invention is with embodiment 1.
Bag sealing coat I:
Prescription: HPMC E5 7.5g
Silicon dioxide 0.07g
Distilled water 100mL
Detailed description of the invention is with embodiment 1.
Bag esomeprazole magnesium medicated layer
Detailed description of the invention is with embodiment 1.
Bag sealing coat II:
Detailed description of the invention is with embodiment 1.
Bag enteric layer
Detailed description of the invention is with embodiment 1.
Embodiment 3
Aspirin is containing the preparation of pill core:
Detailed description of the invention is with embodiment 1.
Bag sealing coat I:
Prescription: HPMC E5 7.5g
Pulvis Talci 0.07g
Distilled water 100mL
Detailed description of the invention is with embodiment 1.
Bag esomeprazole magnesium medicated layer
Detailed description of the invention is with embodiment 1.
Bag sealing coat II:
Detailed description of the invention is with embodiment 1.
Bag enteric layer
Detailed description of the invention is with embodiment 1.
Embodiment 4
The preparation of aspirin Intestine-soluble micro-pill:
Aspirin and adjuvant crossed 80 mesh sieves and mixs homogeneously, doing binding agent with distilled water and prepare soft material.Made soft material is placed in extrusion spheronization machine, and extruded velocity is 18Hz, and round as a ball speed is 21Hz, and the round as a ball time is 3min.By made micropill dry 3h in 50 DEG C of baking ovens.
Bag sealing coat I:
Prescription: HPMC E5 5g
Pulvis Talci 0.06g
Distilled water 100mL
HPMC E5 slowly to be joined under stirring in hot distilled water, after letting cool dissolving, add Pulvis Talci, stand-by.Made aspirin is placed in fluid bed, by sealing coat fluidized coating containing pill core.Control temperature is at about 40 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 27Hz; Hydrojet speed is 2.0mL/min; Dry 30min in fluid bed after coating.
Bag enteric layer
The Eudragit L30D-55 of recipe quantity is joined in the water of stirring, adds PEG6000, the Pulvis Talci of recipe quantity under continuing stirring, until disperse completely.The agglomerated particles and micropellets of Aspirin having wrapped sealing coat I is placed in fluid bed, bag enteric layer.Control temperature is at about 30 ~ 35 DEG C; Atomizing pressure is 0.08 ~ 0.11MPa; Air blast frequency is 29.5Hz; Hydrojet speed is 1.0mL/min; Dry 30min in fluid bed after coating.
The preparation of Esomeprazole enteric pellet:
The sodium bicarbonate of recipe quantity, esomeprazole magnesium, poloxamer are slowly joined successively in the 3%HPMCE5 solution under stirring, after being uniformly dispersed, carry out fluidized bed coating medicine-feeding.Control temperature 37 ~ 40 DEG C; Atomizing pressure 0.15 ~ 0.2MPa; Air blast frequency 28.5Hz; Hydrojet flow velocity 0.5 ~ 1mL/min.Made pill is in 40 DEG C of fluidized drying 30min.
Bag sealing coat II:
HPMC E5 slowly to be joined under stirring in hot distilled water, after letting cool dissolving, add Pulvis Talci and titanium dioxide, stand-by.The made esomeprazole magnesium of bag medicated layer micropill is placed in fluid bed, by sealing coat fluidized coating.Control temperature is at about 40 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 27Hz; Hydrojet speed is 2.0mL/min; Dry 30min in fluid bed after coating.
Bag enteric layer
The Eudragit L30D-55 of recipe quantity is joined in the water of stirring, adds PEG6000, the Pulvis Talci of recipe quantity under continuing stirring, until disperse completely.The agglomerated particles and micropellets of Aspirin having wrapped sealing coat I is placed in fluid bed, bag enteric layer.Control temperature is at about 30 ~ 35 DEG C; Atomizing pressure is 0.08 ~ 0.11MPa; Air blast frequency is 29.5Hz; Hydrojet speed is 1.0mL/min; Dry 30min in fluid bed after coating.
Gained aspirin and Esomeprazole enteric pellet are mixed by predetermined close and obtains aspirin phenacetin caffeine-Esomeprazole enteric pellet.
Claims (3)
1. the preparation method of the compound enteric-coated pellet preparations of aspirin-esomeprazole, it is characterized in that, be made up of active pharmaceutical ingredient aspirin and esomeprazole and other pharmaceutically acceptable adjuvants, the mass ratio of aspirin and esomeprazole is at 3-6:1, esomeprazole is Esomeprazole magnesium salt, do containing pill core with the agglomerated particles and micropellets of Aspirin, its outer bag sealing coat I, esomeprazole magnesium medicine layer, sealing coat II, enteric coating layer successively, comprise step as follows:
(1) preparation of the agglomerated particles and micropellets of Aspirin: after 80 mesh sieves are mixed homogeneously with filler, disintegrating agent, binding agent and stabilizing agent excessively afterwards by aspirin grinding, wet granulation is adopted to prepare soft material, the humidity that made soft material should require than tablet is slightly high, soft material is poured in extruder and extrudes, to extrude bar imports in spheronizator round as a ball, finally by gained the agglomerated particles and micropellets of Aspirin dry 3-4h in 50 DEG C of baking ovens;
(2) sealing coat I is coated: the HPMC solution of preparation 1wt% ~ 3wt%, the silicon dioxide or the Pulvis Talci that add HPMC amount 1wt% ~ 10wt% obtain sealing coat I coating solution, made aspirin is placed in fluid bed containing pill core, sealing coat I coating solution fluidized coating is also dry;
(3) preparation of esomeprazole medicine layer: get esomeprazole magnesium drug powder and be dissolved in or be suspended in solution, and add stabilizing agent, solubilizing agent, under Keep agitation, fluidized bed coating medicine-feeding is carried out to the obtained ball core of step (2), after coating completes, carry out fluid bed drying;
(4) sealing coat II is coated: the HPMC solution of preparation 1wt% ~ 3wt%, and the silicon dioxide or the Pulvis Talci that add HPMC amount 1wt% ~ 10wt% do antiplastering aid, also need to add the titanium dioxide of HPMC amount 0.5% ~ 1.5%, obtain sealing coat II coating solution; The ball core that step (3) is obtained is placed in fluid bed, and sealing coat II coating solution fluidized coating is also dry;
(5) preparation of enteric layer coating solution and coated: enteric layer select in Eudragit L30D-55, Eudragit L30D-55/NE30D, CAP one or more do coating material, and add plasticizer and antiplastering aid is mixed in coating solvent, dry to step (4) product fluidized coating.
2. the preparation method of the compound enteric-coated pellet preparations of aspirin-esomeprazole according to claim 1, it is characterized in that, the mass ratio of aspirin and esomeprazole selects 4-4.5:1.
3. the preparation method of the compound enteric-coated pellet preparations of aspirin-esomeprazole according to claim 1, is characterized in that,
Fluidized coating parameter described in step (2) is: control temperature is at 40 ± 3 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 27Hz; Hydrojet speed is 2.0mL/min;
Fluidized coating parameter described in step (3) is: control temperature 35 ~ 39 DEG C; Atomizing pressure 0.08 ~ 0.2MPa; Air blast frequency 25 ~ 35Hz; Peristaltic pump 0.5 ~ 2.5mL/min;
Step (4) fluidized coating parameter is: control temperature is at 40 ± 3 DEG C; Atomizing pressure is 0.08 ~ 0.12MPa; Air blast frequency is 27Hz; Hydrojet speed is 2.0mL/min;
Step (5) fluidized coating parameter is: control temperature is at 35 ~ 40 DEG C; Atomizing pressure is 0.08 ~ 0.11MPa; Air blast frequency is 29.5Hz; Hydrojet speed is 1.0mL/min.
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| CN110478333A (en) * | 2019-06-20 | 2019-11-22 | 南京知和医药科技有限公司 | Compound omeprazole capsulae enterosolubilis and preparation method thereof |
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