CN111670030A - 包含埃索美拉唑及碳酸氢钠的药剂学制剂 - Google Patents
包含埃索美拉唑及碳酸氢钠的药剂学制剂 Download PDFInfo
- Publication number
- CN111670030A CN111670030A CN201980009629.3A CN201980009629A CN111670030A CN 111670030 A CN111670030 A CN 111670030A CN 201980009629 A CN201980009629 A CN 201980009629A CN 111670030 A CN111670030 A CN 111670030A
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- China
- Prior art keywords
- coating
- omeprazole
- sodium bicarbonate
- enantiomer
- polyvinyl alcohol
- Prior art date
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- Granted
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 title claims abstract description 56
- 235000017557 sodium bicarbonate Nutrition 0.000 title claims abstract description 28
- 229910000030 sodium bicarbonate Inorganic materials 0.000 title claims abstract description 28
- 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 title claims description 21
- 229960004770 esomeprazole Drugs 0.000 title claims description 20
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
- 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 abstract description 38
- 229960000381 omeprazole Drugs 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000011248 coating agent Substances 0.000 claims description 97
- 238000000576 coating method Methods 0.000 claims description 72
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 35
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 35
- 239000000463 material Substances 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 5
- 229940069428 antacid Drugs 0.000 claims description 5
- 239000003159 antacid agent Substances 0.000 claims description 5
- 230000001458 anti-acid effect Effects 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 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 claims 2
- 239000012535 impurity Substances 0.000 abstract description 16
- 239000000203 mixture Substances 0.000 abstract description 11
- 238000009472 formulation Methods 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 27
- 239000003826 tablet Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 14
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000008213 purified water Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 238000005507 spraying Methods 0.000 description 6
- 239000000454 talc Substances 0.000 description 6
- 229910052623 talc Inorganic materials 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- VEVZQDGATGBLIC-OXLUMUBXSA-N magnesium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide;trihydrate Chemical compound O.O.O.[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 VEVZQDGATGBLIC-OXLUMUBXSA-N 0.000 description 4
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- IXEQEYRTSRFZEO-UHFFFAOYSA-N Omeprazole sulfone Chemical compound N1C2=CC(OC)=CC=C2N=C1S(=O)(=O)CC1=NC=C(C)C(OC)=C1C IXEQEYRTSRFZEO-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000007962 solid dispersion Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 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
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 229920001531 copovidone Polymers 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 229940008099 dimethicone Drugs 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 229940087068 glyceryl caprylate Drugs 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000028399 Critical Illness Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010027423 Metabolic alkalosis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000027687 belching Diseases 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
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- 201000000052 gastrinoma Diseases 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K9/0007—Effervescent
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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Abstract
本发明涉及包含奥美拉唑、其对映异构体或药剂学上可接受的盐及碳酸氢钠的稳定的药剂学制剂及其制备方法。具体地,本发明提供一种通过抑制奥美拉唑、其对映异构体或药剂学上可接受的盐及碳酸氢钠直接接触来减少杂质的生成的稳定的制剂。
Description
技术领域
本发明涉及包含奥美拉唑、其对映异构体或药剂学上可接受的盐及碳酸氢钠的稳定的药剂学制剂及其制备方法。具体地,本发明提供一种通过抑制奥美拉唑、其对映异构体或药剂学上可接受的盐及碳酸氢钠直接接触来减少杂质的生成的稳定的制剂。
背景技术
奥美拉唑(omeprazole)的化学名为5-甲氧基-2-[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚磺酰基-1H-苯并咪唑。奥美拉唑以两种异构体形式存在,即,R-异构体及S-异构体。相对于R-异构体,已知S-异构体在治疗效果及副作用方面显著优秀。上述S-异构体为(S)-5-甲氧基-2-[(4-甲氧基-3,5-二甲基-2-吡啶基)-甲基]亚磺酰基-1H-苯并咪唑,通常被称为埃索美拉唑(esomeprazole)。
埃索美拉唑是用于治疗消化不良、消化性溃疡疾病(peptic ulcer disease)、胃食管反流疾病(gastroesophageal reflux disease)及佐林格一埃利森综合征(Zollinger-Ellison syndrome)等的代表性质子泵抑制剂(proton pump inhibitor;PPI)。
在本领域中众所周知,奥美拉唑,尤其,埃索美拉唑在酸性和中性介质中易于分解或变形,更具体地,在pH值为3以下的水溶液中,已知埃索美拉唑的分解半衰期小于10分钟。因此,酸性化合物可促进埃索美拉唑的分解,并且还会受水分、热量、有机溶剂及光的影响。
因此,对于稳定的埃索美拉唑制剂存在许多需求,并且为了解决稳定性问题,韩国专利第384960号中公开了制备包含埃索美拉唑镁盐的微丸后,对其进行肠溶衣后通过添加赋形剂来制成片剂的方法。通过上述方法制备的制剂目前以的商品名市售。
然而,就耐信等肠溶衣片而言,其被设计成在肠中溶解和吸收而不会立即从胃中吸收,因此它不适用于在给药后需要立即治疗的疾病,如胃酸相关疾病。
韩国专利第1104349号中公开了一种肠溶衣片和胶囊,其通过制备成氧化镁和聚维酮的固体分散体剂型来改善奥美拉唑的稳定性和物理性问题点。
韩国专利公告第10-1996-0003605号中公开了一种通过添加奥美拉唑作为有效成分,并添加β-环糊精和氢氧化钠作为稳定成分来制备固体分散体剂型的方法。然而,上述专利中描述的发明存在使用对人体有害的氢氧化钠的问题点。由于制备固体分散体的过程包括将作为有效成分的奥美拉唑溶解于溶剂中的过程,因此,在该过程中需要特殊的稳定剂如氢氧化钠来稳定奥美拉唑。
为了解决这些问题点,韩国专利第679767号中公开了在奥美拉唑中使用碳酸氢钠(sodium bicarbonate)等缓冲液的方法。
然而,在使用大量碳酸氢钠的情况下,具有降低奥美拉唑的功效并诱发副作用的缺点。具体地,在给药大量碳酸氢钠的情况下,胃部肿胀可能会加重危重病人的痛,而碳酸氢钠的吸收可能会导致打嗝,从而引起胃酸向上移动,可使胃食管反流病加重。并且,患有高血压或心力衰竭等症状的患者需要抑制可诱发高血压症状的钠(sodium)的摄入,因此不宜向患有这些症状的患者给药大量碳酸氢钠。并且,向患有各种并发症的患者给药大量碳酸氢钠存在代谢性碱中毒的风险。并且,由于改变胃和尿液pH的缓冲液会影响药物的吸收、分布和代谢过程,因此在将大量碳酸氢钠与奥美拉唑一起使用时,需要多加注意。
并且,由于奥美拉唑或其对映异构体及碳酸氢钠的配合稳定差,导致相互接触的情况下杂质增加的问题。
发明内容
技术问题
本发明人为了在低pH下不稳定的奥美拉唑或其对映异构体的稳定化,开发了一种包含碳酸氢钠作为增加胃中pH的制酸剂(antiacid)的制剂。但是,为了解决同时包含奥美拉唑或其对映异构体及碳酸氢钠时可产生的配合稳定性的问题,适用了各种包衣剂的结果,通过长期的实验和研究确认聚乙烯醇最合适,从而完成了本发明。
并且,聚乙烯醇不仅通过也抑制奥美拉唑或其对映异构体与碳酸氢钠的接触来改善制剂的稳定性,而且还确认通过包衣片剂的外部来进一步改善制剂的稳定性,因此,开发了具有优秀的稳定性的制剂。
技术方案
本发明涉及包含奥美拉唑、其对映异构体或药剂学上可接受的盐及碳酸氢钠,还包含聚乙烯醇作为包衣剂的药剂学制剂。
奥美拉唑的对映体可以为S-异构体或R-异构体,但是,优选地,其为S-异构体的埃索美拉唑。
本发明的“药剂学上可接受的盐”可以为钠、钾、钙、镁、锌、锂等金属盐或铵盐,但并不限定于此。其中,优选地为镁盐。
上述奥美拉唑、其对映体或其药剂学上可接受的盐可以为其溶剂化物,溶剂化物包括一水合物、二水合物、三水合物等水合物,且可以是无定形或结晶。
可将碳酸氢钠作为用于稳定在低pH下不稳定的奥美拉唑或其对映异构体的制酸剂(antacid)来使用。
本发明的包衣剂起到通过分离和/或抑制奥美拉唑、其对映异构体或药剂学上可接受的盐与碳酸氢钠的直接接触来改善配合稳定性的作用。
本发明涉及一种药剂学制剂,其特征在于,包括:第一层,包含奥美拉唑、其对映异构体或其药剂学上可接受的盐;第二层,包含聚乙烯醇作为包衣剂;以及第三层,包含碳酸氢钠作为制酸剂。
并且,本发明的包衣剂还起到通过包衣制剂的外部来改善稳定性的作用。
并且,本发明涉及一种药剂学制剂,其还包括第四层,上述第四层包含聚乙烯醇作为包衣剂。
相对于1重量的奥美拉唑、其对映异构体或药剂学上可接受的盐,可包含0.1重量至7重量的上述第二层及第四层的包衣剂,优选地,可包含0.5重量至5重量的上述第二层及第四层的包衣剂。
本发明的药剂学制剂可通过如下步骤来制备:通过使用包含奥美拉唑、其对映异构体或药剂学上可接受的盐的包衣液对芯进行第一次包衣来制备第一包衣物质的步骤;通过使用包含聚乙烯醇的第二包衣液对上述第一包衣物质进行包衣来制备第二包衣物质的步骤;将上述第二包衣物质与碳酸氢钠一起进行压片来制备压片物质的步骤;以及通过使用包含聚乙烯醇的第三包衣液对上述压片物质进行包衣的步骤。
更具体地,本发明涉及如下的药剂学制剂,即,以埃索美拉唑含量为基准,包含20mg或40mg的埃索美拉唑镁三水合物及800mg的碳酸氢钠,其可通过如下步骤来制备:通过使用包含埃索美拉唑镁三水合物的包衣液对芯进行第一次包衣来制备第一包衣物质的步骤;通过使用包含聚乙烯醇的第二包衣液对上述第一包衣物质进行包衣来制备第二包衣物质的步骤;将上述第二包衣物质与碳酸氢钠一起进行压片来制备压片物质的步骤;以及通过使用包含聚乙烯醇的第三包衣液对上述压片物质进行包衣的步骤。
发明的效果
本发明涉及包含奥美拉唑,其对映异构体或其药剂学上可接受的盐及碳酸氢钠的稳定性得以改善的药剂学制剂。本发明的药剂学制剂通过抑制奥美拉唑与碳酸氢钠的接触来改善配合稳定性,并通过包衣压片而成的片剂来进一步改善制剂的稳定性。
将本发明的制剂制备成单层片剂,不仅制备方法简单并具有优秀的稳定性,而且立即从胃中洗脱并吸收,从而具有优秀的洗脱率及生物利用率。
具体实施方式
下面,通过实施例进一步详细说明本发明。但是,提供这些实施例仅出于有助于理解本发明的示例性目的,本发明的范围并不限定于以下实施例。
实施例1
包含聚乙烯醇(PVA)作为包衣剂的埃索美拉唑片剂的制备
通过如下方法制备包含聚乙烯醇的埃索美拉唑片剂。
1.第一次包衣
加入纯净水和羟丙基纤维素溶解后,通过分散精氨酸、二甲硅油、纯净水、埃索美拉唑镁三水合物(22.3mg;以埃索美拉唑含量为基准是20.00mg)、氧化镁及滑石来制备包衣液。将球形白糖加入流化床颗粒包衣机中,并通过喷雾上述包衣液来制备第一包衣物质。
2.第二次包衣
将聚乙烯醇(7.4mg;相对于片剂的总重量为0.7重量百分比)、滑石、氧化钛、单辛酸甘油酯及月桂基硫酸钠分散在纯净水来制备包衣液。将上述第一包衣物质加入流化床颗粒包衣机中,并通过喷雾上述包衣液来制备第二包衣物质。
3.混合及压片
将上述第二包衣物质、碳酸氢钠(800mg),共聚维酮及交联聚维酮加入混合器并进行混合后,通过加入硬脂富马酸钠来进行润滑并制备颗粒。对制备的颗粒进行压片。
4.第三次包衣
将聚乙烯醇(15.5mg;相对于片剂的总重量,1.5重量百分比)、滑石、氧化钛、单辛酸甘油酯、月桂基硫酸钠、红色氧化铁、黑色氧化铁及黄色氧化铁加入纯净水来制备包衣液。将上述压片物质加入包衣机中,并通过喷雾及干燥包衣液来获得最终包衣片剂。
比较例1
包含羟丙基甲基纤维素作为包衣剂的埃索美拉唑片剂的制备
使用羟丙基甲基纤维素代替上述实施例1的制备方法中聚乙烯醇作为第二次包衣及第三次包衣的包衣剂,并通过如下方法制备。
1.第一次包衣
将羟丙基纤维素溶解于纯净水后,通过分散二甲硅油、埃索美拉唑镁三水合物、氧化镁、滑石、聚乙二醇及吐温80来制备包衣液。将球形白糖加入流化床颗粒包衣机中,并通过喷雾上述包衣液来制备第一包衣物质。
2.第二次包衣
加入羟丙基甲基纤维素、聚乙二醇、氢氧化钠、二甲硅油及滑石分散在纯净水来制备包衣液。将上述第一包衣物质加入流化床颗粒包衣机中,并通过喷雾上述包衣液来制备第二包衣物质。
3.混合及压片
将上述第二包衣物质、碳酸氢钠、共聚维酮及交联聚维酮加入混合器并进行混合后,通过加入硬脂富马酸钠来制备颗粒。对制备的颗粒进行压片。
4.第三次包衣
将羟丙基甲基纤维素、氧化钛、滑石、聚乙二醇、黄色氧化铁、红色氧化铁及黑色氧化铁加入纯净水来制备包衣液。将上述压片物质加入包衣机中,并通过喷雾及干燥包衣液来获得最终包衣片剂。
比较例2及比较例3
包含羟丙基甲基纤维素(HPMC)及聚乙烯醇(PVA)作为包衣剂的埃索美拉唑片剂的
制备
使用羟丙基甲基纤维素代替实施例1的片剂的制备方法中聚乙烯醇作为第二包衣剂,制备比较例2的片剂,并使用羟丙基甲基纤维素代替聚乙烯醇作为第三包衣剂,制备比较例3的片剂。
在实施例1及比较例1至3的制备中使用的包衣剂的种类如下述表1所示。
表1
第二包衣剂 | 第三包衣剂 | |
实施例1 | 聚乙烯醇 | 聚乙烯醇 |
比较例1 | 羟丙基甲基纤维素 | 羟丙基甲基纤维素 |
比较例2 | 羟丙基甲基纤维素 | 聚乙烯醇 |
比较例3 | 聚乙烯醇 | 羟丙基甲基纤维素 |
实验例1
杂质实验
针对于实施例1及比较例1至比较例3的片剂,为了确认稳定性而进行了加速试验,通过分析试验条件来测量杂质。
杂质分析试验
1)检测器:紫外线吸收光度计(测定波长:305nm)
2)柱:菲罗门月神C18(Phenomenex Luna C18)(4.6×150mm,3μm)或与其等同的柱
3)注入量:50μL
4)流量:1.0mL/分钟
5)柱温度:接近30℃的恒温
6)样品温度:接近4℃的恒温
7)移动相:
移动相A:用正丁胺将pH8.7缓冲液、乙腈及甲醇的混合液(7:2:1)调节至pH8.7的溶液
移动相B:pH8.7缓冲液及乙腈的混合液(2:8)
时间(分钟) | 移动相A | 移动相B |
0 | 100 | 0 |
20 | 100 | 0 |
25 | 70 | 30 |
35 | 80 | 20 |
40 | 80 | 20 |
45 | 100 | 0 |
50 | 100 | 0 |
上述pH8.7缓冲液是取0.71g的过氯酸钠(NaClO4)及5mL的正丁胺加入1L的容量瓶,并用过氯酸(HClO4)将用纯净水标线的溶液调至pH8.7的溶液。
杂质试验结果如下述表2至表4所示。
表2奥美拉唑砜含量(基准:0.5%以下)
初始 | 加速1个月 | 加速3个月 | |
实施例1 | 0.08% | 0.11% | 0.15% |
比较例1 | 0.10% | 0.19% | 0.39% |
比较例2 | 0.10% | 0.15% | 0.29% |
比较例3 | 0.10% | 0.15% | 0.29% |
如上述表2所示,实施例1的片剂的奥美拉唑砜含量最少,可知其稳定性最优秀。在加速3个月的情况下,可知比较例1至比较例3的奥美拉唑砜杂质含量为实施例1的2倍以上。
并且,与使用聚乙烯醇作为第二层及第三层中的一种包衣剂的比较例2及比较例3相比,确认使用羟丙基甲基纤维素代替聚乙烯醇作为第二层及第三层的所有包衣剂的比较例1的稳定性更差。
表3其他各个杂质含量(基准:0.2%以下)
初始 | 加速1个月 | 加速3个月 | |
实施例1 | 0.01% | 0.05% | 0.10% |
比较例1 | 0.09% | 0.24% | 0.51% |
比较例2 | 0.06% | 0.19% | 0.32% |
比较例3 | 0.06% | 0.19% | 0.32% |
如上述表3所示,实施例1的片剂的其他各个杂质含量最少,可知其稳定性最优秀。在加速1个月及3个月的情况下,可知比较例1至比较例3的其他各个杂质含量为实施例1的几乎3倍至5倍。在加速3个月的情况下,比较例1至比较例3大于杂质基准0.2%以下的含量,确认不满足稳定性要求。
并且,与使用聚乙烯醇作为第二层及第三层中的一种包衣剂的比较例2及比较例3相比,确认使用羟丙基甲基纤维素代替聚乙烯醇作为第二层及第三层的所有包衣剂的比较例1的稳定性更差。
表4总杂质含量(基准:2.0%以下)
初始 | 加速1个月 | 加速3个月 | |
实施例1 | 0.04% | 0.32% | 0.87% |
比较例1 | 0.29% | 1.08% | 1.11% |
比较例2 | 0.19% | 0.58% | 1.33% |
比较例3 | 0.19% | 0.58% | 1.33% |
如上述表4所示,实施例1的片剂的总杂质含量少,可知其稳定性最优秀。
结果可知,与比较例1至比较例3的片剂相比,实施例1的片剂在各个杂质及总杂质含量方面具有显著优秀的稳定性。
并且,为了阻止奥美拉唑和碳酸氢钠的接触将聚乙烯醇用作包衣剂,当将聚乙烯醇用作包衣剂以包衣制剂的外部时,可知稳定性最优秀。
Claims (8)
1.一种药剂学制剂,其特征在于,包括:
第一层,包含奥美拉唑、其对映异构体或其药剂学上可接受的盐;
第二层,包含聚乙烯醇作为包衣剂;以及
第三层,包含碳酸氢钠作为制酸剂。
2.根据权利要求1所述的药剂学制剂,其特征在于,还包括第四层,上述第四层包含聚乙烯醇作为包衣剂。
3.根据权利要求2所述的药剂学制剂,其特征在于,相对于1重量的奥美拉唑、其对映异构体或其药剂学上可接受的盐,包含0.1重量至7重量的上述第二层及第四层的包衣剂。
4.根据权利要求3所述的药剂学制剂,其特征在于,相对于1重量的奥美拉唑、其对映异构体或其药剂学上可接受的盐,包含0.5重量至5重量的上述第二层及第四层的包衣剂。
5.根据权利要求1所述的药剂学组合物,其特征在于,上述奥美拉唑、其对映异构体或其药剂学上可接受的盐为埃索美拉唑。
6.根据权利要求1所述的药剂学组合物,其特征在于,上述奥美拉唑、其对映异构体或其药剂学上可接受的盐为埃索美拉唑镁盐。
7.一种药剂学制剂的制备方法,包含奥美拉唑、其对映异构体或其药剂学上可接受的盐及碳酸氢钠,其特征在于,包括:
通过使用包含奥美拉唑、其对映异构体或药剂学上可接受的盐的包衣液对芯进行第一次包衣来制备第一包衣物质的步骤;
通过使用包含聚乙烯醇的第二包衣液对上述第一包衣物质进行包衣来制备第二包衣物质的步骤;
将上述第二包衣物质与碳酸氢钠一起进行压片来制备压片物质的步骤;以及
通过使用包含聚乙烯醇的第三包衣液对上述压片物质进行包衣的步骤。
8.一种药剂学制剂的制备方法,以埃索美拉唑含量为基准,包含20mg或40mg的埃索美拉唑镁三水合物以及800mg的碳酸氢钠,其特征在于,包括:
通过使用包含埃索美拉唑镁三水合物的包衣液对芯进行第一次包衣来制备第一包衣物质的步骤;
通过使用包含聚乙烯醇的第二包衣液对上述第一包衣物质进行包衣来制备第二包衣物质的步骤;
将上述第二包衣物质与碳酸氢钠一起进行压片来制备压片物质的步骤;以及
通过使用包含聚乙烯醇的第三包衣液对上述压片物质进行包衣的步骤。
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KR10-2018-0010987 | 2018-01-29 | ||
PCT/KR2019/001183 WO2019147094A1 (en) | 2018-01-29 | 2019-01-28 | Pharmaceutical formulation comprising esomeprazole and sodium bicarbonate |
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JP2021507926A (ja) | 2021-02-25 |
WO2019147094A1 (en) | 2019-08-01 |
US11759428B2 (en) | 2023-09-19 |
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