CN1235018A - Pantoprazole sodium freeze-dried powder injection and preparation method - Google Patents
Pantoprazole sodium freeze-dried powder injection and preparation method Download PDFInfo
- Publication number
- CN1235018A CN1235018A CN 99112872 CN99112872A CN1235018A CN 1235018 A CN1235018 A CN 1235018A CN 99112872 CN99112872 CN 99112872 CN 99112872 A CN99112872 A CN 99112872A CN 1235018 A CN1235018 A CN 1235018A
- Authority
- CN
- China
- Prior art keywords
- freeze
- dried powder
- sodium
- injection
- pantoprazole sodium
- 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.)
- Pending
Links
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 31
- 239000000843 powder Substances 0.000 title claims abstract description 30
- 238000002347 injection Methods 0.000 title claims abstract description 26
- 239000007924 injection Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 239000008139 complexing agent Substances 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- OQZCJRJRGMMSGK-UHFFFAOYSA-M potassium metaphosphate Chemical compound [K+].[O-]P(=O)=O OQZCJRJRGMMSGK-UHFFFAOYSA-M 0.000 claims description 4
- 229940099402 potassium metaphosphate Drugs 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 claims description 3
- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229940102253 isopropanolamine Drugs 0.000 claims description 3
- 235000019983 sodium metaphosphate Nutrition 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 2
- 229940043276 diisopropanolamine Drugs 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- RFCKRIWTGOTBLT-UHFFFAOYSA-L disodium dihydrogen phosphate hydrogen carbonate Chemical compound [Na+].[Na+].OC(O)=O.OP([O-])([O-])=O RFCKRIWTGOTBLT-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 claims description 2
- 229940009662 edetate Drugs 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229940086065 potassium hydrogentartrate Drugs 0.000 claims description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 claims description 2
- 229940074439 potassium sodium tartrate Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229940001593 sodium carbonate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229940076133 sodium carbonate monohydrate Drugs 0.000 claims description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 229960004418 trolamine Drugs 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 5
- 239000001301 oxygen Substances 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 5
- 238000001990 intravenous administration Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 239000003610 charcoal Substances 0.000 abstract description 2
- 238000010253 intravenous injection Methods 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 229940090044 injection Drugs 0.000 description 15
- 239000003814 drug Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229960005019 pantoprazole Drugs 0.000 description 4
- 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 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 238000010525 oxidative degradation reaction Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 206010002243 Anastomotic ulcer Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- -1 phosphodithioethylglycine Chemical compound 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种泮托拉唑钠冻干粉针剂,其特征在于:该针剂为不含结晶水的冻干粉针剂,pH值在9～12.5之间,组成包括泮托拉唑钠、冻干粉支持剂、金属离子络合剂和pH调节剂,重量份数为泮托拉唑钠1份;冻干粉支持剂1～5份;金属离子络合剂0.05～2份。上述配方过滤除炭,除菌,灌装;首先预冻至－55～－35℃,保温1～4小时,开始抽真空,在15～30小时内,将温度升至10～50℃,继续保持真空3～10小时;充氮保藏,即得到冻干粉针剂。本发明对光、热、氧、水等稳定的不含结晶水,便于操作,适于大规模生产,可供静脉滴注给药,避免静脉推注可能导致的毒副作用。A freeze-dried powder injection of pantoprazole sodium, characterized in that: the injection is a freeze-dried powder injection without crystal water, the pH value is between 9 and 12.5, and the composition includes pantoprazole sodium, freeze-dried powder support Agent, metal ion complexing agent and pH regulator, the parts by weight are 1 part of pantoprazole sodium; 1-5 parts of freeze-dried powder support agent; 0.05-2 parts of metal ion complexing agent. The above formula is filtered to remove charcoal, sterilize, and fill; first, pre-freeze to -55--35°C, keep warm for 1-4 hours, start vacuuming, and within 15-30 hours, raise the temperature to 10-50°C, continue Keep the vacuum for 3-10 hours; store it with nitrogen filling, and obtain the freeze-dried powder injection. The invention is stable to light, heat, oxygen, water, etc., does not contain crystal water, is easy to operate, is suitable for large-scale production, can be used for intravenous drip administration, and avoids possible toxic and side effects caused by intravenous injection.
Description
本发明涉及消化性溃疡药，泮托拉唑钠冻干粉针剂的处方及制备方法。The invention relates to a prescription and a preparation method of a peptic ulcer medicine, pantoprazole sodium freeze-dried powder injection.
消化性溃疡包括胃溃疡、十二指肠溃疡、吻合部溃疡、反流性食管炎以及卓一艾氏综合等疾病是危害人体健康的主要疾病之一，而重症患者往往需要注射给药。泮托拉唑钠为质子泵抑制剂类抗溃疡新药。由于泮托拉唑钠对光、热、氧、水的等很敏感，若要制成水针则无法满足贮存及使用时的稳定性要求，又因给药剂量小，所以无法采用固体粉末分装的方法，因此本发明中泮托拉唑钠的剂型为冻干粉针剂。Peptic ulcers, including gastric ulcers, duodenal ulcers, anastomotic ulcers, reflux esophagitis, and Joel-Ehrlich syndrome, are one of the major diseases that endanger human health, and severe patients often need injections. Pantoprazole sodium is a new anti-ulcer drug of proton pump inhibitors. Because pantoprazole sodium is very sensitive to light, heat, oxygen, water, etc., if it is to be made into water injection, it cannot meet the stability requirements during storage and use, and because of the small dosage, it cannot be separated by solid powder. The method of packing, therefore the dosage form of pantoprazole sodium among the present invention is freeze-dried powder injection.
冻干粉针制备工艺及制剂是以冷冻干燥原理制备注射用无菌粉末的制备工艺及用该工艺制备的冻干粉针剂。The preparation process and preparation of freeze-dried powder injection are the preparation process of sterile powder for injection based on the principle of freeze-drying and the freeze-dried powder injection prepared by this process.
泮托拉唑钠冻干粉针已于1995年由德国BykGuloden公司申请了欧洲专利，其制备工艺是将泮托拉唑钠倍半水合物及蔗糖溶于注射用水，冷冻干燥得到冻干粉剂。其缺点是药物的稳定性较差，在光、热、氧、水的作用下会导致氧化降解。Freeze-dried powder of pantoprazole sodium was applied for European patent in 1995 by German BykGuloden company, and its preparation process is to dissolve pantoprazole sodium sesquihydrate and sucrose in water for injection, and freeze-dry to obtain freeze-dried powder. The disadvantage is that the stability of the drug is poor, and it will cause oxidative degradation under the action of light, heat, oxygen, and water.
本发明的目的在于提供一种对光、热、氧、水等稳定的不含结晶水的，并便于操作，适于大规模生产的泮托拉唑钠冻干粉针剂，可供静脉滴注给药，避免静脉推注可能导致的毒副作用。The object of the present invention is to provide a kind of freeze-dried powder injection of pantoprazole sodium that is stable to light, heat, oxygen, water, etc., does not contain crystal water, and is easy to operate, and is suitable for large-scale production, which can be used for intravenous infusion. Administration to avoid possible toxic side effects caused by intravenous injection.
本发明提供了一种泮托拉唑钠冻干粉针剂，其特征在于：该针剂为不含结晶水的冻干粉针剂，pH值在9～12.5之间，组成包括泮托拉唑钠、冻干粉支持剂、金属离子络合剂和pH值调节剂，重量份数为The invention provides a freeze-dried powder injection of pantoprazole sodium, which is characterized in that: the injection is a freeze-dried powder injection without crystal water, the pH value is between 9 and 12.5, and the composition includes pantoprazole sodium, Freeze-dried powder support agent, metal ion complexing agent and pH regulator, parts by weight are
泮托拉唑钠 1份Pantoprazole Sodium 1 part
冻干粉支持剂 1～5份Freeze-dried powder support agent 1 to 5 parts
金属离子络合剂 0.05～2份Metal ion complexing agent 0.05～2 parts
其中冻干粉支持剂是水溶性支持剂，选自甘露醇、葡萄糖、NaCl、右旋糖酐；金属离子络合剂选自依地酸盐、构橼酸、酒石酸、磷酸二硫乙基甘氨酸、及其盐类；pH值调节剂选自二乙醇胺、一乙醇胺、二异丙胺、二异丙醇胺、三乙醇胺、1,2-己二胺、无水碳酸钠、结晶碳酸钠、一水碳酸钠、异丙醇胺、单乙醇胺、氢氧化钠、氢氧化钾、枸橼酸钠、枸橼酸钾、D-酒石酸氢钾、酒石酸钾钠、偏磷酸钾、聚偏磷酸钾、偏磷酸钠、碳酸氢钠、碳酸氢钾、碳酸铵、磷酸氢二钠、磷酸氢二钾。Wherein the freeze-dried powder support agent is a water-soluble support agent selected from mannitol, glucose, NaCl, dextran; the metal ion complexing agent is selected from edetate, structural citric acid, tartaric acid, phosphodithioethylglycine, and Salts; pH regulators are selected from the group consisting of diethanolamine, monoethanolamine, diisopropylamine, diisopropanolamine, triethanolamine, 1,2-hexamethylenediamine, anhydrous sodium carbonate, crystalline sodium carbonate, sodium carbonate monohydrate, Isopropanolamine, monoethanolamine, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, D-potassium hydrogen tartrate, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, sodium metaphosphate, carbonic acid Sodium hydrogen phosphate, potassium hydrogen carbonate, ammonium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate.
本发明还提供了泮托拉唑钠冻干粉针剂的制备方法，其特征在于：取处方量泮托拉唑钠、支持剂和金属离子络合剂加入注射用水搅拌溶解，用pH值调节剂调pH值至适当范围，加入0.1～0.5％的针用活性炭，过滤除炭，除菌，灌装；首先予冻至-55～-35℃，保温1～4小时，开始抽真空，在15～30小时内，将温度升至10～50℃，继续保持真空3～10小时；充氮保藏。The present invention also provides the preparation method of pantoprazole sodium freeze-dried powder injection, it is characterized in that: take prescription amount pantoprazole sodium, support agent and metal ion complexing agent, add water for injection and stir to dissolve, use pH regulator Adjust the pH value to an appropriate range, add 0.1-0.5% activated carbon for needles, filter to remove carbon, sterilize, and fill; Within ~ 30 hours, raise the temperature to 10 ~ 50 ° C, and continue to maintain the vacuum for 3 ~ 10 hours; store with nitrogen.
本发明中使用的支持剂是水溶性支持剂，具有水中易溶的特点，可使本制剂使用对迅速溶解便可临床使用。金属离子络合剂的作用是络合金属离子。使泮托拉唑钠免受金属离子的催化水解氟化，以保证制备和滴注过程中的稳定性，经加入前后稳定性的对比表明，加入金属离子络合剂可以使泮托拉唑钠的稳定性提高，加入量超过2份时，稳定性不再发生明显变化。The support agent used in the present invention is a water-soluble support agent, which has the characteristics of being easily soluble in water, so that the preparation can be used clinically after being dissolved rapidly. The role of the metal ion complexing agent is to complex metal ions. Make pantoprazole sodium free from the catalyzed hydrolysis fluorination of metal ion, to guarantee the stability in the preparation and dripping process, show through the contrast of stability before and after adding, add metal ion complexing agent and can make pantoprazole sodium The stability of the compound is improved, and when the addition amount exceeds 2 parts, the stability does not change significantly.
由于泮托拉唑钠在碱性条件下稳定，所以为了在药物制剂及贮存过程中稳定，需要将pH值调高，通过80℃条件下考察结果可知，泮托拉唑钠在pH11以上稳定性明显提高，而在pH11.5以后降解已非常缓慢，结果见下表。Because pantoprazole sodium is stable under alkaline conditions, it is necessary to increase the pH value in order to be stable in the pharmaceutical preparation and storage process. It can be seen from the investigation results under the condition of 80 ℃ that the stability of pantoprazole sodium is above pH11. significantly improved, but after pH11.5, the degradation is very slow, the results are shown in the table below.
pH值与泮托拉唑钠稳定性的关系The relationship between pH value and the stability of pantoprazole sodium
pH值 含量变化pH value Content change
12 98.712 98.7
11.5 98.511.5 98.5
11 98.111 98.1
10 97.210 97.2
9 95.89 95.8
8 93.68 93.6
7 91.57 91.5
但pH调节剂的量不可过多加入，否则pH值过高，当用100ml 0.9％氯化钠或5％葡萄糖注射剂稀释时，pH值不能降至正常机体可以承受的范围以内，因此将本品的碱度定为pH 9～12.5，最适pH值10～115，当用0.9％氯化钠或5％葡萄糖注射液溶解时，pH值在10以下，在机体可以承受的范围以内，这样就可以使泮托拉唑钠溶解后6小时保持稳定，使临床静脉滴注成为可能。However, the amount of pH regulator should not be added too much, otherwise the pH value is too high. When diluted with 100ml 0.9% sodium chloride or 5% glucose injection, the pH value cannot be reduced to the range that the normal body can bear. The alkalinity is set at pH 9-12.5, and the optimum pH value is 10-115. When dissolved with 0.9% sodium chloride or 5% glucose injection, the pH value is below 10, which is within the range that the body can bear. It can keep pantoprazole sodium stable for 6 hours after dissolving, making clinical intravenous infusion possible.
本发明为泮托拉唑钠冻干粉针剂，制备过程中加入了金属离子络合剂，pH值调节剂，充入了惰性气体，可有效的提高药物的稳定性，避免了药物受光、热、氧、水的等的作用而导致氧化降解，本发明冻干粉针剂不含结晶水，可在室温下贮藏，在注射液中稳定6小时以上可用于静脉滴注。The invention is pantoprazole sodium freeze-dried powder injection. During the preparation process, a metal ion complexing agent and a pH value regulator are added, and an inert gas is filled, which can effectively improve the stability of the drug and avoid the drug being exposed to light and heat. Oxidative degradation is caused by the effects of oxygen, water, etc. The freeze-dried powder injection of the present invention does not contain crystal water, can be stored at room temperature, and can be used for intravenous infusion after being stable in injection for more than 6 hours.
下面通过实施例详述本发明。The present invention is described in detail below by way of examples.
实施例1Example 1
1)制剂处方：泮托拉唑钠 42.4g(相当于泮托拉唑40.0g)1) Preparation prescription: pantoprazole sodium 42.4g (equivalent to pantoprazole 40.0g)
甘 露 醇 140.0gMannitol 140.0g
枸橼酸钠 5.0gSodium citrate 5.0g
氢氧化钠 适量Sodium Hydroxide Appropriate amount
注射用水 2000mlWater for injection
制 备 1000支
2)制备工艺：取处方量泮托拉唑钠、甘露醇、枸橼酸钠，加注射用水1800ml，搅拌使其溶解，用25％NaOH调pH11.5～12.5，加0.3％针用活性炭，室温搅拌20min，过滤除炭，再过微孔滤膜除菌，补加无菌注射用水至2000ml，测定含量后，灌装，每支约2ml，予冻至-40℃，保温2小时，开始冻干，在17个小时内，温度由-40℃升至20℃继续保持真空5小时，取出充氮，加胶塞，压铝盖得成品。2) Preparation process: take the prescribed amount of pantoprazole sodium, mannitol, and sodium citrate, add 1800 ml of water for injection, stir to make it dissolve, adjust the pH to 11.5-12.5 with 25% NaOH, add 0.3% activated carbon for injection, Stir at room temperature for 20 minutes, filter to remove charcoal, and then pass through a microporous membrane to sterilize, add sterile water for injection to 2000ml, measure the content, fill, each about 2ml, freeze to -40°C, keep warm for 2 hours, start Freeze-drying, within 17 hours, the temperature rises from -40°C to 20°C and continues to maintain a vacuum for 5 hours, take out and fill with nitrogen, add rubber stoppers, and press aluminum caps to get the finished product.
实施例2Example 2
泮托拉唑钠 42.4g(相当于泮托拉唑40.0g). Osoma 42.4g (equivalent to osoma 40.0g)
葡 萄 糖 150.0g
依地酸二钠 4.0g
磷酸二氢钠 适量
注 射 用水 2000mlWater for Injection 2000ml
制 备 1000支
制备工艺同实施例1。The preparation process is the same as in Example 1.
实施例3Example 3
泮 托 拉 唑 钠 42.4g(相当于泮托拉唑40.0g)Pantoprazole sodium 42.4g (equivalent to pantoprazole 40.0g)
氯 化 钠 135.0gChloride Sodium 135.0g
二巯乙基甘氨酸 4.8g
异丙醇胺 适量 Isopropanolamine Appropriate amount
注射用水 2000ml
制 备 1000支制备工艺同实施例1。实施例4Preparation of 1000 pieces The preparation process is the same as in Example 1. Example 4
泮托拉唑钠 42.4g(相当于泮托拉唑40.0g) Pantoprazole Sodium 42.4g (equivalent to 40.0g pantoprazole)
右 旋 糖酐 120.0gDextran 120.0g
洒 石 酸钠 6.0gSodium tartrate 6.0g
偏 磷 酸钠 适量Sodium Metaphosphate Appropriate amount
注 射 用水 2000mlWater for injection 2000ml
制 备 1000支制备工艺同实施例1。Preparation of 1000 pieces The preparation process is the same as in Example 1.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99112872 CN1235018A (en) | 1999-04-22 | 1999-04-22 | Pantoprazole sodium freeze-dried powder injection and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99112872 CN1235018A (en) | 1999-04-22 | 1999-04-22 | Pantoprazole sodium freeze-dried powder injection and preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1235018A true CN1235018A (en) | 1999-11-17 |
Family
ID=5276121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99112872 Pending CN1235018A (en) | 1999-04-22 | 1999-04-22 | Pantoprazole sodium freeze-dried powder injection and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1235018A (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002041919A1 (en) * | 2000-11-22 | 2002-05-30 | Altana Pharma Ag | Freeze-dried pantoprazole preparation and pantoprazole injection |
| WO2006034632A1 (en) * | 2004-09-30 | 2006-04-06 | Jiangsu Hansen Pharmaceutical Co., Ltd. | New prazole compound and the use thereof |
| CN1293879C (en) * | 2005-01-20 | 2007-01-10 | 杭州华东医药集团生物工程研究所有限公司 | Freeze-dried powder injection of pantoprazole sodium and its preparation |
| AU2006235847B2 (en) * | 2000-11-22 | 2007-06-07 | Takeda Gmbh | Lyophilized pantoprazole preparation |
| WO2009001163A1 (en) * | 2006-06-01 | 2008-12-31 | Combino Pharm, S.L. | Lyophilized preparations of pantoprazole sodium for injection |
| CN102512418A (en) * | 2010-12-06 | 2012-06-27 | 山东绿叶制药有限公司 | Pantoprazole sodium drug composition and preparation method thereof |
| CN102670524A (en) * | 2012-05-04 | 2012-09-19 | 南京正大天晴制药有限公司 | Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof |
| CN102688204A (en) * | 2012-06-14 | 2012-09-26 | 江苏奥赛康药业股份有限公司 | S-pantoprazole sodium freeze-drying medicament composition and preparation method thereof |
| CN102846559A (en) * | 2012-09-20 | 2013-01-02 | 浙江亚太药业股份有限公司 | Pantoprazole sodium freeze-dry preparation and preparation method thereof |
| CN103202816A (en) * | 2013-05-09 | 2013-07-17 | 成都天台山制药有限公司 | Pantoprazole sodium freeze-dried powder injection |
| WO2014127496A1 (en) * | 2013-02-25 | 2014-08-28 | 海南普利制药股份有限公司 | Pantoprazole sodium freeze-dry preparation and preparing method thereof |
| WO2015055015A1 (en) * | 2013-10-15 | 2015-04-23 | 海南卫康制药(潜山)有限公司 | Pantoprazole sodium composition lyophilized powder injection for injection |
| CN104958265A (en) * | 2015-08-05 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal pantoprazole sodium composition granules for treating digestive system diseases |
| CN105078908A (en) * | 2015-08-24 | 2015-11-25 | 扬子江药业集团有限公司 | Pantoprazole sodium freeze-drying pharmaceutical composition for injection and preparation method thereof |
| CN109061011A (en) * | 2018-10-18 | 2018-12-21 | 成都天台山制药有限公司 | Freeze-dried powder injection of pantoprazole sodium pharmaceutical composition and preparation method |
-
1999
- 1999-04-22 CN CN 99112872 patent/CN1235018A/en active Pending
Cited By (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7351723B2 (en) | 2000-11-22 | 2008-04-01 | Nycomed Gmbh | Freeze-dried pantoprazole preparation and pantoprazole injection |
| WO2002041919A1 (en) * | 2000-11-22 | 2002-05-30 | Altana Pharma Ag | Freeze-dried pantoprazole preparation and pantoprazole injection |
| AU2002216042B2 (en) * | 2000-11-22 | 2006-08-03 | Takeda Gmbh | Freeze-dried pantoprazole preparation and pantoprazole injection |
| EA007602B1 (en) * | 2000-11-22 | 2006-12-29 | Алтана Фарма Аг | Pantoprazole preparation obtained by freeze drying and solution for injections based thereon |
| EP1762249A3 (en) * | 2000-11-22 | 2014-05-14 | Takeda GmbH | Freeze-dried pantoprazole preparation and pantoprazole injection |
| AU2006235847B2 (en) * | 2000-11-22 | 2007-06-07 | Takeda Gmbh | Lyophilized pantoprazole preparation |
| AU2006235847C1 (en) * | 2000-11-22 | 2008-02-21 | Takeda Gmbh | Lyophilized pantoprazole preparation |
| US6780881B2 (en) | 2000-11-22 | 2004-08-24 | Altana Pharma Ag | Freeze-dried pantoprazole preparation and pantoprazole injection |
| KR100910606B1 (en) * | 2000-11-22 | 2009-08-04 | 니코메드 게엠베하 | Lyophilized Pantoprazole Formulation and Pantoprazole Injection |
| CZ304348B6 (en) * | 2000-11-22 | 2014-03-19 | Takeda Gmbh | Process for preparing lyophilized preparation |
| KR100910607B1 (en) | 2000-11-22 | 2009-08-04 | 니코메드 게엠베하 | Freeze-dried pantoprazole preparation and pantoprazole injection |
| US8754108B2 (en) | 2000-11-22 | 2014-06-17 | Takeda, GmbH | Freeze-dried pantoprazole preparation and pantoprazole injection |
| WO2006034632A1 (en) * | 2004-09-30 | 2006-04-06 | Jiangsu Hansen Pharmaceutical Co., Ltd. | New prazole compound and the use thereof |
| CN1293879C (en) * | 2005-01-20 | 2007-01-10 | 杭州华东医药集团生物工程研究所有限公司 | Freeze-dried powder injection of pantoprazole sodium and its preparation |
| WO2009001163A1 (en) * | 2006-06-01 | 2008-12-31 | Combino Pharm, S.L. | Lyophilized preparations of pantoprazole sodium for injection |
| CN102512418B (en) * | 2010-12-06 | 2014-11-26 | 山东绿叶制药有限公司 | Pantoprazole sodium drug composition and preparation method thereof |
| CN102512418A (en) * | 2010-12-06 | 2012-06-27 | 山东绿叶制药有限公司 | Pantoprazole sodium drug composition and preparation method thereof |
| CN102670524A (en) * | 2012-05-04 | 2012-09-19 | 南京正大天晴制药有限公司 | Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof |
| CN102688204A (en) * | 2012-06-14 | 2012-09-26 | 江苏奥赛康药业股份有限公司 | S-pantoprazole sodium freeze-drying medicament composition and preparation method thereof |
| CN102688204B (en) * | 2012-06-14 | 2014-04-16 | 江苏奥赛康药业股份有限公司 | S-pantoprazole sodium freeze-drying medicament composition and preparation method thereof |
| CN102846559B (en) * | 2012-09-20 | 2014-07-09 | 浙江亚太药业股份有限公司 | Pantoprazole sodium freeze-dry preparation and preparation method thereof |
| CN102846559A (en) * | 2012-09-20 | 2013-01-02 | 浙江亚太药业股份有限公司 | Pantoprazole sodium freeze-dry preparation and preparation method thereof |
| WO2014127496A1 (en) * | 2013-02-25 | 2014-08-28 | 海南普利制药股份有限公司 | Pantoprazole sodium freeze-dry preparation and preparing method thereof |
| CN103202816A (en) * | 2013-05-09 | 2013-07-17 | 成都天台山制药有限公司 | Pantoprazole sodium freeze-dried powder injection |
| WO2015055015A1 (en) * | 2013-10-15 | 2015-04-23 | 海南卫康制药(潜山)有限公司 | Pantoprazole sodium composition lyophilized powder injection for injection |
| CN104958265A (en) * | 2015-08-05 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal pantoprazole sodium composition granules for treating digestive system diseases |
| CN105078908A (en) * | 2015-08-24 | 2015-11-25 | 扬子江药业集团有限公司 | Pantoprazole sodium freeze-drying pharmaceutical composition for injection and preparation method thereof |
| CN109061011A (en) * | 2018-10-18 | 2018-12-21 | 成都天台山制药有限公司 | Freeze-dried powder injection of pantoprazole sodium pharmaceutical composition and preparation method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1235018A (en) | Pantoprazole sodium freeze-dried powder injection and preparation method | |
| JP4886158B2 (en) | Lyophilized pantoprazole formulation and pantoprazole injection | |
| KR100598722B1 (en) | Gelled ophthalmic composition comprising xanthan gum | |
| JP6635927B2 (en) | Method for Producing a Stable Low Concentration Injectable Solution of Noradrenaline | |
| CN1368891A (en) | Moxilfloxacin formulation containing common salt | |
| US9283197B1 (en) | More potent and less toxic formulations of epinephrine and methods of medical use | |
| CN1213751C (en) | Formulation of substituted benzimidazoles | |
| AU2010238854B2 (en) | Paracetamol for parenteral administration | |
| CN1293879C (en) | Freeze-dried powder injection of pantoprazole sodium and its preparation | |
| JPH10508598A (en) | Storage-stable aqueous solutions containing thrombin inhibitors | |
| KR20250036905A (en) | Pharmaceutical composition containing pyrrole-type gastric acid secretion inhibitor and method for producing the same | |
| EP1039905B1 (en) | Pharmaceutical formulation comprising glycine as a stabilizer | |
| JP4617303B2 (en) | Flupirtine pharmaceutical form for injection | |
| CN114904001A (en) | A kind of pharmaceutical composition containing vonoprazan acetate and preparation method thereof | |
| WO2014127496A1 (en) | Pantoprazole sodium freeze-dry preparation and preparing method thereof | |
| CN103058999A (en) | Novel pantoprazole sodium compound and pharmaceutical composition thereof | |
| CN116159075A (en) | Polysaccharide instant granule and application thereof in gastroesophageal reflux treatment | |
| US20100010046A1 (en) | Pharmaceutical formulation for parenteral administration | |
| CN116509799B (en) | Naloxone hydrochloride injection and preparation method thereof | |
| CA3263348A1 (en) | Pharmaceutical composition containing pyrrole gastric acid secretion inhibitor and preparation method therefor | |
| CN119385959B (en) | A kind of risedronate sodium tablet and preparation method thereof | |
| CN116077446A (en) | Rabeprazole sodium freeze-dried powder injection and preparation method thereof | |
| CN111973562A (en) | Esomeprazole sodium for injection and preparation method thereof | |
| RU2545903C1 (en) | Pharmaceutical composition in form of lyophilisate for preparation of solution for parenteral application and method of obtaining thereof | |
| CN110652498A (en) | A kind of pharmaceutical dosage form for treating type 2 diabetes and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |