CN1293879C - Freeze-dried powder injection of pantoprazole sodium and its preparation - Google Patents
Freeze-dried powder injection of pantoprazole sodium and its preparation Download PDFInfo
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- CN1293879C CN1293879C CNB2005100234698A CN200510023469A CN1293879C CN 1293879 C CN1293879 C CN 1293879C CN B2005100234698 A CNB2005100234698 A CN B2005100234698A CN 200510023469 A CN200510023469 A CN 200510023469A CN 1293879 C CN1293879 C CN 1293879C
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- sodium
- pantoprazole
- freeze
- pantoprazole sodium
- dried powder
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- 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 39
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 39
- 238000002347 injection Methods 0.000 title claims abstract description 23
- 239000007924 injection Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000000843 powder Substances 0.000 title claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000001447 alkali salts Chemical class 0.000 claims abstract description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 150000007529 inorganic bases Chemical class 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims description 11
- 229960005019 pantoprazole Drugs 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000001509 sodium citrate Substances 0.000 claims description 9
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 229920002307 Dextran Polymers 0.000 claims description 5
- 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 5
- 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 5
- 239000008103 glucose Substances 0.000 claims description 5
- 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 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001508 potassium citrate Substances 0.000 claims description 4
- 229960002635 potassium citrate Drugs 0.000 claims description 4
- 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 4
- 235000011082 potassium citrates Nutrition 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 4
- 229910000397 disodium phosphate Inorganic materials 0.000 claims 2
- 235000019800 disodium phosphate Nutrition 0.000 claims 2
- 230000008014 freezing Effects 0.000 claims 2
- 238000007710 freezing Methods 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 2
- 235000017550 sodium carbonate Nutrition 0.000 claims 2
- 235000011083 sodium citrates Nutrition 0.000 claims 2
- 239000000463 material Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 238000004108 freeze drying Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract 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 description 17
- 229940090044 injection Drugs 0.000 description 12
- 229940124274 edetate disodium Drugs 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000008215 water for injection Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 208000034158 bleeding Diseases 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 239000008139 complexing agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- -1 hydrogen sodium oxide Chemical class 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WHCXDEORRDVLKS-UHFFFAOYSA-N 6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole;sodium Chemical group [Na].COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC WHCXDEORRDVLKS-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940026447 pantoprazole injection Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域technical field
本发明属于药物制剂领域，更具体地说是涉及泮托拉唑钠冻干粉针剂及其制备方法。The invention belongs to the field of pharmaceutical preparations, and more specifically relates to pantoprazole sodium freeze-dried powder injection and a preparation method thereof.
背景技术Background technique
泮托拉唑钠(Pantoprazole Sodium)，化学名为5-二氟甲氧基-2-[(3，4-二甲氧基-2-吡啶基)-甲基]-亚磺酰基-1H-苯骈咪唑钠盐。泮托拉唑钠为质子泵抑制剂类抗溃疡药。注射用泮托拉唑钠主要用于胃溃疡、十二指肠溃疡急症出血和预防出血。由于其对光、热、氧、水等都很敏感，所以不适合于制成水针而适合于粉针剂。Pantoprazole Sodium (Pantoprazole Sodium), the chemical name is 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfinyl-1H- Benzimidazole Sodium Salt. Pantoprazole sodium is a proton pump inhibitor antiulcer drug. Pantoprazole Sodium for Injection is mainly used for acute bleeding and prevention of bleeding from gastric ulcer and duodenal ulcer. Because it is very sensitive to light, heat, oxygen, water, etc., it is not suitable for making water injections but suitable for powder injections.
在以往的文献中，已有不少有关泮托拉唑钠制成冻干粉针剂的报导，比如在中国专利《泮托拉唑冻干制剂和泮托拉唑注射剂》(公开号CN1476335A，公开日2004年2月18日)中披露了将“泮托拉唑钠、乙二胺四乙酸和/或其适当的盐以及氢氧化钠和/或碳酸钠的水溶液冷冻干燥”制成冻干制剂；但用这一技术方案制备的制剂稳定性不好，当其溶解在注射液中，2至4小时内含量就会下降，影响药效。在中国专利《泮托拉唑冻干粉针剂及制备方法》(公开号CN1235018A，公开1999年11月17日)中披露了一种制备泮托拉唑钠冻干粉针剂的方法，其处方是由泮托拉唑钠(1份)、冻干粉支持剂(1-5份)、金属离子络合剂(0.05-2份)和pH调节剂组成的。这一技术方案所用的药用辅料量比较大，从而带来一些副作用。In previous literature, existing many relevant reports of pantoprazole sodium making freeze-dried powder injection, such as in Chinese patent " pantoprazole freeze-dried preparation and pantoprazole injection " (publication number CN1476335A, disclosed On February 18, 2004), it was disclosed that "freeze-drying the aqueous solution of pantoprazole sodium, ethylenediaminetetraacetic acid and/or its suitable salt and sodium hydroxide and/or sodium carbonate" was made into a lyophilized preparation ; But the preparation stability prepared with this technical scheme is not good, when it is dissolved in the injection, content will drop in 2 to 4 hours, affects drug effect. Disclosed a kind of method for preparing pantoprazole sodium freeze-dried powder injection in Chinese patent " pantoprazole freeze-dried powder injection and preparation method " (publication number CN1235018A, open on November 17th, 1999), its prescription is It consists of pantoprazole sodium (1 part), freeze-dried powder support agent (1-5 parts), metal ion complexing agent (0.05-2 parts) and pH regulator. The amount of pharmaceutical adjuvant used in this technical scheme is relatively large, thereby bringing some side effects.
发明内容Contents of the invention
本发明要解决的技术问题是：提供一种副作用小，稳定性好的泮托拉唑钠冻干粉针剂。The technical problem to be solved in the present invention is: provide a kind of pantoprazole sodium freeze-dried powder injection with little side effect and good stability.
本发明提供了一种泮托拉唑钠冻干粉针剂，按重量份数计，其组成包括：The invention provides a kind of freeze-dried powder injection of pantoprazole sodium, by weight, its composition comprises:
泮托拉唑钠(按泮托拉唑计) 1份Pantoprazole sodium (according to pantoprazole) 1 part
赋形剂 0--0.125份Excipients 0--0.125 parts
弱酸强碱盐 0.075--0.125份Weak acid and strong alkali salt 0.075--0.125 parts
依地酸二钠 0.025--0.0375份Disodium edetate 0.025--0.0375 parts
无机碱 适量；Appropriate amount of inorganic bases;
在本发明中，可以不添加赋形剂，但为了使冻干粉针的外观更美观，可以添加少量的赋形剂。赋形剂可以选自甘露醇、葡萄糖、右旋糖酐等；弱酸强碱盐可以选自枸橼酸钠、碳酸钠、枸橼酸钾、磷酸氢二钠等；无机碱可以选自氢氧化钠、碳酸氢钠、氢氧化钾等。In the present invention, no excipient may be added, but a small amount of excipient may be added in order to make the appearance of the lyophilized powder more beautiful. Excipients can be selected from mannitol, glucose, dextran, etc.; weak acid and strong base salts can be selected from sodium citrate, sodium carbonate, potassium citrate, disodium hydrogen phosphate, etc.; inorganic bases can be selected from sodium hydroxide, carbonic acid Sodium Hydrogen, Potassium Hydroxide, etc.
优选的处方为(按重量份数计)：Preferred prescription is (by weight):
泮托拉唑钠(按泮托拉唑计) 1份Pantoprazole sodium (calculated as pantoprazole) 1 part
赋形剂 0.125份Excipients 0.125 parts
弱酸强碱盐 0.125份Weak acid strong base salt 0.125 parts
依地酸二钠 0.0375份Disodium Edetate 0.0375 parts
无机碱 适量；Inorganic alkali Appropriate amount;
其中赋形剂可以选自甘露醇、葡萄糖、右旋糖酐等；弱酸强碱盐可以选自枸橼酸钠、碳酸钠、枸橼酸钾、磷酸氢二钠等；无机碱可以选自氢氧化钠、碳酸氢钠、氢氧化钾等。Wherein the excipient can be selected from mannitol, glucose, dextran, etc.; the weak acid and strong base salt can be selected from sodium citrate, sodium carbonate, potassium citrate, disodium hydrogen phosphate, etc.; the inorganic base can be selected from sodium hydroxide, Sodium bicarbonate, potassium hydroxide, etc.
经实验，本发明的赋形剂优选甘露醇，弱酸强碱盐优选枸橼酸钠；考虑到泮托拉唑为钠盐，且无机碱在处方中加入量不能太多，所以无机碱优选氢氧化钠。Through experiments, the preferred excipient of the present invention is mannitol, and the weak acid and strong base salt is preferably sodium citrate; considering that pantoprazole is a sodium salt, and the addition of inorganic bases in the prescription should not be too much, the preferred inorganic bases are hydrogen sodium oxide.
所以，更优选的处方为(按重量份数计)：So, more preferred prescription is (by weight):
泮托拉唑钠(按泮托拉唑计) 1份；Pantoprazole sodium (calculated as pantoprazole) 1 part;
甘露醇 0.125份；Mannitol 0.125 parts;
枸橼酸钠 0.125份；Sodium citrate 0.125 parts;
依地酸二钠 0.0375份；Disodium edetate 0.0375 parts;
氢氧化钠 适量。Sodium Hydroxide Appropriate amount.
本发明通过对辅料的精心挑选及对各个辅料用量的严格限制，减少因辅料加入量大而可能对患者产生的副作用，提高用药安全性，在达到药用标准同时，更进一步地提高药物的稳定性。Through the careful selection of auxiliary materials and the strict restriction on the dosage of each auxiliary material, the present invention reduces the possible side effects on patients due to the large amount of auxiliary materials added, improves the safety of medication, and further improves the stability of drugs while meeting the medicinal standards. sex.
在现有技术中赋形剂选用甘露醇、葡萄糖，氯化钠、右旋糖酐，并且用量很大，与活性成分的重量份数比为1至5比1。这些物质除了作为药用辅料外，其本身也有其药理作用，比如甘露醇能提高血浆渗透压，产生脱水作用，在临床上可以用于预防急性肾功能衰竭及治疗青光眼和脑水肿等。所以在药物制剂中应以尽量加入少量的甘露醇。同样道理，其他辅料，如葡萄糖，氯化钠、右旋糖酐，也都有其自己的药理作用，人体应尽量少摄入。本发明通过对处方的改进，加入极少量的辅料而达到符合药用标准的制剂。In the prior art, the excipients are selected from mannitol, glucose, sodium chloride, and dextran, and the dosage is large, and the ratio by weight to the active ingredient is 1 to 5:1. In addition to being used as pharmaceutical excipients, these substances also have their own pharmacological effects. For example, mannitol can increase plasma osmotic pressure and produce dehydration. It can be used clinically to prevent acute renal failure and treat glaucoma and cerebral edema. Therefore, a small amount of mannitol should be added as much as possible in the pharmaceutical preparations. In the same way, other excipients, such as glucose, sodium chloride, and dextran, also have their own pharmacological effects, and the human body should take as little as possible. The invention achieves the preparation meeting the pharmaceutical standard by improving the prescription and adding a very small amount of auxiliary materials.
为了尽量减少辅料的加入量，本发明对辅料进行了精心地挑选，比如除了依地酸二钠外，也可以采用其他金属离子络合剂来络合金属离子，但经过实验发现，其他任何金属络合剂的使用量都将大大超过依地酸二钠的量才能达到使用依地酸二钠的效果，而加入依地酸二钠只需微量即可。In order to reduce the addition of auxiliary materials as much as possible, the present invention carefully selects auxiliary materials. For example, in addition to disodium edetate, other metal ion complexing agents can also be used to complex metal ions. However, it has been found through experiments that any other metal The usage amount of complexing agent will greatly exceed the amount of edetate disodium to achieve the effect of using edetate disodium, and only a small amount of edetate disodium is added.
此外，通过实验可以发现，在处方中加入依地酸二钠0.025--0.0375份，即可提高其在膜过滤注射用水生产的0.9％氯化钠注射液中的稳定性。如果加入量过多，依地酸二钠会螯合血液中的钙离子，患者会因此而流失过多的钙。正是考虑到最大限度地降低在临床上对人体内钙的流失，在本发明中加入0.025--0.0375份依地酸二钠，依注射用泮托拉唑钠的每次用量40mg计，其中含有1--1.5mg依地酸二钠，理论上只能螯合0.105--0.158mg钙离子，故其用药是安全的，不会引起钙离子流失的副作用。并且注射用泮托拉唑钠主要用于胃溃疡、十二指肠溃疡急症出血和预防出血，病人使用时间很短，约为3--5天，对体内钙的损失不大。In addition, it can be found through experiments that adding 0.025--0.0375 parts of edetate disodium to the prescription can improve its stability in 0.9% sodium chloride injection produced by membrane filtration water for injection. If too much is added, edetate disodium will chelate calcium ions in the blood, and the patient will lose too much calcium as a result. Just considering to reduce to the greatest extent clinically to the loss of calcium in the human body, add 0.025--0.0375 part of edetate disodium in the present invention, according to each dosage 40mg of pantoprazole sodium for injection, wherein Containing 1--1.5 mg of edetate disodium, theoretically it can only chelate 0.105--0.158 mg of calcium ions, so its medication is safe and will not cause side effects of calcium ion loss. In addition, pantoprazole sodium for injection is mainly used for gastric ulcer, duodenal ulcer emergency bleeding and prevention of bleeding. The patient's use time is very short, about 3-5 days, and the loss of calcium in the body is not large.
同时，本发明也充分地考虑了制成制剂后的稳定性问题。在本发明的处方中含有弱酸强碱盐，在本发明中，选用弱酸强碱盐并不是作为pH调节剂，而是作为稳定剂使用的。泮托拉唑钠冻干粉针中加弱酸强碱盐，比如枸橼酸钠后，可以保证其在生理盐水中的稳定性。同时，如果只选用依地酸二钠而不加入无机碱，在配制的过程中，很容易析出泮托拉唑。本发明在配制时同时选用了依地酸二钠与无机碱，这样可以使溶液成碱性，不会析出泮托拉唑，考虑到泮托拉唑为钠盐，且无机碱在处方中加入量不能太多，所以无机碱以氢氧化钠为佳。Simultaneously, the present invention also fully considers the stability problem after preparation. The prescription of the present invention contains salt of weak acid and strong base. In the present invention, the salt of weak acid and strong base is not used as a pH regulator, but as a stabilizer. Adding weak acid and strong base salts, such as sodium citrate, to the freeze-dried powder of pantoprazole sodium can ensure its stability in normal saline. At the same time, if only edetate disodium is used without adding inorganic base, pantoprazole is easy to separate out during the preparation process. The present invention has selected edetate disodium and inorganic base simultaneously when preparing, can make solution become alkaline like this, can not separate out pantoprazole, consider that pantoprazole is sodium salt, and inorganic base is added in prescription The amount should not be too much, so sodium hydroxide is the preferred inorganic base.
本发明的处方经过多次实验，将处方中辅料的加入量降至了最低的限度。但通过实验及临床的应用证实，这种含有极少量的辅料的处方有着很好的稳定性，在4小时内颜色、澄清度和含量未发生明显变化(详见下表)：
本发明的处方简单，克服了因辅料加入过多而带来的副作用，患者使用更安全；同时配成的制剂具有更好的稳定性。也因辅料用量的减少而降低产品的生产成本，更适宜于工业化大生产。The prescription of the invention is simple, overcomes the side effects caused by adding too much auxiliary material, and is safer for patients; meanwhile, the formulated preparation has better stability. It also reduces the production cost of the product due to the reduction in the amount of auxiliary materials, and is more suitable for industrialized mass production.
本发明还提供了一种制备泮托拉唑钠冻干粉针剂的方法，包括以下步骤：按处方量称取弱酸强碱盐与依地酸二钠用注射用水溶解，用无机碱调pH至10.0～10.5左右，再加入处方量的泮托拉唑钠，视情况加入或不加入赋形剂，继续加注射用水至规定体积，粗过滤后用0.2μ微孔无菌膜过滤，至溶液澄清度合格后，测定含量，计算每瓶装量约2ml，灌装后按冻干工艺冷冻干燥，压盖、密封后包装。The present invention also provides a method for preparing freeze-dried powder injection of pantoprazole sodium, comprising the following steps: taking weak acid strong base salt and edetate disodium according to the prescription amount and dissolving them with water for injection, adjusting the pH to 10.0 to 10.5, then add the prescribed amount of pantoprazole sodium, add or not add excipients according to the situation, continue to add water for injection to the specified volume, filter through a 0.2μ microporous sterile membrane after coarse filtration, until the solution is clear After passing the test, measure the content, calculate the filling volume of each bottle to be about 2ml, freeze-dry according to the freeze-drying process after filling, pack after pressing the cap and sealing.
经检验，用本发明的制备工艺制备的泮托拉唑钠冻干粉针剂的各项指标均符合要求。After inspection, all indexes of the pantoprazole sodium freeze-dried powder injection prepared by the preparation process of the present invention meet the requirements.
具体实施方式Detailed ways
下面结合实施例对本发明做一具体的描述。The present invention will be described in detail below in conjunction with the embodiments.
实施例1Example 1
称取枸橼酸钠5.0g，依地酸二钠1.5g，用注射用水溶解，用适量1％氢氧化钠调pH至10.0，再加入40.0g泮托拉唑钠和5.0g甘露醇，继续加注射用水至规定体积，粗过滤后用0.2μ微孔无菌膜过滤，至溶液澄清度合格后，测定含量，计算每瓶装量约2ml，分装成1000瓶，灌装后按冻干工艺冷冻干燥，压盖、密封后包装。每瓶含泮托拉唑钠40mg。经检验，标示含量为97.8％，水份小于6.0％，澄清度与澄明度均符合规定。Weigh 5.0 g of sodium citrate and 1.5 g of disodium edetate, dissolve them in water for injection, adjust the pH to 10.0 with an appropriate amount of 1% sodium hydroxide, then add 40.0 g of pantoprazole sodium and 5.0 g of mannitol, and continue Add water for injection to the specified volume, filter it with a 0.2μ microporous sterile membrane after coarse filtration, measure the content after the solution clarity is qualified, calculate the filling volume of each bottle to be about 2ml, divide it into 1000 bottles, and follow the freeze-drying process after filling Freeze-dried, sealed and packaged. Each bottle contains 40mg of pantoprazole sodium. After inspection, the marked content is 97.8%, the water content is less than 6.0%, and the clarity and clarity are in compliance with the regulations.
实施例2Example 2
称取碳酸钠3.0g，依地酸二钠1g，用注射用水溶解，用适量碳酸氢钠调pH至10.4，再加入40.0g泮托拉唑钠，继续加注射用水至规定体积，粗过滤后用0.2μ微孔无菌膜过滤，至溶液澄清度合格后，测定含量，计算每瓶装量约2ml，分装成1000瓶，灌装后按冻干工艺冷冻干燥，压盖、密封后包装。每瓶含泮托拉唑钠40mg。经检验，各项指标均符合要求。Weigh 3.0 g of sodium carbonate and 1 g of edetate disodium, dissolve them with water for injection, adjust the pH to 10.4 with an appropriate amount of sodium bicarbonate, then add 40.0 g of pantoprazole sodium, continue to add water for injection to the specified volume, and after coarse filtration Filter with a 0.2μ microporous sterile membrane, measure the content after the clarity of the solution is qualified, calculate the filling volume of each bottle to be about 2ml, divide it into 1000 bottles, freeze-dry according to the freeze-drying process after filling, press the cap, seal and pack. Each bottle contains 40mg of pantoprazole sodium. After inspection, all indicators meet the requirements.
Claims (4)
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| CN101961309B (en) * | 2010-09-15 | 2012-06-27 | 河南辅仁怀庆堂制药有限公司 | Process for preparing pantoprazole sodium for injection |
| CN102000034B (en) * | 2010-10-13 | 2011-12-21 | 江苏奥赛康药业股份有限公司 | S-pantoprazole sodium composite for injection and preparation method thereof |
| CN102225063B (en) * | 2011-05-10 | 2012-10-10 | 江苏奥赛康药业股份有限公司 | A kind of pantoprazole sodium composition for injection |
| CN103271882A (en) * | 2013-05-30 | 2013-09-04 | 瑞阳制药有限公司 | Small-volume pantoprazole sodium freeze-dried powder injection and preparation method and production device thereof |
| CN103301125A (en) * | 2013-06-27 | 2013-09-18 | 海南卫康制药(潜山)有限公司 | Levorotatory pantoprazole sodium composition for injection |
| CN103622921A (en) * | 2013-08-30 | 2014-03-12 | 浙江金华康恩贝生物制药有限公司 | Pantoprazole sodium freeze-dried powder injection used for injection and preparation method thereof |
| CN103550173A (en) * | 2013-10-15 | 2014-02-05 | 海南卫康制药(潜山)有限公司 | Pantoprazole sodium composition freeze-dried powder injection for injection |
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| CN1235018A (en) * | 1999-04-22 | 1999-11-17 | 沈阳东宇药业有限公司 | Pantoprazole sodium freeze-dried powder injection and preparation method |
| CN1476335A (en) * | 2000-11-22 | 2004-02-18 | ��̹��ҽҩ��˾ | Pantoprazole freeze-dried preparation and pantoprazole injection |
| WO2004080440A1 (en) * | 2003-03-11 | 2004-09-23 | Korea United Pharm, Inc. | Process for the preparing of hardcapsule formulation containing lansoprazole |
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| CN1235018A (en) * | 1999-04-22 | 1999-11-17 | 沈阳东宇药业有限公司 | Pantoprazole sodium freeze-dried powder injection and preparation method |
| CN1476335A (en) * | 2000-11-22 | 2004-02-18 | ��̹��ҽҩ��˾ | Pantoprazole freeze-dried preparation and pantoprazole injection |
| WO2004080440A1 (en) * | 2003-03-11 | 2004-09-23 | Korea United Pharm, Inc. | Process for the preparing of hardcapsule formulation containing lansoprazole |
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