CN107669642A - A kind of dextrorotation Iprazole sodium freeze-dried powder injection - Google Patents
A kind of dextrorotation Iprazole sodium freeze-dried powder injection Download PDFInfo
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- CN107669642A CN107669642A CN201710878582.7A CN201710878582A CN107669642A CN 107669642 A CN107669642 A CN 107669642A CN 201710878582 A CN201710878582 A CN 201710878582A CN 107669642 A CN107669642 A CN 107669642A
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- Prior art keywords
- sodium
- dextrorotation
- freeze
- powder injection
- injection
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Links
- 238000002347 injection Methods 0.000 title claims abstract description 88
- 239000007924 injection Substances 0.000 title claims abstract description 88
- 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 title claims abstract description 62
- 239000011734 sodium Substances 0.000 title claims abstract description 62
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 62
- 239000000843 powder Substances 0.000 title claims description 63
- ZQGDDMFDBZPGCD-UHFFFAOYSA-N sodium 2-[(4-methoxy-3-methylpyridin-2-yl)methylsulfinyl]-5-pyrrol-1-ylbenzimidazol-3-ide Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(C=C3N=2)N2C=CC=C2)=C1C ZQGDDMFDBZPGCD-UHFFFAOYSA-N 0.000 claims abstract description 43
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000012535 impurity Substances 0.000 claims abstract description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 84
- 238000000034 method Methods 0.000 claims description 28
- 238000004108 freeze drying Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 208000025865 Ulcer Diseases 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 18
- 231100000397 ulcer Toxicity 0.000 claims description 18
- 238000005374 membrane filtration Methods 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 14
- 150000007529 inorganic bases Chemical class 0.000 claims description 13
- 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 11
- 229930195725 Mannitol Natural products 0.000 claims description 11
- 239000000594 mannitol Substances 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- 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 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 235000010447 xylitol Nutrition 0.000 claims description 6
- 229920002307 Dextran Polymers 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 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 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 239000000811 xylitol Substances 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- 229960002675 xylitol Drugs 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 4
- 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 4
- 208000000718 duodenal ulcer Diseases 0.000 claims description 4
- 201000005917 gastric ulcer Diseases 0.000 claims description 4
- 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 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 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 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 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 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
- 238000002360 preparation method Methods 0.000 abstract description 13
- 230000004888 barrier function Effects 0.000 abstract description 3
- 235000015424 sodium Nutrition 0.000 description 61
- HRRXCXABAPSOCP-UHFFFAOYSA-N ilaprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC(=CC=C3N=2)N2C=CC=C2)=C1C HRRXCXABAPSOCP-UHFFFAOYSA-N 0.000 description 12
- 229950008491 ilaprazole Drugs 0.000 description 12
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 11
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 10
- 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 description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 10
- 229910052782 aluminium Inorganic materials 0.000 description 10
- 239000004411 aluminium Substances 0.000 description 10
- 150000003851 azoles Chemical class 0.000 description 10
- 230000033228 biological regulation Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000011049 filling Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 235000013350 formula milk Nutrition 0.000 description 10
- 238000011068 loading method Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 238000012859 sterile filling Methods 0.000 description 10
- 239000003643 water by type Substances 0.000 description 10
- 238000005303 weighing Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- -1 sorbierite Chemical compound 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 208000030961 allergic reaction Diseases 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229940126409 proton pump inhibitor Drugs 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 206010042220 Stress ulcer Diseases 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical class CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 229920001577 copolymer Polymers 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
- 238000002224 dissection Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940106977 lansoprazole 30 mg Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 229940080133 omeprazole 20 mg Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940006344 pantoprazole 40 mg Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 235000020610 powder formula Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 150000003742 xyloses Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of dextrorotation Iprazole sodium injection and preparation method thereof.In parts by weight, the powder-injection includes 1 part of dextrorotation Ilaprazole Sodium, 0.05 0.30 parts of natrium adetate.The dextrorotation Iprazole sodium injection of the present invention solves the technical barrier that wherein impurity is significantly increased as the holding time increases, and its property is stable, meets the requirement of clinical treatment.
Description
Technical field
The present invention relates to a kind of powder-injection of proton pump inhibitor and its production and use, and in particular to a kind of right side
Revolve freeze drying powder injection of Ilaprazole Sodium and its production and use.
Background technology
Ilaprazole Sodium (Ilaprazole Sodium), chemical name is：5- (1 hydrogen-pyrroles -1- bases) -2- [[(4- first
Epoxide -3- methyl) -2- pyridine radicals]-methyl]-sulfinyl -1 hydrogen-benzimidazole sodium salt.Iprazole (Ilaprazole,
IY-81149, Yi Lila azoles) it is in the proton pump inhibitor of the novel therapeutic ulcer of invention in 1988, in 26 countries (bag
Include China) patented mandate.Be superior to list at present due to the toxicity of Iprazole, security and curative effect other 4
(the effect of 5mg Iprazoles, is equivalent to Omeprazole 20mg, Lansoprazole 30mg, Pantoprazole 40mg, thunder for individual drawing azole drug
Shellfish draws azoles 20mg), it is the most strong proton pump inhibitor of Acidinhibitor.
China 200680001258.7 discloses dextrorotation Iprazole and its salt.Rat acute gastric ulcer model pharmacological evaluation
Show that dextrorotation Iprazole compares more efficiently gastric acid secretion inhibiting and ulcer with Iprazole raceme, but do not have subsequently
Continue to study the message that dextrorotation Iprazole applies to clinic, also disclosed without dextrorotation Iprazole preparation relevant information.
CN102038648B discloses a kind of Iprazole sodium injection and preparation method thereof, and it is applied to can not be orally
Patient with severe symptoms, such as the AGML bleeding, the Acute Gastric Mucosal infringement that occur under digestive ulcerative bleeding, stress ulcer
Cause after such as major trauma gross stress reaction and prevention seriously disease (such as cerebral hemorrhage, severe trauma) and stomach operation
UGB situations such as.However, found in long-term practice, Iprazole sodium powder pin disclosed in CN102038648B
Agent：(1) can increase in the impurity (hereinafter referred to as impurity A) of storage Chinese style 1 for a long time；(2) allergic reaction occurs in Clinical practice,
Influence Clinical practice.
Stored for a long time for CN102038648B and the defects of impurity A increase occur, ZL201610217743.3 have adjusted auxiliary
The species and content of material, formula include Ilaprazole Sodium and EDTA-2Na, obtain the Iprazole that impurity A will not dramatically increase
Sodium injection.
There is the defects of allergic reaction, ZL201610217745.2 adjustment mannitol for CN102038648B Clinical practices
With EDTA-2Na content, formula includes Ilaprazole Sodium, mannitol and EDTA-2Na, obtains a kind of allergic reaction and significantly subtract
Few Iprazole sodium injection.
Patent CN105982866A, CN105769777A, CN105769778A also individually disclose the Ai Pu of steady quality
Draw azoles sodium injection.
Found through studying for a long period of time, the impurity (hereinafter referred to as impurity B) of the formula 2 of dextrorotation Ilaprazole Sodium degraded can be with preservation
Time increases and content increases so as to influence powder-injection stability, although and having above-mentioned impurity in raceme Ilaprazole Sodium
Prove that its content does not increase substantially by hot and humid experiment.And the powder-injection formula being related in above-mentioned patent is not
Solve the above problems, it is therefore desirable to redesign the dextrorotation Ai Pu that an adverse reaction is few, property is stablized, adapts to clinical demand
Draw azoles sodium freeze-drying powder formula.
The content of the invention
Because the degradation impurity in dextrorotation Ilaprazole Sodium includes impurity A, B and other impurities, content can be with preservation
The growth of time and increase substantially, research staff, which has found not providing by existing literature, effectively controls this kind of impurity content
Technical inspiration, by researcher by carrying out largely groping to test to different auxiliary material species, different auxiliary material dosage, contain from difference
Enter in the auxiliary materials such as the mannitol of amount, EDTA-2Na, xylitol, glucose, dextran, lactose, sucrose, sorbierite, glycine
Row screening, it is final to determine dextrorotation Iprazole sodium injection formula.
It is an object of the invention to provide a kind of dextrorotation Iprazole sodium freeze-dried powder injection.Dextrorotation Ai Pu of the present invention
It is not directly to separate to obtain from racemization Ilaprazole Sodium to draw azoles sodium, and initiation material and the racemization of its synthesis step and synthesis end
Pula azoles sodium synthesis step and the initiation material of synthesis have differences, and cause dextrorotation Ilaprazole Sodium raw material impurity species and content
Had differences with racemization Iprazole sodium impurity, so as to cause dextrorotation Ilaprazole Sodium to meet with and disappear when preparing freeze drying powder injection
Revolve the different technical barrier of body.
It is a further object of the invention to provide a kind of property stabilization, there is good therapeutic effect, can adapt to clinic
The dextrorotation Iprazole sodium freeze-dried powder injection of demand.
The above-mentioned purpose of the present invention is achieved by the following technical solution：
A kind of freeze drying powder injection of dextrorotation Iprazole sodium salt, the freeze drying powder injection include following components：Dextrorotation Ai Pu
Draw azoles sodium, natrium adetate；Wherein, 1 part of dextrorotation Ilaprazole Sodium, natrium adetate 0.05-0.30 parts.
Preferably, natrium adetate is 0.20-0.30 parts.
It is highly preferred that natrium adetate is 0.24-0.30 parts.
Most preferably, natrium adetate is 0.24 part.
Preferably, the freeze drying powder injection also includes the mannitol of 2.4-18 parts.
Preferably, the freeze drying powder injection also includes inorganic base.
In above-mentioned powder-injection, without adding antioxidant, you can the product stablized.The effect of inorganic base be for
PH value is adjusted, its dosage those skilled in the art can be adjusted according to actual conditions, as long as can be by dextrorotation Ai Pu
The solution ph of azoles sodium freeze-dried powder injection is drawn to maintain 9.1-12.0.Preferably, pH value maintains 11.5-12.0, more has
Beneficial to the technique effect for reaching the present invention.
Inorganic base may be selected from one kind in sodium hydroxide, potassium hydroxide, sodium acid carbonate, saleratus or disodium hydrogen phosphate etc.
It is or a variety of.Preferably, inorganic base is sodium hydroxide.Hydrochloric acid etc. may be selected in inorganic acid.
In above-mentioned powder-injection, it can also include：Xylitol, glucose, dextran, trehalose, sucrose, sorbierite,
One or more in glycine.
Specifically, xylitol, glucose, dextran, trehalose, sucrose, sorbierite, glycine are in above-mentioned powder-injection
In bulking value portion rate (g/ml) can be：Xylitol 1.0%-2.0%；Glucose 0.5%-3.0%；Dextran
1.0%-2.0%；Lactose 1.0%-1.8%；Sucrose 0.8%-1.2%；Sorbierite 0.8%-1.2%；Glycine
1.0%-1.5%.
It is a further object of the invention to provide the method for preparing above-mentioned powder-injection, this method comprises the following steps：
(1) water for injection is cooled to less than 25 DEG C in advance；
(2) natrium adetate of formula ratio is added, adjusts pH to 9.1-12.0 with inorganic base, such as sodium hydroxide, preferably
For 11.5-12.0；
(3) the dextrorotation Ilaprazole Sodium of formula ratio is added, fully after dissolving, water for injection is continuously added, with inorganic base, example
As sodium hydroxide adjusts pH to 9.1-12.0, preferably 11.5-12.0；
(4) solution freezes after membrane filtration.
The above method the step of in (4), it is preferable that solution freezes by 0.2 μm of membrane filtration after twice.
It is a further object of the invention to provide above-mentioned dextrorotation Iprazole sodium freeze-dried powder injection to prepare for treating
Purposes in the pharmaceutical composition of ulcer.
Preferably, ulcer can be occurred under gastric ulcer, duodenal ulcer, digestive ulcerative bleeding, stress ulcer
AGML bleeding or Acute Gastric Mucosal infringement.It is furthermore preferred that the ulcer is gastric ulcer.
It is a further object of the invention to provide above-mentioned dextrorotation Iprazole sodium freeze-dried powder injection to prepare impurity B steady
Purposes in the fixed pharmaceutical composition comprising Ilaprazole Sodium.
By hot and humid it is demonstrated experimentally that supplementary product kind and addition can significantly affect dextrorotation Ai Pu in stability experiment
The content of the degradability impurity B of azoles sodium freeze-dried powder injection is drawn, can solve the problem that dextrorotation Iprazole Chinese style B impurity is big using the formula
The technical barrier that width increases.
Embodiment
The present invention is described further in conjunction with the embodiments, but these embodiments are not limitation of the present invention.
Embodiment 1：The preparation of dextrorotation Ilaprazole Sodium
1g dextrorotation Iprazole, 5mL isopropanols are added into 50mL single port bottles, stirring, then add 0.33g sodium hydroxide water
Solution (40%), solid gradually dissolves.It is concentrated under reduced pressure and removes solvent, stirring adds 6mL isopropyl ethers, separates out a large amount of white solids,
Filter, be dried under reduced pressure to obtain 0.7g white powders.
Embodiment 2：The system of dextrorotation Iprazole sodium freeze-dried powder injectionIt is standby
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.2 part of natrium adetate), detailed process comprises the following steps：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 2.0g natrium adetates, is then adjusted with 5mol/L sodium hydroxide
Save pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, is fully mended after dissolving and injects water to 1000g, so
Afterwards again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiment 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium
Lid, is recorded as lot number IY001.
Embodiment 3：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.15 part of natrium adetate), detailed process includes following step
Suddenly：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 1.5g natrium adetates, is then adjusted with 5mol/L sodium hydroxide
Save pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, is fully mended after dissolving and injects water to 1000g, so
Afterwards again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiment 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium
Lid, is recorded as lot number IY002.
Embodiment 4：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.10 part of natrium adetate), detailed process includes following step
Suddenly：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 1.0g natrium adetates, is then adjusted with 5mol/L sodium hydroxide
Save pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, is fully mended after dissolving and injects water to 1000g, so
Afterwards again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiment 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium
Lid, is recorded as lot number IY003.
Embodiment 5：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.05 natrium adetate), detailed process comprises the following steps：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 0.5g natrium adetates, is then adjusted with 5mol/L sodium hydroxide
Save pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, is fully mended after dissolving and injects water to 1000g, so
Afterwards again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiments 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid,
It is recorded as lot number IY004.
Embodiment 6：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.24 part of natrium adetate), detailed process includes following step
Suddenly：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 2.4g natrium adetates, is then adjusted with 5mol/L sodium hydroxide
Save pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, is fully mended after dissolving and injects water to 1000g, so
Afterwards again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiments 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid,
It is recorded as lot number IY005.
Embodiment 7：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.30 part of natrium adetate), detailed process includes following step
Suddenly：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 3.0g natrium adetates, is then adjusted with 5mol/L sodium hydroxide
Save pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, is fully mended after dissolving and injects water to 1000g, so
Afterwards again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiments 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid,
It is recorded as lot number IY006.
Embodiment 8：Impurity content contrast in freeze drying powder injection stability test
Impurity content contrasts in lot number IY001, IY002, IY003, IY005, IY006 freeze drying powder injection stability test
Lot number IY001：From embodiment 2；Containing 1 part of dextrorotation Ilaprazole Sodium, 0.20 part of natrium adetate
Lot number IY002；From embodiment 3；Containing 1 part of dextrorotation Ilaprazole Sodium, 0.15 part of natrium adetate
Lot number IY003；From embodiment 4；Containing 1 part of dextrorotation Ilaprazole Sodium, 0.10 part of natrium adetate
Lot number IY005：From embodiment 6；Containing 1 part of dextrorotation Ilaprazole Sodium, 0.24 part of natrium adetate
Lot number IY006：From embodiment 7；Containing 1 part of dextrorotation Ilaprazole Sodium, 0.30 part of natrium adetate
Specification：10mg
Investigation condition：40 DEG C ± 2 DEG C, RH75% ± 5%
Packaging：Neutral borosilicate tubular injection bottle, injection freeze-drying aseptic powdery, which is used, covers polytetrafluoroethylene (PTFE)/ethene
Co-polymer membrane chlorinated butyl rubber bung.
Experimental result is shown in Table 1.
Conclusion：From shown in upper table 1, the content of impurity B is with stable in IY001, IY002, IY003, IY005 and IY006
Property experiment carry out and increase, wherein IY002 and IY003 impurity B increasing degree are larger, and IY001, IY005 and IY006's is miscellaneous
Matter B increasing degree is smaller than IY002's and IY003.
At 0 month, the impurity content difference of above-mentioned batch was little, all 0.04% or so；After 1 month, each batch is miscellaneous
There is nuance in matter B content, and IY002 and IY003 are slightly below 0.20%, and IY001, IY005 and IY006 are left 0.10%
It is right；After 3 months, IY002 and IY003 impurity B content increase soon, exceed well over IY001, IY005 and IY006；After 6 months,
What IY002 and IY003 impurity B content was above 0.4%, IY003 is even more to be higher than 0.50%, IY001, IY005 and IY006's
Impurity B content is below 0.30%, IY005 and IY006 0.2% or so.
IY001, IY002, IY003, IY005 and IY006 difference are that EDTA-2Na content is different, according to form 1
Result, with the increase of EDTA-2Na contents, increasing degree of the impurity B in stability experiment can be reduced.Dextrorotation Ai Pula
When EDTA-2Na contents are not less than 0.20 part in azoles sodium freeze-drying powder agent prescription, impurity B increasing degree can be preferable；Work as EDTA-
2Na contents are 0.24 part, and impurity B increasing degree can be minimum, and EDTA-2Na dosages are few.It is preferable right according to principle of reasonableness
It is 0.20 part -0.30 part to revolve EDTA-2Na contents in Iprazole sodium freeze-dried powder injection formula, and EDTA-2Na contents are 0.24
It is optimal during part.
Table 1：The stability test result of 5 batches of dextrorotation Iprazole sodium freeze-dried powder injections
Embodiment 9：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.26 part of natrium adetate, 2.4 portions of mannitol), detailed process
Comprise the following steps：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, 2.6g natrium adetates and 24g mannitol is added, then uses 5mol/L
Sodium hydroxide regulation pH to 11.5-12.0.10g dextrorotation Ilaprazole Sodium bulk drugs are added, fully add injection after dissolving
Water is to 1000g, then again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers the lid of material-compound tank after terminating
Son.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.015g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiments 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid.
Embodiment 10：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.4 part of sodium thiosulfate, 0.26 part of natrium adetate), specifically
Process comprises the following steps：
1) following weight feeding is pressed：Sodium thiosulfate 4.0g, natrium adetate 2.6g, dextrorotation Ilaprazole Sodium 10.0g；
2) by sodium thiosulfate, natrium adetate 1300g, 4 DEG C of water for injection dissolvings, with 2mol/L sodium hydroxide solutions
PH value is adjusted to 10.5, adds dextrorotation Ilaprazole Sodium, pH value is adjusted to 10.5 with 2mol/L sodium hydroxide solutions again fully after dissolving,
4 DEG C of waters for injection are finally added to 1500g；
3) it is degerming with the membrane filtration 2 times that aperture is 0.2 μm；
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.5g/ bottles：In cillin bottle 10mL), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
CN102038648B embodiments 2-4 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid.
Embodiment 11：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.28 natrium adetate part, 3.2 portions of mannitol, 1.6 parts of xyloses
Alcohol), detailed process comprises the following steps：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 2.8g natrium adetates, 32g mannitol, 16g xylitols, then
PH to 11.5-12.0 is adjusted with 5mol/L sodium hydroxide.10g dextrorotation Ilaprazole Sodium bulk drugs are added, are fully mended after dissolving
1000g is injected water to, then again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers after terminating matches somebody with somebody
The lid of batch can.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.5g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
The embodiment of the present invention 1 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid.
Embodiment 12：The preparation of dextrorotation Iprazole sodium freeze-dried powder injection
The present embodiment is to prepare 1000 bottles of dextrorotation Iprazole sodium freeze-dried powder injection (labelled amounts using the method for the present invention：
10mg dextrorotation Ilaprazole Sodiums, containing 1 part of dextrorotation Ilaprazole Sodium, 0.26 part of natrium adetate, 3.2 portions of mannitol, 1 portion of grape
Sugar), detailed process comprises the following steps：
1) 900ml waters for injection are cooled to less than 25 DEG C in advance.
2) about 800ml water for injection is first weighed, adds 2.6g natrium adetates, 32g mannitol, 10g glucose, then
PH to 11.5-12.0 is adjusted with 5mol/L sodium hydroxide.10g dextrorotation Ilaprazole Sodium bulk drugs are added, are fully mended after dissolving
1000g is injected water to, then again with 5mol/L sodium hydroxide regulation pH to 11.5-12.0.Dissolving covers after terminating matches somebody with somebody
The lid of batch can.
3) membrane filtration of the solution Jing Guo 0.2 μm of twice is to weighing area.
4) by filtrate, with automatic filling machine, (Nanjing Bojian Science Co., Ltd KFG~300 types are linear partly to be fallen to fill in sterile filling
Install) 1000 bottles of (specifications are sub-packed in the loading amount of 1.5g/ bottles：In cillin bottle 10ml), partly fall plug；
5) it is lyophilized with freeze drying box (Edward's Tian Li pharmacy System Co., Ltd GLZ~10 type freeze dryer), freeze program with
The embodiment of the present invention 1 is identical, obtains dextrorotation Iprazole sodium freeze-dried powder injection, vacuum tamponade, outlet, rolls aluminium lid.
Embodiment 13：The pharmacological activity experiment of freeze drying powder injection
SD big white mouse 60.Fasting 24h before experiment.Abdominal cavity is opened under etherization, by internal diameter 5mm, long 30mm glass
Glass pipe is disposed vertically on body of stomach serosal surface, is added into tube chamber after glacial acetic acid 0.2ml, 1.5min and is dipped in out ice vinegar with cotton swab
Acid, suture operation otch.Postoperative normal diet, animal was randomly divided into 6 groups in second day, every group of 10 SD big white mouse：Control group
(distilled water), treatment group 1 (embodiment 2), treatment group 2 (embodiment 3), treatment group 3 (embodiment 4), treatment group 4 (embodiment 6),
Treatment group 5 (embodiment 7)；Continuous intraperitoneal injection 15d.Stomach is taken out in dissection, and is fixed with formaldehyde, and stomach is splitted along greater curvature,
It is open and flat on a glass, measurement ulcer vertical and horizontal footpath d1, d2.Ulcer area S is calculated with formula S=π × (d1/2) × (d2/2)
(mm2), data withRepresent, t- check analyses are carried out using SPSS softwares.The computational methods of ulcer inhibition rate：Ulcer presses down
Rate processed=(control group ulcer area-treatment group's ulcer area)/control group ulcer area × 100%.As a result see the table below：
Table 2
Shown by testing data, treatment group 1-5 has therapeutic effect to ulcer, and can repairing ulcer area.But control
The therapeutic effect of 1,4 and 5 pair of ulcer for the treatment of group is slightly good with treatment group 2 and 3, shows that 2,6 and 7 pairs of ulcer of embodiment have good control
Treatment acts on.
General principle, principal character and the advantages of the present invention of the present invention has been shown and described above.The skill of the industry
For art personnel it should be appreciated that the present invention is not limited to the above embodiments, described in above-described embodiment and specification is explanation
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (10)
1. a kind of dextrorotation Iprazole sodium freeze-dried powder injection, it is characterised in that the freeze drying powder injection includes dextrorotation Iprazole
1 part of sodium, natrium adetate 0.05-0.30 parts.
2. dextrorotation Iprazole sodium freeze-dried powder injection as claimed in claim 1, it is characterised in that natrium adetate be 0.20 part-
0.30 part, it is preferable that natrium adetate is 0.24-0.30 parts, it is highly preferred that natrium adetate is 0.24 part.
3. dextrorotation Iprazole sodium freeze-dried powder injection as claimed in claim 1, it is characterised in that the freeze drying powder injection also includes
2.4-18 the mannitol of part.
4. dextrorotation Iprazole sodium freeze-dried powder injection as claimed in claim 1, it is characterised in that the freeze drying powder injection is additionally added
Inorganic base, the one kind of the inorganic base in sodium hydroxide, potassium hydroxide, sodium acid carbonate, saleratus or disodium hydrogen phosphate
It is or several, it is preferable that the inorganic base is sodium hydroxide.
5. dextrorotation Iprazole sodium freeze-dried powder injection as claimed in claim 1, it is characterised in that the freeze drying powder injection also includes
One or more in xylitol, glucose, dextran, lactose, sucrose, sorbierite or glycine.
6. a kind of method of the dextrorotation Iprazole sodium freeze-dried powder injection prepared any one of Claims 1-4, its feature
It is, comprises the following steps：
(1) water for injection is cooled to less than 25 DEG C in advance；
(2) natrium adetate of formula ratio is added, pH to 9.1-12.0 is adjusted with inorganic base；
(3) the dextrorotation Ilaprazole Sodium of formula ratio is added, fully after dissolving, continuously adds water for injection, pH is adjusted with inorganic base
To 9.1-12.0；
(4) solution freezes after membrane filtration.
7. method as claimed in claim 6, it is characterised in that in step (2) and (3), the inorganic base is sodium hydroxide.
8. method as claimed in claims 6 or 7, it is characterised in that in step (2) and (3), with inorganic base adjust pH to
11.5-12.0.
9. the method as any one of claim 6 to 8, it is characterised in that in step (4), the solution passes through 0.2
μm membrane filtration freeze afterwards twice.
10. dextrorotation Iprazole sodium freeze-dried powder injection described in claim 1-4 is preparing the pharmaceutical composition or system for the treatment of ulcer
Purposes in the stable pharmaceutical composition of standby impurity, the ulcer is gastric ulcer or duodenal ulcer.
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| CN105769777A (en) * | 2016-04-02 | 2016-07-20 | 丽珠医药集团股份有限公司 | Sodium ilaprazole freeze-dried powder injection |
| CN105769778A (en) * | 2016-04-02 | 2016-07-20 | 丽珠医药集团股份有限公司 | Sodium ilaprazole powder injection and preparation method thereof |
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| US20080200515A1 (en) * | 2006-12-29 | 2008-08-21 | Tap Pharmaceutical Products Inc. | Solid state forms of enantiopure ilaprazole |
| CN105769777A (en) * | 2016-04-02 | 2016-07-20 | 丽珠医药集团股份有限公司 | Sodium ilaprazole freeze-dried powder injection |
| CN105769778A (en) * | 2016-04-02 | 2016-07-20 | 丽珠医药集团股份有限公司 | Sodium ilaprazole powder injection and preparation method thereof |
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| SEO-KYUNG KIM ET AL.: ""Preformulation study of a proton pump inhibitor Ilaprazole"", 《J THERM ANAL CALORIM》 * |
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