CN105616412B - A kind of pharmaceutical composition containing moxifloxacin hydrochloride - Google Patents
A kind of pharmaceutical composition containing moxifloxacin hydrochloride Download PDFInfo
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- CN105616412B CN105616412B CN201410598172.3A CN201410598172A CN105616412B CN 105616412 B CN105616412 B CN 105616412B CN 201410598172 A CN201410598172 A CN 201410598172A CN 105616412 B CN105616412 B CN 105616412B
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- China
- Prior art keywords
- injection
- moxifloxacin
- added
- sodium chloride
- carbon dioxide
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- 229960005112 Moxifloxacin hydrochloride Drugs 0.000 title claims abstract description 54
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 title claims abstract description 54
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 110
- 239000000203 mixture Substances 0.000 claims abstract description 59
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000011780 sodium chloride Substances 0.000 claims abstract description 55
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 54
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 54
- 229960003702 moxifloxacin Drugs 0.000 claims abstract description 37
- FABPRXSRWADJSP-MEDUHNTESA-N Moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims abstract description 36
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 36
- 230000003750 conditioning Effects 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000004471 Glycine Substances 0.000 claims abstract description 6
- 239000004615 ingredient Substances 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 84
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 53
- 238000001914 filtration Methods 0.000 claims description 50
- 238000003756 stirring Methods 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 37
- 238000002347 injection Methods 0.000 claims description 36
- 239000007924 injection Substances 0.000 claims description 36
- 230000001186 cumulative Effects 0.000 claims description 25
- 238000005262 decarbonization Methods 0.000 claims description 25
- 230000001954 sterilising Effects 0.000 claims description 25
- 239000012528 membrane Substances 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 abstract description 47
- 239000000654 additive Substances 0.000 abstract description 10
- 238000007792 addition Methods 0.000 abstract description 9
- 230000000996 additive Effects 0.000 abstract description 9
- 150000002500 ions Chemical class 0.000 abstract description 9
- 229910052751 metal Inorganic materials 0.000 abstract description 7
- 239000002184 metal Substances 0.000 abstract description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 6
- 239000002738 chelating agent Substances 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- 238000005286 illumination Methods 0.000 abstract description 5
- -1 moxifloxacin hydrochlorides Chemical class 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 57
- 229960004424 Carbon Dioxide Drugs 0.000 description 52
- 229960002668 sodium chloride Drugs 0.000 description 51
- 238000006731 degradation reaction Methods 0.000 description 38
- 239000012535 impurity Substances 0.000 description 38
- 229940090044 Injection Drugs 0.000 description 35
- 230000015556 catabolic process Effects 0.000 description 35
- 230000004059 degradation Effects 0.000 description 35
- 230000000052 comparative effect Effects 0.000 description 33
- 239000001301 oxygen Substances 0.000 description 20
- 229910052760 oxygen Inorganic materials 0.000 description 20
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000001187 sodium carbonate Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000000844 anti-bacterial Effects 0.000 description 3
- 230000003115 biocidal Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000005660 chlorination reaction Methods 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
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 239000001184 potassium carbonate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 2
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 2
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 2
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003078 antioxidant Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229940079866 intestinal antibiotics Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000001782 photodegradation Methods 0.000 description 2
- 238000005950 photosensitized reaction Methods 0.000 description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- IFQSXNOEEPCSLW-DKWTVANSSA-N (2R)-2-amino-3-sulfanylpropanoic acid;hydron;chloride Chemical compound Cl.SC[C@H](N)C(O)=O IFQSXNOEEPCSLW-DKWTVANSSA-N 0.000 description 1
- DWNBOPVKNPVNQG-LURJTMIESA-N (2S)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 229960000583 Acetic Acid Drugs 0.000 description 1
- BIGPRXCJEDHCLP-UHFFFAOYSA-N Ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 241000040710 Chela Species 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N Ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010018913 Haemolysis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 229960000448 Lactic acid Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N Phenylsilane Chemical group [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 231100000614 Poison Toxicity 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 206010037844 Rash Diseases 0.000 description 1
- XBHBWNFJWIASRO-UHFFFAOYSA-N Sarafloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 description 1
- 229950007734 Sarafloxacin Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010046736 Urticarias Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 230000002924 anti-infective Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000003385 bacteriostatic Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000005518 electrochemistry Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229940020367 moxifloxacin Injection Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000003969 polarography Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000012601 sub-visual particle Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 description 1
Abstract
The present invention relates to a kind of pharmaceutical composition containing moxifloxacin hydrochloride, and containing moxifloxacin hydrochloride, sodium chloride, PH conditioning agents, air displacer carbon dioxide and water for injection, and the pH value of composition is between 4.1~4.6；Preferred pharmaceutical compositions are made up of following six kinds of medicinal ingredients：400g moxifloxacin hydrochlorides（In terms of MOXIFLOXACIN）, 200g glycine, 2kg sodium chloride, appropriate PH conditioning agents, appropriate carbon dioxide, add and inject water to 250L；Also containing carbonate soluble 0.005%w/v~0.01%w/v in particularly preferred composition.The product, which does not have to addition such as metal ion chelation agent, solubilizer, may bring the additive of risk, the content of catabolite just can be effectively controlled, under high temperature or strong illumination, its catabolite does not also increase significantly, the stability of product is more preferable, and security is higher.
Description
Technical field
The present invention relates to pharmaceutical composition, more particularly, to a kind of composition containing moxifloxacin hydrochloride of stabilization
And preparation method thereof.
Background technology
MOXIFLOXACIN is forth generation fluoroquinolone antibiotics, and because it has, has a broad antifungal spectrum, drug resistance be low, antibacterial action
By force, the advantages that long half time, it has also become very effective anti-infective.The Yuan Yan producers of MOXIFLOXACIN are Bayer A.Gs,
In November, 2001, moxifloxacin hydrochloride chloride injection agent obtain U.S. FDA approval listing, and 2005 in Discussion on Chinese Listed, trade name
To visit multiple pleasure.Compared with other formulations, injection has and not influenceed by pH value, enzyme, food etc., and absorb fast, effect is rapid,
Without advantages such as first pass effect, bioavilability height, therefore develop MOXIFLOXACIN injection and use it for clinic, for those not
The patient with severe symptoms that can be administered orally or be badly in need of short time action is particularly significant.
However, FQNS especially in aqueous, is easy to degrade under light illumination to photo-labile
Reaction, present invention applicant, which studies, to be found, moxifloxacin hydrochloride mainly produces two kinds of catabolites, impurity during light degradation
F（The fluoro- 8- methoxies -1,4- dihydros -4- oxygen -3- quinoline carboxylic acids of 1- cyclopropyl -7- amino -6-）With impurity G（1- cyclopropyl -7- ﹛
（S,S）The ring of -2,8- diazas-two [4.3.0] nonyl- 8- Ji ﹜ -6- hydroxyl -8- methoxy -1,4- dihydro -4- oxygen -3- quinoline carboxylic acids）,
Its structural formula is as follows：
Present invention applicant has further been found that the above-mentioned light degradation triggered by illumination is reacted, and can enter under the high temperature conditions
One step is aggravated, and this may reduce medicine antibacterial activity, influence the term of validity of product, such as Ciprofloxacin, sarafloxacin are in light
Its antibacterial activity is just in significantly reduce trend in conversion process（Appoint red flower bud fluffy, fluoroquinolone antibiotics light degradation in water
The change of bacteriostatic activity in journey, Environmental Chemistry, the 5th phase of volume 33 in 2014,753-759）；On the other hand, during light degradation
Caused some poisonous metabolites or intermediate, it may be combined with body skin protein and photosensitized reaction occurs（Bi Guihong, quinoline
The photosensitized reaction analysis of promise ketone antibiotic, the practical medicine of China, the 13rd phase of volume 6 in 2011,202-203）, show as skin
The mucocutaneous symptom such as rash, itch, nettle rash, pain, produce patient uncomfortable.Therefore, it is more preferable to develop photostability, degraded production
Thing content is lower, and the higher composition containing moxifloxacin hydrochloride of Product Safety is that very have clinical meaning.
CN1368891A discloses a kind of containing the Moses that the amount based on MOXIFLOXACIN is 0.04%~0.4% weight/volume
The water formulation of husky star hydrochloride and the sodium chloride of 0.4%~0.9% weight/volume, inventor's non-glucose etc. using sodium chloride
Sugar or sugar alcohol solution are used as isotonic regulator, so as to avoid that triple role occurs between MOXIFLOXACIN, ion and sugar or sugar alcohol, drop
Low sensitiveness of the parenteral solution to iron ion, obtains the more stable composition containing moxifloxacin hydrochloride, but this stabilization
It is showed only as occurring without sub- visual particle in solution, the Photodegradation Products of MOXIFLOXACIN can not be effectively controlled, this
Patent application people is prepared for the composition containing moxifloxacin hydrochloride according to its patent methods described, and respectively at 40 DEG C and
Placed under 4500xl strong illuminations 10 days, it is 0.07% and 0.13% that as a result light degradation impurity is increased respectively by 0.01%.
CN102000024A discloses a kind of metal ion chelation agent containing 0.0001%~0.1% weight/volume, hydrochloric acid
The composition of MOXIFLOXACIN, sodium chloride, water for injection etc., specification record it when placing 6 months for 40 DEG C, and maximum list is miscellaneous to be
0.03%~0.05%, always miscellaneous is 0.07%~0.09%；CN103830164A is disclosed containing 0.005%~0.6% weight/volume
The moxifloxacin compositions of solubilizer and the metal ion chelation agent of 0.001%~0.1% weight/volume, specification record its
40 DEG C when placing 6 months, it is maximum single it is miscellaneous be 0.011%~0.021%, it is total it is miscellaneous is 0.023%~0.043%, although above two group
Compound is by maximum single miscellaneous and total miscellaneous control in relatively low level, but they are all by adding metal ion chela in the composition
The additive such as mixture or solubilizer, but metal ion chelation agent such as natrium adetate, can chelate internal calcium ion, cause people
Internal blood calcium concentration is reduced, and solubilizer such as Tween 80, and serious haemolysis can be produced when dosage is larger, contains above-mentioned addition
Potential risks be present to health after human body is injected into the composition of agent.
Because parenteral solution direct injection enters blood circulation system, the selection of its additive and improper use may produce sternly
The potential safety hazard of weight, thus the selection of additive should be prudent in parenteral solution, and dosage is controlled as far as possible, if it is possible, not making preferably
The additive of risk may be brought with such as metal ion chelation agent, solubilizer etc..And prior art contains moxifloxacin hydrochloride
Composition, if not adding above-mentioned additive, its catabolite can not be controlled effectively, especially in high temperature and intense light irradiation
Penetrate down, the phenomenon that catabolite increases becomes apparent.Prior art still needs new technology to solve containing moxifloxacin hydrochloride
Safety issue caused by the composition photo-labile of star.
The content of the invention
It is an object of the invention to provide a kind of more preferable composition containing moxifloxacin hydrochloride of photostability, described group
The content of degradation products of compound is extremely low, and under high temperature or strong illumination, its catabolite does not also increase significantly, and composition
The additives such as metal ion chelation agent, solubilizer can not be contained, Product Safety is higher.
The invention provides a kind of composition containing moxifloxacin hydrochloride, is adjusted containing moxifloxacin hydrochloride, sodium chloride, PH
Agent, air displacer and water for injection are saved, its air displacer refers to carbon dioxide, and the pH value of composition is 4.1~4.6
Between.
The PH conditioning agents are selected from hydrochloric acid and sodium hydroxide.
The feed postition of the air displacer carbon dioxide is：Hydrochloric MOXIFLOXACIN, sodium chloride, the PH that will be prepared
The composition of conditioning agent and water for injection adds container for injection before container for injection is injected and/or after injection container for injection
In, preferably by the composition of the hydrochloric MOXIFLOXACIN prepared, sodium chloride, PH conditioning agents and water for injection in injection injection
Added before container and after injection container for injection in container for injection.
After the addition of the carbon dioxide refers to that carbon dioxide adds container for injection and sealed, gas in container for injection
The remaining oxygen of body is less than 5% v/v, preferably shorter than 2% v/v.
Carbonate soluble 0.005%w/v~0.01%w/v can also be contained in the composition.
The carbonate is one or both of sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus.
The invention provides a kind of preparation method of the composition containing moxifloxacin hydrochloride：Prescription is added in Agitation Tank
The water for injection of volume 80% is measured, moxifloxacin hydrochloride is added, stirring and dissolving, adds sodium chloride, stirring and dissolving；By cumulative volume
0.05%w/v add activated carbon, stir 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirs, with hydrochloric acid or
Sodium hydroxide adjusts pH value between 4.1~4.6；With 0.22um filter membrane refined filtration decoction, lucifuge and under infrared light irradiation, noting
Penetrate with air displacer carbon dioxide is added in container, be then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH and adjust
The solution of agent is saved, second of addition air displacer carbon dioxide, is sealed, sterilizing.
Present invention also offers the preparation method of composition of the another kind containing moxifloxacin hydrochloride：Added in Agitation Tank
The water for injection of recipe quantity volume 80%, the carbonate of solubility is added, stirring and dissolving, then adds moxifloxacin hydrochloride, stirred
Dissolving, adds sodium chloride, stirring and dissolving；Activated carbon is added by the 0.05%w/v of cumulative volume, is stirred 20 minutes, filtering decarbonization；
Benefit is added to the full amount of water for injection, and stirs, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter
Film refined filtration decoction, lucifuge and under infrared light irradiation, air displacer carbon dioxide is added in container for injection, is then injected into
The solution of the hydrochloric MOXIFLOXACIN, sodium chloride and the PH conditioning agents that prepare, second of addition air displacer carbon dioxide, envelope
Mouthful, sterilizing.
In order to obtain photostability, preferably the composition containing moxifloxacin hydrochloride, present invention applicant first attempt to
Sugar or glycitols additive are added in solution containing moxifloxacin hydrochloride and sodium chloride, such as glucose, sucrose, mannitol, mountain
Pears alcohol and glycerine etc., and its dosage is screened in 1%w/v~30%w/v concentration ranges, as a result find above-mentioned carbohydrate additive and unfavorable
In the stability of composition, the composition of preparation is placed 10 days respectively under 40 DEG C and 4500xl strong illuminations, as a result light degradation
It is 0.09% and 0.17% that impurity is increased respectively by 0.01%.
Present invention applicant's referenced patent document, the PH of composition of the adjustment containing moxifloxacin hydrochloride is attempted again to difference
Scope, if pH value is 3.0~4.0,4.0~5.0,5.0~6.0,6.0~7.0, or adjusted with a variety of different PH conditioning agents
The pH value of composition is saved, such as organic acid or organic base, specially acetic acid, malic acid, lactic acid, citric acid, tartaric acid and maleic acid；
Inorganic acid or inorganic base, specially hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate etc.,
Influence caused by the light degradation reaction of different PH scopes or different PH conditioning agents on composition to observe, as a result find,
Composition prepared by the above method, its light degradation impurity are placed 10 days respectively under 40 DEG C and 4500xl strong illuminations, occurred
Significant growth.
Present invention applicant's referenced patent document, reattempts and antioxidant is added in the composition containing moxifloxacin hydrochloride
Such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite or sodium thiosulfate, amino acid such as L-cysteine hydrochloride, glycine, paddy
Propylhomoserin or aspartic acid etc., or addition 0.5%v/v~30% v/v ethanol, to investigate stabilization of the aforementioned stable agent to composition
Property whether have humidification, as a result find that composition prepared by the above method is placed respectively under 40 DEG C and 4500xl strong illuminations
10 days, as a result light degradation impurity was 0.11%~0.16% by 0.01% increase.
Present invention applicant is chanced on by largely testing, when containing moxifloxacin hydrochloride, sodium chloride, PH regulation
Agent, water for injection composition in, between the pH value of composition is adjusted into 4.1~4.6, and add air displacer titanium dioxide
During carbon, the effect that fabulous control composition Photodegradation Products are produced and increased can be unexpectedly produced, and when air displacer is
Nitrogen either other inert gases when or composition pH value outside 4.1~4.6 scopes, can not but reach above-mentioned skill
Art effect, the possible explanation to such a phenomenon are that carbon dioxide is dissolved in caused HCO in water for injection3 -And CO3 2-Exist in PH
When 4.1~4.6, the light degradation reaction to MOXIFLOXACIN generates inhibitory action, so as to increase the stability of composition.
On the basis of above-mentioned technical proposal implementation, after carbon dioxide adds container for injection and seals, its injection
When the remaining oxygen of gas is less than 5%v/v in container, the composition of preparation under 40 DEG C and 4500xl strong illuminations respectively at placing 10
My god, rapid substantial amounts of growth is not presented for its light degradation impurity, is placed 6 months at 40 DEG C after lucifuge packaging, its light degradation impurity is low
In 0.05%；After carbon dioxide adds container for injection and seals, the remaining oxygen of gas is less than 2%v/v in its container for injection
When, the effect for suppressing light degradation impurity is more preferable.
The feed postition of the air displacer carbon dioxide is：Hydrochloric MOXIFLOXACIN, sodium chloride, the PH that will be prepared
The composition of conditioning agent and water for injection adds container for injection before container for injection is injected and/or after injection container for injection
In, preferably by the composition of the hydrochloric MOXIFLOXACIN prepared, sodium chloride, PH conditioning agents and water for injection in injection injection
Added before container and after injection container for injection in container for injection, can so obtain more preferable replacement result.
PH conditioning agents of the present invention can be various organic acids, organic base or inorganic acid, inorganic base, but in order to avoid
Introduce unnecessary ion, preferably hydrochloric acid and sodium hydroxide.
In composition of the present invention containing moxifloxacin hydrochloride, 0.005%w/v~0.01%w/v can also be contained
Soluble carbonate, under the collective effect of carbon dioxide and carbonate, the composition that now prepares respectively at 40 DEG C and
Placed 10 days under 4500xl strong illuminations, light degradation impurity does not increase, is placed 6 months at 40 DEG C after lucifuge packaging, light drop
Solution impurity can be controlled in less than 0.02%.
The invention provides a kind of preparation method of the composition containing moxifloxacin hydrochloride：Prescription is added in Agitation Tank
The water for injection of volume 80% is measured, moxifloxacin hydrochloride is added, stirring and dissolving, adds sodium chloride, stirring and dissolving；By cumulative volume
0.05%w/v add activated carbon, stir 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirs, with hydrochloric acid or
Sodium hydroxide adjusts pH value between 4.1~4.6；With 0.22um filter membrane refined filtration decoction, lucifuge and under infrared light irradiation, noting
Penetrate with air displacer carbon dioxide is added in container, be then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH and adjust
The solution of agent is saved, second of addition air displacer carbon dioxide, is sealed, sterilizing.The combination prepared by above-mentioned preparation method
Thing, light degradation impurity content can be controlled in relatively low level when initial preparation is completed, so as to after long-term place compared with
The light degradation impurity content of composition prepared by other method is lower.
Container for injection of the present invention, due to the presence of carbon dioxide, what those skilled in the art can suspect, it is excellent
Choosing has the container that good barrier acts on to gas but it is also possible to be plastics of the sealing not as good as vial using vial is this
Bottle, the non-pvc multi-layer co-extruded film soft bags with certain permeability, when using said vesse, preferably it is full of in its outer cover one
The stronger aluminium bag of the sealing of carbon dioxide, avoids, because sealing problem causes carbon dioxide excessive, influenceing air displacer two
Carbonoxide plays its due effect.
In the present invention, oxygen is not the reason for causing light degradation impurity to produce and increase, to determine gas in container
Remaining oxygen, it is whether abundant in order to characterize the addition of carbon dioxide, if produce enough HCO3 -And CO3 2Ion is to reach
Suppress the effect of light degradation reaction.Remaining oxygen of the present invention, it can use and pass through electrochemistry or spectrum analysis or ultrasonic wave
Etc. principle, the instrument of unit partial pressure of oxygen measure is measured, such as the OxytransM-E of oxygen content is determined by optical principle
Portable oxygen analyser, formula oxygen analyser etc. is taken using the OX-12B of polarography principle and overlay film oxygen determination determination of electrode oxygen content, can be with
Selected according to the required precision of the container for injection and measure that use.The remaining oxygen that the present invention determines refers to container for injection
Oxygen content in the gas componant of inner top aggregation, rather than the oxygen content in container for injection in liquid.
The content of light degradation impurity of the present invention, is to be detected by high performance liquid chromatography, specific method is as follows：
Lucifuge operates.Precision measures the composition containing moxifloxacin hydrochloride in right amount, adds dilution（Weigh the 0.5g tetrabutyls
Ammonium hydrogen sulfate and 1.0g potassium dihydrogen phosphates, are dissolved in 500ml water, add 2.0ml phosphoric acid and 0.05g anhydrous sodium sulfites, add
Water is diluted to 1000ml）Dilution is made containing about MOXIFLOXACIN 1mg solution in every 1ml, as need testing solution；Precision measures suitable
Need testing solution is measured, is made with diluted containing about the solution of 1 μ g MOXIFLOXACINs in every 1ml, as contrast solution.Take respectively
Moxifloxacin hydrochloride light degradation impurity F and G reference substance are appropriate, add dilution to dissolve and dilute and are made in every 1ml containing about 0.1
Mg solution, as positioning solution.According to high performance liquid chromatography（Two D of annex V of Chinese Pharmacopoeia version in 2010）Experiment, use
Phenyl silane bonded silica gel is filler（5 μm, 4.6 × 250mm）；Mobile phase A is buffer solution（The sulphur of the tetrabutyl containing 0.5g in 1L water
Sour hydrogen ammonium, 1.0g potassium dihydrogen phosphates and 3.4g phosphoric acid）, Mobile phase B is methanol, and according to the form below carries out gradient elution.45 DEG C of column temperature；Inspection
Survey wavelength is 293nm；Flow velocity is 1.3ml/min.Take the μ l of positioning solution 20 to inject liquid chromatograph, record chromatogram, appearance
Position is impurity F（Retention time about 37 minutes）, impurity G（Retention time about 37 minutes）.The μ l of contrast solution 20 are taken to inject liquid phase
Chromatograph, detector sensitivity is adjusted, the peak height for making principal component chromatographic peak is about the 20% of full scale, then to measure control molten for precision
Liquid and each 20 μ l of need testing solution, liquid chromatograph is injected separately into, records chromatogram.
The percentage composition of light degradation impurity=（AF is supplied/AMX is compareed+AG is supplied/AMX is compareed）×1000×100%
In formula：AF is suppliedFor the peak area of impurity F in need testing solution
AG is suppliedFor the peak area of impurity G in need testing solution
AMX is compareedFor the peak area of MOXIFLOXACIN in contrast solution
1000 be extension rate.
Comparative example
Comparative example 1
The moxifloxacin hydrochloride, sodium chloride, sodium hydrogensulfite of recipe quantity are added in Agitation Tank, add appropriate injection
Water, stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to
Full dose, stir, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification dispenses, embedding sterilizing.
Comparative example 2
The moxifloxacin hydrochloride, sodium chloride, glycine of recipe quantity are added in Agitation Tank, appropriate water for injection is added, stirs
Dissolving is mixed, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection,
Stir, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/
Bottle specification packing, embedding sterilizing.
Comparative example 3
The moxifloxacin hydrochloride, sodium chloride, ethanol of recipe quantity are added in Agitation Tank, add appropriate water for injection, is stirred
Dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirs
Mix uniformly, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottles
Specification dispenses, embedding sterilizing.
Comparative example 4
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, nitrogen is first passed through in vial, is then injected into the molten of the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Liquid, nitrogen is passed through for the second time, seal, sterilizing.
Comparative example 5
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, be passed through carbon dioxide for the second time, embedding, sterilizing.
Comparative example 6
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 7.1~8.0 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, be passed through carbon dioxide for the second time, seal, sterilizing.
Comparative example 7
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 6.1~7.0 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, be passed through carbon dioxide for the second time, seal, sterilizing.
Comparative example 8
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 5.5~6.0 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, be passed through carbon dioxide for the second time, seal, sterilizing.
Comparative example 9
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 4.7~5.4 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, be passed through carbon dioxide for the second time, seal, sterilizing.
Comparative example 10
The moxifloxacin hydrochloride, sodium chloride, sodium carbonate of recipe quantity are added in Agitation Tank, appropriate water for injection is added, stirs
Dissolving is mixed, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection,
Stir, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/
Bottle specification packing, is first passed through carbon dioxide in vial, is then injected into hydrochloric MOXIFLOXACIN, sodium chloride, the carbon prepared
The solution of sour sodium and PH conditioning agent, is passed through carbon dioxide for the second time, seals, sterilizing.
Comparative example 11
The moxifloxacin hydrochloride, sodium chloride, sodium acid carbonate of recipe quantity are added in Agitation Tank, add appropriate water for injection,
Stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to entirely
Amount, is stirred, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification is dispensed, and carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, chlorination
The solution of sodium, sodium acid carbonate and PH conditioning agents, carbon dioxide is passed through for the second time, seal, sterilizing.
Comparative example 12
The moxifloxacin hydrochloride, sodium chloride, sodium acid carbonate of recipe quantity are added in Agitation Tank, add appropriate water for injection,
Stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to entirely
Amount, is stirred, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification dispenses, and seals, sterilizing.
Comparative example 13
The moxifloxacin hydrochloride, sodium chloride, sodium acid carbonate of recipe quantity are added in Agitation Tank, add appropriate water for injection,
Stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to entirely
Amount, is stirred, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification dispense, first nitrogen is passed through in vial, be then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride,
The solution of sodium acid carbonate and PH conditioning agents, nitrogen is passed through for the second time, seal, sterilizing.
The composition containing moxifloxacin hydrochloride prepared according to the methods described of comparative example 1~13, it is portable using OX-12B
Formula oxygen analyser detects the remaining oxygen of gas in comparative example 4~11 and the container for injection of comparative example 13, then makes comparative example 1~13
Standby composition is divided into three parts, wherein two parts of not packaged are respectively placed in the environment of 40 DEG C and 4500xl strong illuminations place 10
It carries out Acceleration study, is placed in after another lucifuge packaging under 40 DEG C of environment and places 6 months progress stability experiments, then examined respectively
The content of its light degradation impurity is surveyed, as a result see the table below.
Comparative example 1~3 adds antioxidant, amino acid and organic reagent, but its light degradation impurity in the composition respectively
Still significantly increase under high temperature and illumination；Comparative example 4 has been passed through inert nitrogen gas in the composition, although will to a certain degree
On MOXIFLOXACIN is isolated with oxygen, but the growth to light degradation impurity does not have inhibitory action；Comparative example 5~9 is respectively by group
The pH value of compound is passed through carbon dioxide again after adjusting to different range, be as a result only passed through dioxy when pH value is 4.1~4.6
Obvious inhibitory action could be played to light degradation impurity by changing carbon, and by light degradation Control of Impurities below 0.05%；Comparative example 10
~11 add different Sodium Carbonate Additive and sodium acid carbonate respectively on the basis of the prescription of comparative example 5, find when its content exists
More than 0.005%w/v, good synergy can be played with the carbon dioxide being passed through, from regardless of whether real in acceleration or stability
In testing, its light degradation impurity can be controlled below 0.02%；Comparative example 12 is not passed through carbon dioxide in the composition, only adds
Sodium acid carbonate is added, comparative example 13 adds sodium acid carbonate in the case where being passed through nitrogen, as a result finds not to be passed through carbon dioxide or logical
Enter and add sodium acid carbonate under other gases, can not play a part of significantly controlling degradation impurity.
Brief description of the drawings
Fig. 1 is detection collection of illustrative plates of the comparative example 4 of the present invention in the light degradation impurity of 0 day.
Fig. 2 is the detection collection of illustrative plates of light degradation impurity of the comparative example 4 of the present invention when placing 6 months for 40 DEG C.
Fig. 3 is detection collection of illustrative plates of the comparative example 5 of the present invention in the light degradation impurity of 0 day.
Fig. 4 is the detection collection of illustrative plates of light degradation impurity of the comparative example 5 of the present invention when placing 6 months for 40 DEG C.
Fig. 5 is detection collection of illustrative plates of the comparative example 6 of the present invention in the light degradation impurity of 0 day.
Fig. 6 is the detection collection of illustrative plates of light degradation impurity of the comparative example 6 of the present invention when placing 6 months for 40 DEG C.
Fig. 7 is detection collection of illustrative plates of the comparative example 12 of the present invention in the light degradation impurity of 0 day.
Fig. 8 is the detection collection of illustrative plates of light degradation impurity of the comparative example 12 of the present invention when placing 6 months for 40 DEG C.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, seal, sterilizing.
Embodiment 2
The moxifloxacin hydrochloride, sodium chloride, glycine of recipe quantity are added in Agitation Tank, appropriate water for injection is added, stirs
Dissolving is mixed, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection,
Stir, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 250ml/
Bottle specification packing, injects the solution of the hydrochloric MOXIFLOXACIN prepared, sodium chloride, glycine and PH conditioning agents, then passes to
Carbon dioxide, seal, sterilizing.
Embodiment 3
The moxifloxacin hydrochloride of recipe quantity, sodium chloride are added in Agitation Tank, add appropriate water for injection, stirring and dissolving,
By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit adds to the full amount of water for injection, and stirring is equal
It is even, pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, by 200ml/ bottle specifications
Packing, carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents
Solution, be passed through carbon dioxide for the second time, seal, sterilizing.
Embodiment 4
The moxifloxacin hydrochloride, sodium chloride, sodium acid carbonate of recipe quantity are added in Agitation Tank, add appropriate water for injection,
Stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to entirely
Amount, is stirred, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification is dispensed, and carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, chlorination
The solution of sodium, sodium acid carbonate and PH conditioning agents, carbon dioxide is passed through for the second time, seal, sterilizing.
Embodiment 5
The moxifloxacin hydrochloride, sodium chloride, saleratus of recipe quantity are added in Agitation Tank, add appropriate water for injection,
Stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to entirely
Amount, is stirred, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification is dispensed, and carbon dioxide is first passed through in vial, is then injected into the hydrochloric MOXIFLOXACIN prepared, chlorination
The solution of sodium, saleratus and PH conditioning agents, carbon dioxide is passed through for the second time, seal, sterilizing.
Embodiment 6
The moxifloxacin hydrochloride of recipe quantity, sodium chloride, saleratus, potassium carbonate are added in Agitation Tank, add appropriate note
Penetrate and use water, stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Add injection
Water is stirred to full dose, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration medicine
Liquid, dispensed by 250ml/ bottles specification, carbon dioxide is first passed through in vial, it is husky to be then injected into the hydrochloric Moses prepared
Star, sodium chloride, potassium carbonate, the solution of saleratus and PH conditioning agents, are passed through carbon dioxide for the second time, seal, sterilizing.
Embodiment 7
200L water for injection is added in Agitation Tank, moxifloxacin hydrochloride is added, stirring and dissolving, adds sodium chloride,
Stirring and dissolving；By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Benefit injects water to entirely
Amount, is stirred, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With 0.22um filter membrane refined filtration decoction, press
250ml/ bottles specification is dispensed, lucifuge and under infrared light irradiation, and air displacer carbon dioxide is added in vial, is then noted
Enter the solution of the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents, second of addition air displacer carbon dioxide,
Sealing, sterilizing.
Embodiment 8
200L water for injection is added in Agitation Tank, sodium acid carbonate is added, stirring and dissolving, then adds moxifloxacin hydrochloride
Star, stirring and dissolving, add sodium chloride, stirring and dissolving；By the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes,
Filtering decarbonization；Benefit is added to the full amount of water for injection, and stirs, and pH value is adjusted between 4.1~4.6 with hydrochloric acid or sodium hydroxide；With
0.22um filter membrane refined filtration decoction, by the packing of 250ml/ bottles specification, lucifuge and under infrared light irradiation, added in vial empty
Gas displacer carbon dioxide, the solution of the hydrochloric MOXIFLOXACIN prepared, sodium chloride and PH conditioning agents is then injected into, second
Air displacer carbon dioxide is added, is sealed, sterilizing.
The composition containing moxifloxacin hydrochloride is prepared according to the methods described of embodiment 1~8, uses the portable surveys of OX-12B
Oxygen instrument detects its remaining oxygen, and composition then is divided into three parts, wherein two parts it is not packaged be respectively placed in 40 DEG C and 4500xl it is strong
Placed in the environment of light irradiation and carry out within 10 days Acceleration study, be placed in after another lucifuge packaging under 40 DEG C of environment and place 6 months
Row stability experiment, then the content of its light degradation impurity is detected respectively, as a result it see the table below.
Composition prepared by the methods described of embodiment 6~8, lucifuge are placed under 25 DEG C of environment after packing and place 24 months
Row long-term experiment, then the content of its light degradation impurity and total miscellaneous content are detected respectively, as a result it see the table below.
。
Claims (1)
1. a kind of pharmaceutical composition containing moxifloxacin hydrochloride and glycine, it is characterised in that the composition is by following several
Medicinal ingredient forms：
,
Its preparation method is：The moxifloxacin hydrochloride, sodium chloride, glycine of recipe quantity are added in Agitation Tank, add appropriate note
Penetrate and use water, stirring and dissolving, by the 0.05% of cumulative volume（w/v）Activated carbon is added, is stirred 20 minutes, filtering decarbonization；Add injection
With water to full dose, stir, between sodium hydroxide tune PH values to 4.1~4.6；With 0.22 μm of filter membrane refined filtration
Decoction, dispensed by 250ml/ bottles specification, inject the hydrochloric MOXIFLOXACIN prepared, sodium chloride, glycine and PH conditioning agents
Solution, carbon dioxide is then passed to, sealed, sterilizing.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410598172.3A CN105616412B (en) | 2014-10-31 | 2014-10-31 | A kind of pharmaceutical composition containing moxifloxacin hydrochloride |
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| CN201410598172.3A CN105616412B (en) | 2014-10-31 | 2014-10-31 | A kind of pharmaceutical composition containing moxifloxacin hydrochloride |
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| CN101732246A (en) * | 2009-12-24 | 2010-06-16 | 济南百诺医药科技开发有限公司 | Moxifloxacin aqueous solution type injection |
| CN102631316B (en) * | 2012-04-27 | 2014-11-12 | 天津红日药业股份有限公司 | Moxifloxacin injection preparation |
| CN103356479B (en) * | 2013-07-29 | 2015-05-13 | 湖南华纳大药厂有限公司 | Moxifloxacin hydrochloride injection aqua |
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Address after: 610041, No. 2, building 4, No. 201, building C, nine Hing Road, 6 hi tech Zone, Sichuan, Chengdu, 402 Applicant after: Chengdu state bio medicine Co., Ltd. Address before: 610041 Sichuan Province, Chengdu hi tech Zone, No. nine Hing Road, building C, No. 6, building No. 2, No. 201 Applicant before: Chengdu Guohong Medicine Co., Ltd. |
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Effective date of registration: 20191204 Address after: No. 606, Hexing Road, Yangma Town, Chongzhou City, Chengdu City, Sichuan Province Patentee after: Chengdu Zhengkang Pharmaceutical Co., Ltd. Address before: 610041, No. 2, building 4, No. 201, building C, nine Hing Road, 6 hi tech Zone, Sichuan, Chengdu, 402 Patentee before: Chengdu state bio medicine Co., Ltd. |