CN113018268A - 一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 - Google Patents
一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 Download PDFInfo
- Publication number
- CN113018268A CN113018268A CN201911352666.2A CN201911352666A CN113018268A CN 113018268 A CN113018268 A CN 113018268A CN 201911352666 A CN201911352666 A CN 201911352666A CN 113018268 A CN113018268 A CN 113018268A
- Authority
- CN
- China
- Prior art keywords
- freeze
- delafloxacin meglumine
- injection
- dried
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229950006412 delafloxacin Drugs 0.000 title claims abstract description 91
- AHJGUEMIZPMAMR-WZTVWXICSA-N 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F AHJGUEMIZPMAMR-WZTVWXICSA-N 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- 238000002347 injection Methods 0.000 title claims abstract description 50
- 239000007924 injection Substances 0.000 title claims abstract description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000661 sodium alginate Substances 0.000 claims abstract description 34
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 34
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000000463 material Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- 239000012074 organic phase Substances 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000006070 nanosuspension Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- 238000002390 rotary evaporation Methods 0.000 claims description 21
- 239000000839 emulsion Substances 0.000 claims description 20
- 238000004108 freeze drying Methods 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 20
- 239000012071 phase Substances 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 238000009210 therapy by ultrasound Methods 0.000 claims description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000004945 emulsification Methods 0.000 claims description 11
- 239000012528 membrane Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 239000003963 antioxidant agent Substances 0.000 claims description 8
- 230000003078 antioxidant effect Effects 0.000 claims description 8
- 235000006708 antioxidants Nutrition 0.000 claims description 8
- 239000003223 protective agent Substances 0.000 claims description 7
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229930003268 Vitamin C Natural products 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- 239000011718 vitamin C Substances 0.000 claims description 6
- 235000019154 vitamin C Nutrition 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 229920001992 poloxamer 407 Polymers 0.000 claims description 5
- 229940044476 poloxamer 407 Drugs 0.000 claims description 5
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 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
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 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 3
- 229930003427 Vitamin E Natural products 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 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 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 229960001484 edetic acid Drugs 0.000 claims description 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 235000019165 vitamin E Nutrition 0.000 claims description 3
- 229940046009 vitamin E Drugs 0.000 claims description 3
- 239000011709 vitamin E 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
- 239000007864 aqueous solution Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 6
- 239000003814 drug Substances 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000011068 loading method Methods 0.000 abstract description 3
- 238000001035 drying Methods 0.000 description 51
- 238000007710 freezing Methods 0.000 description 36
- 230000008014 freezing Effects 0.000 description 36
- 239000002245 particle Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 17
- 239000000843 powder Substances 0.000 description 12
- 238000005192 partition Methods 0.000 description 10
- 238000004321 preservation Methods 0.000 description 10
- 238000000859 sublimation Methods 0.000 description 10
- 230000008022 sublimation Effects 0.000 description 10
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000011265 semifinished product Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 230000001276 controlling effect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010041925 Staphylococcal infections Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 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 2
- 210000003022 colostrum Anatomy 0.000 description 2
- 235000021277 colostrum Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 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 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- BKVAAWMQOQLENB-UHFFFAOYSA-N 15-hydroxy stearic acid Chemical compound CCCC(O)CCCCCCCCCCCCCC(O)=O BKVAAWMQOQLENB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 108010041052 DNA Topoisomerase IV Proteins 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 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 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 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 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 229960001425 deferoxamine mesylate Drugs 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 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 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
-
- 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
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种注射用德拉沙星葡甲胺冻干制剂及其制备方法,属于医药技术领域。本发明制备的注射用德拉沙星葡甲胺冻干制剂,由德拉沙星葡甲胺和海藻酸钠制备成复合物,再与药学上可接受的其他辅料制备而成。本发明制备的注射用德拉沙星葡甲胺冻干制剂制备方法简单可控,有效解决了德拉沙星葡甲胺制剂存在的水溶性差、稳定性差,普通注射剂较难达到高载药量的问题。
Description
技术领域
本发明涉及医药技术领域,且特别涉及一种注射用德拉沙星葡甲胺冻干制剂及其制备方法。
背景技术
德拉沙星(英文名:delafloxacin)是由日本Wakunaga制药有限公司研制的一种氟喹诺酮类化合物,其作用机制与其他氟喹诺酮类药物相同,作用于细菌DNA促旋酶和拓扑异构酶IV,突出的抑酶活性可降低细菌耐药突变的选择性,有望成为治疗呼吸道、泌尿道感染以及单纯性淋病、急性细菌性皮肤及皮肤结构感染等病症的候选药物。其对耐喹诺酮类药物MRSA菌的抗菌活性至少是左氧氟沙星、环丙沙星、加替沙星、莫西沙星的32倍(本品的MIC90≤0.5ug/mL,上述其他药物MIC90均大于16ug/mL);而对MRSA的抗菌活性是达托霉素的2倍。
然而,德拉沙星难溶于水,在将其注入人体后不能有效地随体循环靶向到达感染部位,而且容易被巨噬细胞吞噬排除体外,无法发挥理想的治疗效果。专利CN103705942A和CN104958296A利用磺丁基醚-β-环糊精来提高德拉沙星的溶解度,其中德拉沙星的溶解度可达30mg/ml。目前为止环糊精类作为注射用辅料,国内虽有两家该辅料的生产商连同相对应的制剂正在进行临床研究,但尚未批准生产。有资料显示,该辅料有一定的肾毒性和溶血性,也有致癌性,而且可能存在未知的更严重的毒副作用。
专利CN107789324A提供一种注射用德拉沙星葡甲胺的新组方,减少了磺丁基醚-β-环糊精的使用量,专利CN107789323A利用15-羟基硬脂酸聚乙二醇酯以及无水乙醇来代替磺丁基醚-β-环糊精,增加德拉沙星的溶解度。但是德拉沙星的溶解度还有待提高。
因此,需要一种更令人满意的德拉沙星制剂,来解决德拉沙星葡甲胺做成制剂存在水溶性差、稳定性差、载药量低的问题。
发明内容
本发明的主要目的在于提供一种用于静脉注射的德拉沙星葡甲胺注射用冻干纳米混悬剂,有效解决了德拉沙星葡甲胺存在的水溶性差、稳定性差、普通注射剂较难达到高载药量的问题。
本发明采用以下技术方案:
一种注射用德拉沙星葡甲胺冻干制剂,其由德拉沙星葡甲胺和海藻酸钠制备成复合物,再与药学上可接受的其他辅料制备成冻干制剂。
优选地,所述注射用德拉沙星葡甲胺冻干制剂中德拉沙星葡甲胺和海藻酸钠的重量份比为1:1~20。
优选地,所述药学上可接受的其他辅料包括表面活性剂、冻干保护剂、抗氧剂、pH调节剂。
进一步优选地,所述表面活性剂选自泊洛沙姆407、十二烷基硫酸钠、羧甲基纤维素钠、阿洛索中的一种或多种。
进一步优选地,所述冻干保护剂选自蔗糖、乳糖、葡萄糖、麦芽糖、甘露醇、山梨醇中的一种或多种。
进一步优选地,所述抗氧剂选自维生素E、乙二胺四乙酸、盐酸半胱氨酸、维生素C、亚硫酸盐类中的一种或多种。
进一步优选地,所述的pH调节剂为盐酸、磷酸、乙酸、柠檬酸中的一种或多种,pH调节为6~7。
进一步优选地,所述注射用德拉沙星葡甲胺冻干制剂,由以下重量份的组分组成:德拉沙星葡甲胺1份、海藻酸钠1~20份、表面活性剂1~30份、冻干保护剂1~20份、抗氧剂0.05~0.1份、pH调节剂适量。
本发明还提供一种注射用德拉沙星葡甲胺冻干制剂的制备方法:
(1)将德拉沙星葡甲胺和海藻酸钠溶解在有机溶剂中,在低于50~60℃条件下密闭搅拌反应20~30h,旋转蒸发除去有机溶剂,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
(2)将步骤(1)所得复合物用有机溶剂溶解,形成有机相;将表面活性、抗氧剂配成水溶液;将有机相与水相混合搅拌,添加冻干保护剂,用pH调节剂调整pH在6~7,形成初乳;
(3)将步骤(2)所得初乳转入高压均质机进行纳米乳化,形成平均粒径小于500nm的纳米乳剂,超声得纳米混悬剂,真空旋转蒸发除有机溶剂,所得混合物过0.22μm膜滤除菌;灌装,冻干,即得注射用德拉沙星葡甲胺冻干制剂。
优选地,所述的有机溶剂为甲醇或二氯甲烷。
优选地,步骤(1)中,以mL/g计,所述的有机溶剂体积用量比德拉沙星葡甲胺和海藻酸钠总质量为40~80:1。
优选地,步骤(2)中,以mL/g计,所述的有机溶剂体积用量比德拉沙星葡甲胺和海藻酸钠总质量为10~20:1。
优选地,所述步骤(3)高压均质过程中压力为10000~21750psi。
优选地,所述步骤(3)高压均质过程中控制温度为50~60℃。
优选地,所述步骤(3)高压均质过程中,均质循环1~3次。
优选地,所述步骤(3)中冻干过程包括以下几个阶段:
预冻阶段:将灌装并半加塞的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度范围为-45~-40℃之间,时间2~4h;
升华干燥阶段:干燥箱内的真空度达到80mTorr~120mTorr时,将主干燥温度升至-17.5~-12.5℃,用时4~6h,升温后保温时间8~12h;
再干燥阶段:将再干燥温度升高至20~30℃;用时2~4h;将干燥箱内的真度抽至极限真空,保温时间5~7h,得注射用德拉沙星葡甲胺冻干制剂。
本发明注射用德拉沙星葡甲胺冻干制剂的制备方法是在表面活性剂的作用下,利用高压乳匀机或者超声粉碎机的高剪切和空化作用,制备得到粒径小于500nm的纳米混悬剂,通过冷冻干燥制成稳定的固体粉针剂。
本发明注射用德拉沙星葡甲胺冻干制剂的优点是:(1)本发明纳米混悬剂冻干粉具有良好的稳定性,有利于药物长期储存和运输,提高了临床用药的安全性。(2)本纳米混悬剂冻干粉的药物含量较高,有效地解决了德拉沙星葡甲胺水溶性差,药物含量低的问题;本发明制得的注射用德拉沙星葡甲胺冻干制剂使得德拉沙星在水中的溶解度达到200mg/ml~300mg/ml。
具体实施方式
现通过以下实施例来进一步描述本发明制剂的制备过程和实施效果,但本发明的保护范围并不局限于以下实施例。
实施列1:
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于253mL的甲醇溶液中,得到有机相;将有机相密闭搅拌反应25h,控制反应温度在55℃,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去甲醇,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于66mL甲醇溶解,得到有机相;将维生素C、阿洛索溶解于66mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加甘露醇混合均匀,用1M盐酸溶液调节pH至6.5,形成初乳;
3)将初乳混合物转入高压均质机,压力19100psi,控制温度55℃,循环2次,进行纳米乳化,将制得的初混悬剂在500W的功率下超声30次,超声时间为5秒/次,制得纳米混悬剂,平均粒径为409.1nm,PDI0.103;通过在真空旋转蒸发器上,控制温度低于60℃,真空4小时旋转蒸发除尽甲醇,所得混合物采用0.22um膜滤过,除菌。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,预冻温度为-43℃,时间3h;
升华干燥阶段:干燥箱内的真空度达到100mTorr时,将主干燥温度升至-15.5℃,用时5h,升温后保温时间10h;
再干燥阶段:将再干燥温度升高至25℃;用时3h;将干燥箱内的真度抽至极限真空,保温时间6h,得注射用德拉沙星葡甲胺冻干制剂。
实施例2
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于333mL的二氯甲烷溶液中,得到有机相;将有机相密闭搅拌反应30h,控制反应温度在60℃,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去二氯甲烷,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于86mL甲醇溶解,得到有机相;将维生素E、泊洛沙姆407溶解于86mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加蔗糖混合均匀,用1M磷酸溶液调节pH至7,形成初乳;
3)将初乳混合物转入高压均质机,压力20000psi,控制温度55℃,循环3次,进行纳米乳化,将制得的初混悬剂在700W的功率下超声35次,超声时间为5秒/次,制得纳米混悬剂,平均粒径为412.3nm,PDI0.115;通过在真空旋转蒸发器上,控制温度低于60℃,真空5小时旋转蒸发除尽甲醇,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-45℃,时间4h;
升华干燥阶段:干燥箱内的真空度达到110mTorr时,将主干燥温度升至-16.5℃,用时6h,升温后保温时间11h;
再干燥阶段:将再干燥温度升高至28℃;用时4h;将干燥箱内的真度抽至极限真空,保温时间7h,得注射用德拉沙星葡甲胺冻干制剂。
实施例3
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于130mL的二氯甲烷溶液中,得到有机相;将有机相密闭搅拌反应20h,控制反应温度在50℃,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去二氯甲烷,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于31mL二氯甲烷溶解,得到有机相;将乙二胺四乙酸、十二烷基硫酸钠溶解于31mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加乳糖混合均匀,用乙酸溶液调节pH至6,形成初乳;
3)将初乳混合物转入高压均质机,压力18000psi,控制温度60℃,循环2次,进行纳米乳化,将制得的初混悬剂在300W的功率下超声25次,超声时间为4秒/次,制得纳米混悬剂,平均粒径为417.5nm,PDI0.118;通过在真空旋转蒸发器上,控制温度低于60℃,真空3小时旋转蒸发除尽二氯甲烷,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-40℃,时间2h;
升华干燥阶段:干燥箱内的真空度达到90mTorr时,将主干燥温度升至-13.5℃,用时4h,升温后保温时间8h;
再干燥阶段:将再干燥温度升高至22℃;用时2h;将干燥箱内的真度抽至极限真空,保温时间5h,得注射用德拉沙星葡甲胺冻干制剂。
实施例4
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于727mL的甲醇溶液中,得到有机相;将有机相密闭搅拌反应30h,控制反应温度在60℃,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去甲醇,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于182mL二氯甲烷溶解,得到有机相;将维生素C、羧甲基纤维素钠溶解于182mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加葡萄糖和山梨醇混合均匀,用柠檬酸溶液调节pH至7,形成初乳;
3)将初乳混合物转入高压均质机,压力18000psi,控制温度50℃,循环3次,进行纳米乳化,将制得的初混悬剂在800W的功率下超声40次,超声时间为4秒/次,制得纳米混悬剂,平均粒径为421.6nm,PDI0.121;通过在真空旋转蒸发器上,控制温度低于60℃,真空5小时旋转蒸发除尽二氯甲烷,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-40℃,时间4h;
升华干燥阶段:干燥箱内的真空度达到120mTorr时,将主干燥温度升至-12.5℃,用时6h,升温后保温时间12h;
再干燥阶段:将再干燥温度升高至30℃;用时4h;将干燥箱内的真度抽至极限真空,保温时间7h,得注射用德拉沙星葡甲胺冻干制剂。
实施例5
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于35mL的甲醇溶液中,得到有机相;将有机相密闭搅拌反应20h,控制反应温度在50℃以下,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去甲醇,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于9mL甲醇溶解,得到有机相;将盐酸半胱氨酸、阿洛索和十二烷基硫酸钠溶解于9mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加麦芽糖混合均匀,用1M盐酸溶液调节pH至6.5,形成初乳;
3)将初乳混合物转入高压均质机,压力10000psi,控制温度50℃,循环1次,进行纳米乳化,将制得的初混悬剂在200W的功率下超声20次,超声时间为4秒/次,制得纳米混悬剂,平均粒径为423.4nm,PDI0.139;通过在真空旋转蒸发器上,控制温度低于60℃,真空3小时旋转蒸发除尽甲醇,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-45℃,时间2h;
升华干燥阶段:干燥箱内的真空度达到80mTorr时,将主干燥温度升至-17.5℃,用时4h,升温后保温时间8h;
再干燥阶段:将再干燥温度升高至20℃;用时2h;将干燥箱内的真度抽至极限真空,保温时间5h,得注射用德拉沙星葡甲胺冻干制剂。
实施例6
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于957mL的甲醇溶液中,得到有机相;将有机相密闭搅拌反应35h,控制反应温度在65℃以下,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去甲醇,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于280mL二氯甲烷溶解,得到有机相;将盐酸半胱氨酸、去氧胆酸钠解于280mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加甘露醇混合均匀,用1M盐酸溶液调节pH至6.5,形成初乳;
3)将初乳混合物转入高压均质机,压力22000psi,控制温度65℃,循环5次,进行纳米乳化,将制得的初混悬剂在900W的功率下超声45次,超声时间为6秒/次,制得纳米混悬剂,平均粒径为465.2nm,PDI0.242;通过在真空旋转蒸发器上,控制温度低于60℃,真空4小时旋转蒸发除尽二氯甲烷,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-35℃,时间3h;
升华干燥阶段:干燥箱内的真空度达到130mTorr时,将主干燥温度升至-11℃,用时5h,升温后保温时间10h;
再干燥阶段:将再干燥温度升高至20℃;用时3h;将干燥箱内的真度抽至极限真空,保温时间6h,得注射用德拉沙星葡甲胺冻干制剂。
实施例7
组方:
制备方法:
1)将德拉沙星葡甲胺和海藻酸钠溶解于23mL的甲醇溶液中,得到有机相;将有机相密闭搅拌反应15h,控制反应温度在45℃,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去甲醇,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
2)将德拉沙星葡甲胺和海藻酸钠形成的复合物溶解于4mL甲醇溶解,得到有机相;将甲磺酸去铁胺、阿洛索溶解于4mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加海藻糖混合均匀,用1M枸橼酸溶液调节pH至6.5,形成初乳;
3)将初乳混合物转入高压均质机,压力8000psi,控制温度45℃,进行纳米乳化,将制得的初混悬剂在150W的功率下超声15次,超声时间为5秒/次,制得纳米混悬剂,平均粒径为468.0nm,PDI0.246;通过在真空旋转蒸发器上,控制温度低于60℃,真空5小时旋转蒸发除尽甲醇,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-50℃,时间2h;
升华干燥阶段:干燥箱内的真空度达到80mTorr时,将主干燥温度升至-18.5℃,用时4h,升温后保温时间8h;
再干燥阶段:将再干燥温度升高至20℃;用时2h;将干燥箱内的真度抽至极限真空,保温时间5h,得注射用德拉沙星葡甲胺冻干制剂。
对比例1
组方:
制备方法:
1)将德拉沙星葡甲胺和泊洛沙姆407溶解于253mL的甲醇溶液中,得到有机相;将有机相密闭搅拌反应25h,控制反应温度在60℃,将有机相混合液导入真空旋转蒸发器的烧瓶内,旋转蒸发除去甲醇,形成均匀的德拉沙星葡甲胺和卵磷脂的复合物;
2)将德拉沙星葡甲胺和泊洛沙姆407形成的复合物溶解于66mL甲醇溶解,得到有机相;将维生素C、阿洛索溶解于66mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加甘露醇混合均匀,用1M盐酸溶液调节pH至6.5,形成初乳;
3)将初乳混合物转入高压均质机,压力19100psi,控制温度低于55℃,循环2次,进行纳米乳化,将制得的初混悬剂在500W的功率下超声30次,超声时间为5秒/次,制得纳米混悬剂,平均粒径为536nm;PDI:0.324;通过在真空旋转蒸发器上,控制温度低于60℃,真空4小时旋转蒸发除尽甲醇,所得混合物采用0.22um膜滤过,除菌,通过滤过除去注射剂限制的大颗粒和不溶物。
4)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,并使半成品在尽可能短的时间内达到预冻温度,预冻温度为-43℃,时间4h;
升华干燥阶段:干燥箱内的真空度达到100mTorr时,将主干燥温度升至-15.5℃,用时6h,升温后保温时间11h;
再干燥阶段:将再干燥温度升高至25℃;用时3h;将干燥箱内的真度抽至极限真空,保温时间6h,得注射用德拉沙星葡甲胺冻干制剂。
对比例2
组方:
制备方法:
1)将德拉沙星葡甲胺溶解于66mL甲醇溶解,得到有机相;将维生素C、阿洛索溶解于66mL纯净水中,得到水相;将有机相与水相混合搅拌,再添加甘露醇混合均匀,用1M盐酸溶液调节pH至6.5,形成初乳;
2)将初乳混合物转入高压均质机,压力19100psi,控制温度60℃,循环2次,进行纳米乳化,将制得的初混悬剂在500W的功率下超声30次,超声时间为5秒/次,制得纳米混悬剂,平均粒径为560nm,PDI0.351;通过在真空旋转蒸发器上,控制温度55℃,真空3小时旋转蒸发除尽甲醇,所得混合物采用0.22um膜滤过,除菌;
3)制备冻干粉:
预冻阶段:将灌装并半加塞的上述纳米混悬剂置于冻干机箱内的隔板上进行预冻,预冻温度为-43℃,时间2h;
升华干燥阶段:干燥箱内的真空度达到100mTorr时,将主干燥温度升至-15.5℃,用时5h,升温后保温时间10h;
再干燥阶段:将再干燥温度升高至25℃;用时3h;将干燥箱内的真度抽至极限真空,保温时间6h,得注射用德拉沙星葡甲胺冻干制剂。
稳定性试验
(1)平均粒径及多分散系数的考察将实施例1~7及对比例1、2制备的注射用德拉沙星葡甲胺冻干制剂,按市售包装,在温度40℃士2℃、相对湿度75%士5%的条件下放置6个月,分别于第0、1、3、6月后,用0.9%氯化钠进行复溶,并测定平均粒径及多分散系数,结果如表1。
表1平均粒径及多分散系数结果
由表1可见,本发明实施例1~7制备的注射用德拉沙星葡甲胺冻干制剂复溶后粒径小加速放置6个月,随着天数的增加粒径随变化不大,具有较好的稳定性,且能在较长时间内保持良好的稳定性,而对比例1、2的粒径较大,加速后粒径变化也明显增大,稳定性较差。
(2)长期试验
将实施例1~7及对比例1、2制备的注射用德拉沙星葡甲胺冻干制剂进行对比试验,市售包装,在温度25℃士2℃,相对湿度60%士10%的条件下放置12个月,具体的试验结果见表2。
表2在长期试验结果
备注:■白色至类白色冻干块状物;●无色澄明液体。
由上述长期试验数据可以看出,本发明实施例1~7制备的注射用德拉沙星葡甲胺冻干制剂外关状态、水分、有关物质、含量均没有明显的变化,说明本发明制备的注射用德拉沙星葡甲胺冻干制剂稳定性好,可长期储存和运输。虽然对比例1和2的的外观状态未发生明显变化,但其水分、有关物质、含量均有较明显的变化,稳定性较差。
Claims (10)
1.一种注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述冻干制剂由德拉沙星葡甲胺和海藻酸钠制备成复合物,再与药学上可接受的其他辅料制备而成。
2.如权利要求1所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述德拉沙星葡甲胺和海藻酸钠的重量份比为1:1~20。
3.如权利要求1所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述药学上可接受的其他辅料包括表面活性剂、冻干保护剂、抗氧剂、pH调节剂。
4.如权利要求3所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述表面活性剂选自泊洛沙姆407、十二烷基硫酸钠、羧甲基纤维素钠、阿洛索中的一种或多种。
5.如权利要求3所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述冻干保护剂选自蔗糖、乳糖、葡萄糖、麦芽糖、甘露醇、山梨醇中的一种或多种。
6.如权利要求3所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述抗氧剂选自维生素E、乙二胺四乙酸、盐酸半胱氨酸、维生素C、亚硫酸盐类中的一种或多种。
7.如权利要求3所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于:所述的pH调节剂为盐酸、磷酸、乙酸、柠檬酸中的一种或多种。
8.如权利要求1-7任一项所述的注射用德拉沙星葡甲胺冻干制剂,其特征在于,由以下重量份的组分组成:德拉沙星葡甲胺1份、海藻酸钠1~20份、表面活性剂1~30份、冻干保护剂1~20份、抗氧剂0.05~0.1份、pH调节剂适量。
9.一种注射用德拉沙星葡甲胺冻干制剂的制备方法,其特征在于,包括以下步骤:
(1)将德拉沙星葡甲胺和海藻酸钠溶解在有机溶剂中,温度在50~60℃条件下密闭搅拌反应20~30h,旋转蒸发除去有机溶剂,形成均匀的德拉沙星葡甲胺和海藻酸钠的复合物;
(2)将步骤(1)所得复合物用有机溶剂溶解,形成有机相;将表面活性、抗氧剂配成水溶液;将有机相与水相混合搅拌,添加冻干保护剂,用pH调节剂调整pH在6~7,形成初乳;
(3)将步骤(2)所得初乳转入高压均质机进行纳米乳化,超声得纳米混悬剂,真空旋转蒸发除有机溶剂,所得混合物过膜滤除菌;灌装,冻干,即得注射用德拉沙星葡甲胺冻干制剂。
10.如权利要求9所述的注射用德拉沙星葡甲胺冻干制剂的制备方法,其特征在于:所述的有机溶剂为甲醇或二氯甲烷。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911352666.2A CN113018268B (zh) | 2019-12-25 | 2019-12-25 | 一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911352666.2A CN113018268B (zh) | 2019-12-25 | 2019-12-25 | 一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113018268A true CN113018268A (zh) | 2021-06-25 |
CN113018268B CN113018268B (zh) | 2024-02-02 |
Family
ID=76452296
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911352666.2A Active CN113018268B (zh) | 2019-12-25 | 2019-12-25 | 一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113018268B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103040770A (zh) * | 2013-02-05 | 2013-04-17 | 南京碧迪可医药科技有限公司 | 一种诺卡沙星冻干粉针剂的制备方法 |
US20130156827A1 (en) * | 2010-07-09 | 2013-06-20 | Xinjian Li | Sodium alginate crosslinked slow-release moxifloxacin microsphere, the preparation method and the use thereof, and target vascular occlusive agent of the microsphere |
CN105189513A (zh) * | 2013-03-08 | 2015-12-23 | 麦林塔医疗有限公司 | 葡萄糖醇,1-脱氧-1-(甲胺基)-,1-(6-氨基-3,5-二氟吡啶-2-基)-8-氯-6-氟-1,4-二氢-7-(3-羟基氮杂环丁烷-l-基)-4-氧-3-喹啉羧酸盐的结晶形态 |
US20180250227A1 (en) * | 2014-11-19 | 2018-09-06 | Fmc Corporation | Nanosuspension formulation |
CN108743527A (zh) * | 2018-08-06 | 2018-11-06 | 鲁南制药集团股份有限公司 | 一种盐酸替罗非班注射液及其制备方法 |
-
2019
- 2019-12-25 CN CN201911352666.2A patent/CN113018268B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130156827A1 (en) * | 2010-07-09 | 2013-06-20 | Xinjian Li | Sodium alginate crosslinked slow-release moxifloxacin microsphere, the preparation method and the use thereof, and target vascular occlusive agent of the microsphere |
CN103040770A (zh) * | 2013-02-05 | 2013-04-17 | 南京碧迪可医药科技有限公司 | 一种诺卡沙星冻干粉针剂的制备方法 |
CN105189513A (zh) * | 2013-03-08 | 2015-12-23 | 麦林塔医疗有限公司 | 葡萄糖醇,1-脱氧-1-(甲胺基)-,1-(6-氨基-3,5-二氟吡啶-2-基)-8-氯-6-氟-1,4-二氢-7-(3-羟基氮杂环丁烷-l-基)-4-氧-3-喹啉羧酸盐的结晶形态 |
US20180250227A1 (en) * | 2014-11-19 | 2018-09-06 | Fmc Corporation | Nanosuspension formulation |
CN108743527A (zh) * | 2018-08-06 | 2018-11-06 | 鲁南制药集团股份有限公司 | 一种盐酸替罗非班注射液及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN113018268B (zh) | 2024-02-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101502533B1 (ko) | 우수한 안정성을 갖는 택산 유도체 함유 주사제용동결건조 조성물 및 이의 제조방법 | |
CN100396276C (zh) | 依普西龙组合物 | |
JP2009523770A (ja) | タキサン医薬製剤、固形タキサン組成物、前記固形タキサン組成物の調製方法、前記固形タキサン組成物を可溶化するための組成物および注射可能なタキサン製剤のための構成要素のセット(キット) | |
CN102458112A (zh) | 纳米颗粒制剂及其用途 | |
CN102056596A (zh) | 纳米颗粒制剂及其用途 | |
JP6182262B2 (ja) | 抗がん剤を含む安定な水溶性医薬組成物 | |
JP6734971B2 (ja) | がん治療薬 | |
CN102755296B (zh) | 一种含有福沙吡坦的无菌冻干制剂及其制备方法 | |
KR101731155B1 (ko) | 안정화된 보리코나졸 조성물 | |
JP6770754B2 (ja) | 輸液又は注射として及び輸液濃縮物の静脈内投与のためのレボシメンダンの改善された調製物 | |
CN110870914A (zh) | 氨基酸类营养素的应用以及包含它的药物组合物 | |
CN102370622A (zh) | 一种载药物纳米粒及其制备方法和应用 | |
WO2020034989A1 (zh) | 一种可注射的药物组合物及其制备方法 | |
WO2011134368A1 (zh) | 果胶-阿霉素轭合物的冻干制剂及制备方法 | |
CN101229131A (zh) | 具有降低喜树碱类药物胃肠毒性的新型纳米微粒制剂 | |
WO2016008289A1 (zh) | 一种盐酸伊立替康纳米脂束制剂及其制备方法 | |
US20160015691A1 (en) | Use of mtor inhibitors for prevention of neuroendocrine tumor development and growth | |
CN116617160A (zh) | 水性混悬液及制备方法、冻干粉及应用、脂肪消减注射剂 | |
CN113018268B (zh) | 一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 | |
WO2016008401A1 (zh) | 一种含多西他赛的药物组合物 | |
CN107137349B (zh) | 一种藤黄酸纳米混悬剂及其制备方法 | |
BR112020024590A2 (pt) | Formulações de tegavivint e compostos relacionados | |
WO2022152021A1 (zh) | 含有难溶性抗肿瘤活性剂的药物组合物及其制备方法 | |
WO2017107894A1 (zh) | 药物包合物,其制剂和制备方法 | |
CN104800191A (zh) | 佐米曲普坦纳米冻干粉及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |