CN102038636B - Taxane medicine solution containing chelating agent and preparation method thereof - Google Patents
Taxane medicine solution containing chelating agent and preparation method thereof Download PDFInfo
- Publication number
- CN102038636B CN102038636B CN200910070932.2A CN200910070932A CN102038636B CN 102038636 B CN102038636 B CN 102038636B CN 200910070932 A CN200910070932 A CN 200910070932A CN 102038636 B CN102038636 B CN 102038636B
- Authority
- CN
- China
- Prior art keywords
- emulsion
- grams
- solution
- minutes
- injection
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 194
- 238000002360 preparation method Methods 0.000 title claims abstract description 80
- 229940123237 Taxane Drugs 0.000 title claims abstract description 20
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 title claims abstract description 18
- 239000002738 chelating agent Substances 0.000 title abstract description 14
- 239000000839 emulsion Substances 0.000 claims abstract description 177
- 238000001990 intravenous administration Methods 0.000 claims abstract description 35
- 239000000243 solution Substances 0.000 claims description 226
- 229940079593 drug Drugs 0.000 claims description 145
- 239000007924 injection Substances 0.000 claims description 100
- 238000002347 injection Methods 0.000 claims description 100
- 230000001954 sterilising effect Effects 0.000 claims description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 78
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 64
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 60
- 239000003921 oil Substances 0.000 claims description 59
- 235000019198 oils Nutrition 0.000 claims description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 57
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 53
- 238000007789 sealing Methods 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 45
- 238000004659 sterilization and disinfection Methods 0.000 claims description 43
- 230000001804 emulsifying effect Effects 0.000 claims description 39
- 238000004806 packaging method and process Methods 0.000 claims description 39
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 38
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 38
- 210000003022 colostrum Anatomy 0.000 claims description 37
- 235000021277 colostrum Nutrition 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 29
- 239000012982 microporous membrane Substances 0.000 claims description 27
- 230000001476 alcoholic effect Effects 0.000 claims description 26
- 229940063683 taxotere Drugs 0.000 claims description 26
- 238000010008 shearing Methods 0.000 claims description 24
- 239000003643 water by type Substances 0.000 claims description 23
- 238000012856 packing Methods 0.000 claims description 22
- 239000008215 water for injection Substances 0.000 claims description 20
- 238000004945 emulsification Methods 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 229920003023 plastic Polymers 0.000 claims description 18
- 239000004033 plastic Substances 0.000 claims description 18
- 230000001105 regulatory effect Effects 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 125000002185 docetaxel anhydrous group Chemical group 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 14
- 239000003549 soybean oil Substances 0.000 claims description 14
- 235000012424 soybean oil Nutrition 0.000 claims description 14
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 12
- 229940093633 tricaprin Drugs 0.000 claims description 12
- 239000008347 soybean phospholipid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 229920001983 poloxamer Polymers 0.000 claims description 6
- 239000006185 dispersion Substances 0.000 abstract description 54
- 239000007788 liquid Substances 0.000 abstract description 45
- 239000003305 oil spill Substances 0.000 abstract description 17
- 239000002131 composite material Substances 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 77
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 72
- 229930012538 Paclitaxel Natural products 0.000 description 58
- 229960001592 paclitaxel Drugs 0.000 description 58
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 58
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 39
- 229960003668 docetaxel Drugs 0.000 description 27
- 235000015165 citric acid Nutrition 0.000 description 26
- 235000011121 sodium hydroxide Nutrition 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- 125000002456 taxol group Chemical group 0.000 description 17
- 239000002960 lipid emulsion Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 12
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 11
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 11
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 11
- 239000005642 Oleic acid Substances 0.000 description 11
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 11
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 11
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 11
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229940108949 paclitaxel injection Drugs 0.000 description 9
- 239000003995 emulsifying agent Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 7
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- 229960003511 macrogol Drugs 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- -1 polyoxyethylene Polymers 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 239000004310 lactic acid Substances 0.000 description 6
- 235000014655 lactic acid Nutrition 0.000 description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 6
- 229920000053 polysorbate 80 Polymers 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000013329 compounding Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000007812 deficiency Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229940127554 medical product Drugs 0.000 description 5
- 239000003186 pharmaceutical solution Substances 0.000 description 5
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 4
- 108091022875 Microtubule Proteins 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 235000011090 malic acid Nutrition 0.000 description 4
- 210000004688 microtubule Anatomy 0.000 description 4
- 210000000582 semen Anatomy 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 238000011105 stabilization Methods 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 239000011732 tocopherol Substances 0.000 description 4
- 229930003799 tocopherol Natural products 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 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 description 3
- 206010018910 Haemolysis Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 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 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 201000007386 factor VII deficiency Diseases 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 239000001630 malic acid Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 125000002640 tocopherol group Chemical group 0.000 description 3
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-N 0.000 description 2
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-elemene Chemical compound CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- 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 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- LKUNXBRZDFMZOK-GFCCVEGCSA-N Capric acid monoglyceride Natural products CCCCCCCCCC(=O)OC[C@H](O)CO LKUNXBRZDFMZOK-GFCCVEGCSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 241000222336 Ganoderma Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 235000019485 Safflower oil Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 235000019262 disodium citrate Nutrition 0.000 description 2
- 239000002526 disodium citrate Substances 0.000 description 2
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 235000021323 fish oil Nutrition 0.000 description 2
- 239000009969 fructus bruceae Substances 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000003813 safflower oil Substances 0.000 description 2
- 235000005713 safflower oil Nutrition 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 235000019149 tocopherols Nutrition 0.000 description 2
- QBUKAFSEUHGMMX-MTJSOVHGSA-N (5z)-5-[[3-(1-hydroxyethyl)thiophen-2-yl]methylidene]-10-methoxy-2,2,4-trimethyl-1h-chromeno[3,4-f]quinolin-9-ol Chemical class C1=CC=2NC(C)(C)C=C(C)C=2C2=C1C=1C(OC)=C(O)C=CC=1O\C2=C/C=1SC=CC=1C(C)O QBUKAFSEUHGMMX-MTJSOVHGSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 235000003935 Hippophae Nutrition 0.000 description 1
- 241000229143 Hippophae Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008602 kang-lai-te Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000001100 mitostatic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 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 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 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
- A61K9/08—Solutions
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a taxane medicine solution containing a chelating agent and a preparation method therefore as well as application of the taxane medicine solution with an emulsion. Before being applied, the medicine solution is dispersed in the emulsion, shaken to be uniform and then can be used for intravenous drip; since a chelating agent is added, stable time of the medicine solution dispersing in the emulsion is prolonged unexpectedly, and the problem of oil spill on dispersion liquid is also solved, thereby further improving the safety and the effectiveness of clinical administration. The invention also provides the preparation method of the taxane medicine solution, a composite containing the taxane medicine solution and the emulsion, and a combined package consisting of the taxane medicine solution and the emulsion, as well as the emulsion containing the chelating agent.
Description
Invention field
The present invention relates to drug preparation technique, be specifically related to a kind of taxane medicine solution and preparation method thereof.
Background technology
Taxane (taxanes) class medicine comprises paclitaxel (paclitaxel, business is called Taxol) and Docetaxel (docetaxel, commodity are called Taxotem), is two kinds of taxanes cancer therapy drugs being ratified by FDA.Taxone is the cytotoxic agent of a quasi-representative, there is broad-spectrum anti-tumor effect, the preinvasive cancers such as breast carcinoma, ovarian cancer, small cell lung cancer, nonsmall-cell lung cancer, incidence squamous cell carcinoma and malignant melanoma and metastatic carcinoma are all had to stronger effect, its Anticancer Effect and Mechanism is by the polymerization of stimulating catheter bundle, promote microtubule dimer to be assembled into microtubule, and cause microtubule overstable and suppress the restructuring of microtubule net kinetics, finally make cancer cell multiplication stop at the stage of mitostatic phase, reach antineoplastic object.
Paclitaxel and Taxotere alcohol-soluble and water-soluble are very little, and water-soluble (approximately 4 μ g/ml) hardly, oral absorption rate is only 2%～4%, therefore can only intravenously administrable.In order to improve the water solublity of paclitaxel, the paclitaxel injection of clinical practice is by polyoxyethylene castor oil and dehydrated alcohol (50: 50, V/V) the colourless thick concentrated solution of making, although this double solvent has solved the problems of dissolution of paclitaxel, but in this injection, contain the polyoxyethylene castor oil easily causing allergic reaction, after medication, there is the anaphylaxiss such as dyspnea, flushing, palpitating speed, erythra, to patient, brought potential safety hazard and misery.And alcoholic solution two parts that Docetaxel clinical preparation is tween 80 solution and 13% form, during medication, be dispersed in normal saline medium-sized vein drop, although solved the problems of dissolution of Docetaxel, but this injection contains the tween 80 with haemolysis, easily there is hemolytic reaction in clinical application, safety is poor.In view of clinical existing preparation exists many deficiencies, old friends are comparatively active to the research and development of taxone injection.To the research of taxone injection, be mainly that to take the crosslinked precursor of liposome, fat milk, nanoparticle, albumin, cyclodextrin clathrate etc. be study hotspot in recent years.Current key problem in technology concentrates in the biocompatibility, body of the selection of material in the problem such as toleration and dosage form stability.Although some dosage form research makes a breakthrough, because drug loading is low, do not reach effective medicine concentration, its application is still restricted.
From Fortner etc., (Am.J.Hosp.Pharm. (1975) 32,582-584)) report, poorly water soluble drugs is dissolved in suitable solvent for injection and makes drug solution, during use, be scattered in injectable emulsion and instil, this form of administration is progressively for everybody payes attention to.
" the non-intestinal of paclitaxel is stablized toxic formulation " (Chinese patent: 97196934.5) of B.S Anderson, by PEG400 and dimethyl acetylamide, the ratio with 3: 1 forms the medicine solvent of drug solution part, although dimethyl acetylamide can improve the dissolution velocity of medicine, also increased the toxic and side effects of pharmaceutical preparation simultaneously.Zhou Lianfang etc. (the poisonous effect progress [J] of dimethyl acetylamide. Chinese Professional medical science, 2009,36 (1): 66-67) report, point out that dimethyl acetylamide can cause that large mice loses weight, neurodeatrophia, brain wave changes, the infringements such as lung, stomach, liver, kidney.
Wu Tianguang city etc. " medical composition that contains poorly water soluble drugs " (Chinese patent: 200680007345.3), the medicine solvent of drug solution part is mainly comprised of PEG400 and oleic acid.R.C. sieve etc. (pharmaceutic adjuvant handbook [M]. original work the 4th edition: 476) show, oleic acid can cause breaking of erythrocyte, there is hemolytic, in Britain, be only allowed in non-injection.
" a kind of concentration emulsifier that contains paclitaxel analog compound and using method thereof " (Chinese patent: 200410025522.3), contain surfactant in drug solution part, as Tween 80, polyvidone, lecithin etc. of Hu Yufang.These surfactants all have certain hemolytic and zest.
For make taxone safer, effective, stable, be economically applied to clinical, bring into play better its antitumor action, we have developed a kind of assembly packaging, contain solution packing and the medicinal Emulsion packing of taxone in assembly packaging, two kinds of packings are discrete, and combination is put together.Before medication, drug solution is dispersed in Emulsion, shake up, get final product intravenous drip, the present invention has added chelating agen in this combination medicament, the dispersion stability that drug solution is dispersed in Emulsion significantly improves, overcome the deficiency of dispersion liquid oil spill, improved safety and the effectiveness of this drug delivery system.
Summary of the invention
The invention provides a kind of taxone compositions, formulated by taxane medicine solution and Emulsion two parts medicament, wherein in drug solution or Emulsion, contain chelating agen, content is preferably 0.1-1% (grams per milliliter) of 0.05-2% (grams per milliliter).Described formulated be to be 1 by volume: the ratio of 10-100 is mixed drug solution and Emulsion.Preferably 1: the ratio of 20-50 is mixed, and most preferably is the ratio of 1: 25.
Compositions of the present invention, because added chelating agen in taxane medicine solution or Emulsion before preparation, makes taxone show strong stability after mixing with injectable emulsion.
The invention provides a kind of taxane medicine solution for this reason, wherein contain taxone, chelating agen, solvent.
Preferably the ratio of each component is:
Taxone 1-8% (grams per milliliter)
Chelating agen 0.05-2% (grams per milliliter)
All the other are solvent and the other medicines carrier that adds if desired.
Preferred the ratio of each component is:
Taxone 1-6% (grams per milliliter)
Chelating agen 0.1-1% (grams per milliliter)
All the other are solvent and the other medicines carrier that adds if desired.
Wherein said other medicines carrier is in the process of obtain solution, adds as required, as: cosolvent, isotonic agent, surfactant, pH value regulator etc., these carriers can add, also can not add, according to taxone, the character of intercalating agent and solvent is selected.
Solution of the present invention, described taxone is any taxone, the paclitaxel preferably having gone on the market or Docetaxel.
Solution of the present invention, wherein said chelating agen is added in the solution of medicine, wherein said chelating agen is selected from: the mixture of one or more in ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodiumedetate, sodium versenate, disodium citrate, optimization citric acid, lactic acid, ethylenediaminetetraacetic acid, disodiumedetate, most preferably disodiumedetate.
Solution of the present invention, described solvent is selected from one or more the mixture in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, propylene glycol, glycerol, dehydrated alcohol, water for injection; Preferred PEG400.
The present invention also comprises the preparation method of solution of the present invention, comprises taxone and chelating agen are dissolved in solvent, adds if desired the step of other medicines carrier.
Preferably comprise the steps: to take paclitaxel or Docetaxel, chelating agen is to solvent, and at 50-100 ℃, heated and stirred or shearing are dissolved, and then with solvent, are settled to full dose; Adding bulking value percentage composition is the needle-use activated carbon of 0.01%-3% grams per milliliter, under the heating-up temperature of 25-100 ℃, adsorbs 15-120 minute, and then filtration, subpackage, sealing, sterilization, obtain.
The present invention also provides a kind of drug regimen packing, by taxane medicine solution of the present invention and Emulsion assembly packaging, is formed, and two kinds of medicaments are loaded in respectively in container, discrete placement, and assembly packaging is together.Assembly packaging of the present invention, be by taxane medicine solution of the present invention and medicinal Emulsion, be potted in respectively in plastic bottle or vial, two kinds of medicines are with 1: 10-10: 1 ratio assembly packaging together, preferably the ratio of 1: 1, is packaged in same large packing container.With a use amount, be packaged as suitable.
Emulsion of the present invention is a kind of emulsification preparation of oil mixing with water, is that oils medicine or medicine oil solution are dispersed in formed non-homogeneous dispersion in disperse medium with drop state, has dividing of Orally taken emulsion, intravenous injection emulsion.The present invention uses intravenous Emulsion, preferred intravenous lipid emulsion, concrete as: in 20%/long-chain fat Emulsion, 20% long-chain fat Emulsion etc.
Emulsion of the present invention is commercially available injectable emulsion product or the Emulsion product of preparing according to prior art.Generally contain Seepage regulator, pH adjusting agent, the waters for injection etc. such as oil for injection, emulsifying agent, antioxidant.
Feature of the present invention is, in Emulsion of the present invention, can add chelating agen, content is preferably 0.1-1% (grams per milliliter) of 0.05-2% (grams per milliliter), described chelating agen is selected from: the mixture of one or more in ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodiumedetate, sodium versenate, disodium citrate, optimization citric acid, lactic acid, ethylenediaminetetraacetic acid, disodiumedetate, most preferably disodiumedetate.
Emulsion of the present invention, wherein said oil for injection is selected from pungent tricaprin, sad monoglyceride, Sunfat GDC-S, Trivent OCG, Ganoderma spore oil, capric acid monoglyceride, capric acid diglyceride, tricaprin, pungent capric acid monoglyceride, Semen Coicis oil, Oleum Fructus Bruceae, Herba Artemisiae Annuae oil, pungent capric acid diglyceride, soybean oil, fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, Oleum Curcumae, safflower oil, Oleum sesami, Semen Maydis oil, elemene oil, the mixture of one or more in Bulbus Allii wet goods, its heavy content is 1-30% grams per milliliter.
Preferred oil for injection is selected from one or more the mixture in pungent tricaprin, soybean oil, and content is 10-30% grams per milliliter.
Wherein said emulsifying agent is selected from one or more mixture of soybean phospholipid, egg yolk lecithin, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, DOPC, POPC, DSPE, PLURONICS F87, and its content is 0.5-5% grams per milliliter.Preferred emulsifying agent is selected from one or more the mixture in soybean phospholipid, egg yolk lecithin, and content is 0.8-3% grams per milliliter.
Wherein said antioxidant is tocopherol, and its content is 0-0.5% grams per milliliter.Preferred content is 0-0.3% grams per milliliter.
Wherein said regulator such as Seepage such as Deng is selected from one or more in glycerol, sorbitol, mannitol, glucose, sodium chloride, is preferably glycerol.
Wherein said pH adjusting agent is selected from one or more in citric acid, malic acid, hydrochloric acid, acetic acid, lactic acid, sodium carbonate, sodium bicarbonate, sodium hydroxide, is preferably sodium hydroxide, regulates pH to 6.0-9.0.The preferred pH to 6.5-8.5 that regulates.
The preparation method of used for intravenous injection Emulsion is existing routine techniques, as oil for injection, antioxidant are mixed, is heated to 50-90 ℃, adds emulsifying agent, stirs or shear to make emulsifiers dissolve, obtains oil phase; Isoosmotic adjusting agent, stabilizing agent are added in appropriate water for injection, be heated to 50-90 ℃ of stirring and dissolving, obtain water; Oil phase and water are mixed at 50-90 ℃ of temperature, and with emulsification pretreatment device emulsifying or stirring and emulsifying 5-60 minute, rotating speed is 5000-30000 rev/min, obtains colostrum.By the further emulsifying of colostrum, then use water for injection standardize solution, by pH adjusting agent, regulating pH is 6.0-9.0, filters, subpackage, fills nitrogen, sealing, sterilization, obtains.
Generally the preparation process of Emulsion comprises emulsifiers dissolve in oil for injection or emulsifiers dissolve in water.Wherein the further emulsifying of colostrum is to adopt high pressure homogenizer emulsifying, and pressure is 5000-25000psi.Sterilization in the preparation process of Emulsion is adopt rotating type high-pressure steam sterilization pan, flowing steam or cross the sterilizations such as microporous filter membrane, high temperature sterilize temperature 100-121 ℃ wherein, time 8-45 minute.Filtration device in the preparation process of Emulsion, includes but not limited to microporous filter membrane, sand stick, vertical molten funnel or bag type filter.Emulsion is white or off-white color emulsion liquid, has opalescence, and mean diameter is 100-500nm, and pH is 6.0-9.0.
The present invention also comprises the using method of taxane medicine solution of the present invention, the method comprises that by taxane medicine solution and medicinal Emulsion be 1 by volume: 10-100, the preferred ratio of 1: 25, drug solution is dispersed in Emulsion, shake up, intravenous drip, also can add the medicine after disperseing with Emulsion normal saline or glucose solution for injection.
Below data declaration beneficial effect of the present invention by experiment.
1, containing chelating agen (citric acid) and the stability comparison that does not contain the front dispersion liquid of paclitaxel injection compositions administration of chelating agen
For further substantial feature and the beyond thought effect that contains chelating agen in the present invention that embody, we will not make comparisons with the stability that does not contain the front dispersion liquid of paclitaxel injection compositions administration of chelating agen to containing chelating agen (citric acid).
Drug solution according to the embodiment preparation described in embodiment 1 containing chelating agen (citric acid), obtains for examination drug solution; According to the embodiment described in embodiment 1, remove citric acid preparation not containing the drug solution of chelating agen, obtain control drug solution; Draw respectively above-mentionedly for 4 milliliters of examination drug solution and control drug solution, be dispersed in respectively described in embodiment 1 100 milliliters in antigalactic, shake up, obtain test sample.With high performance liquid chromatograph, particle size determination instrument, measure respectively this dispersion liquid at medicament contg, the particle diameter of different time points; When measuring content, first with syringe, extract the microporous filter membrane that appropriate dispersion liquid is crossed 0.45 μ m, measure the content of filtrate Chinese medicine, calculate sign percentage composition, with this content, evaluate whether crystallization of medicine; Particle diameter is directly measured, and perusal outward appearance, the results are shown in Table 1, table 2.
Table 1 be take the study on the stability containing dispersion liquid before the paclitaxel injection compositions administration of chelating agen (citric acid) that embodiment 1 is representative (disperse Emulsion as from antigalactic)
Table 2 take that embodiment 1 is representative not containing the study on the stability of dispersion liquid before the paclitaxel injection compositions administration of chelating agen (citric acid) (disperse Emulsion as from antigalactic)
Interpretation of result:
From table 1 and the comparison of test results of table 2, draw, press equally embodiment 1 prepared containing chelating agen (citric acid) with do not contain under the prerequisite of paclitaxel injection compositions of chelating agen, containing the dispersion stable of chelating agen, for up to more than 6 days, and containing dispersion stable time of chelating agen, be not about 3 days; From apparent, containing in the dispersion liquid of chelating agen 6 days without oil spill phenomenon, apparent better, and not more containing the oil spill of chelating agen, and along with the prolongation of time, oil spill increases gradually, apparent poor; Particle diameter changes not quite within stabilization time, and when having medicine to separate out, particle diameter becomes large.
Result shows, paclitaxel injection compositions containing chelating agen (citric acid) has significant effect, its Heterosis improves the dispersion stability than not containing the paclitaxel injection compositions of chelating agen greatly, and the beyond thought deficiency that overcomes dispersion liquid oil spill.Therefore further embodied, to contain chelating agen be the feature that the present invention has substantive excellent results.
2, containing chelating agen (disodiumedetate) with containing chelating agen the administration of Docetaxel injection composition before the estimation of stability of dispersion liquid
For further substantial feature and the beyond thought effect that contains chelating agen in the present invention that embody, we will not make comparisons with the stability that does not contain the front dispersion liquid of Docetaxel injection composition administration of chelating agen to containing chelating agen (disodiumedetate).
The Docetaxel injection composition containing chelating agen (disodiumedetate) according to the embodiment preparation described in embodiment 2, obtains test sample respectively; According to the embodiment described in embodiment 2, remove chelating agen (disodiumedetate) preparation not containing the Docetaxel injection composition of chelating agen, obtain control sample; Draw respectively and above-mentionedly for 4 milliliters of examination and the drug solutions of control sample, be dispersed in respectively in 100 milliliters of Emulsions separately, shake up, obtain test sample.With high performance liquid chromatograph, particle size determination instrument, measure respectively this dispersion liquid at medicament contg, the particle diameter of different time points; When measuring content, first with syringe, extract the microporous filter membrane that appropriate dispersion liquid is crossed 0.45 μ m, measure the content of filtrate Chinese medicine, calculate sign percentage composition, with this content, evaluate whether crystallization of medicine; Particle diameter is directly measured, and perusal outward appearance, the results are shown in Table 3, table 4.
Table 3 be take the study on the stability containing dispersion liquid before the Docetaxel injection composition administration of chelating agen (disodiumedetate) that embodiment 2 is representative (disperse Emulsion as from antigalactic)
Table 4 take that embodiment 2 is representative not containing the study on the stability of dispersion liquid before the Docetaxel injection composition administration of chelating agen (disodiumedetate) (disperse Emulsion as from antigalactic)
Interpretation of result:
From table 3 and the comparison of test results of table 4, draw, press equally embodiment 2 prepared containing chelating agen (disodiumedetate) with do not contain under the prerequisite of Docetaxel injection composition of chelating agen, containing the dispersion stable of chelating agen, for up to more than two weeks, and containing dispersion stable time of chelating agen, be not about 6 days; From apparent, containing in the dispersion liquid two weeks of chelating agen without oil spill phenomenon, apparent better, and not more containing the oil spill of chelating agen, and along with the prolongation of time, oil spill increases gradually, apparent poor; Particle diameter changes not quite within stabilization time, and when having medicine to separate out, particle diameter becomes large.
Result shows, Docetaxel injection composition containing chelating agen (disodiumedetate) has significant effect, its Heterosis improves the dispersion stabilization than not containing the Docetaxel injection composition of chelating agen greatly, and the beyond thought deficiency that overcomes dispersion liquid oil spill, therefore further embodied, to contain chelating agen be the feature that the present invention has substantive excellent results.
3, containing the present invention of chelating agen (disodiumedetate) and the contrast test that contains dimethyl acetylamide and contrast patent working scheme
Patent (Chinese patent: show 97196934.5), this patent is mainly to have added dimethyl acetylamide on the basis of PEG400, the ratio of itself and PEG400 is 1: 3, its drug loading is 25 mg/ml.According to this embodiment compounding pharmaceutical solution, in contrast drug solution; According to the embodiment compounding pharmaceutical solution described in embodiment 18, obtain for examination drug solution; Draw respectively 4 milliliters of above-mentioned control drug solution, for examination drug solution, be dispersed in respectively in 100 milliliters of commercially available Emulsions described in embodiment 18.Shake up, obtain test sample.With high performance liquid chromatograph, measure respectively this dispersion liquid at the medicament contg of different time points; When measuring content, first with syringe, extract the microporous filter membrane that appropriate dispersion liquid is crossed 0.45 μ m, measure the content of filtrate Chinese medicine, calculate sign percentage composition, with this content, evaluate whether crystallization of medicine; And perusal outward appearance, the results are shown in Table 5.
Table 5 is containing the preparation dispersion liquid of the present invention of chelating agen (disodiumedetate) and the study on the stability (dispersion Emulsion is commercially available Emulsion) that contains dimethyl acetylamide and contrast proprietary preparation dispersion liquid
Interpretation of result:
By test, drawn, in identical commercially available Emulsion disperse medium, containing the dispersion stable of the present composition of chelating agen (disodiumedetate) for up to more than 24 hours, and containing dimethyl acetylamide control formulation dispersion stable deficiency of time 6 hours; From outward appearance angle, evaluate, preparation dispersion liquid of the present invention is without oil spill phenomenon, and more serious containing dimethyl acetylamide control formulation dispersion liquid oil spill, has a large amount of oil stain wall built-ups, chelating agen add beyond thought this problem that solved.Visible preparation scheme of the present invention with contrast patent and compare and there is significant advantage and beyond thought effect.Therefore further embodied, to contain chelating agen be the feature that the present invention has substantive excellent results.
4, contain the present invention and the contrast test that contains oleic acid patent working scheme of chelating agen (ethylenediaminetetraacetic acid)
At publication (Chinese patent: show 200680007345.3), this patent is mainly to have added oleic acid on the basis of PEG400, and its consumption is 0.01-5%.With reference to its embodiment, prepare respectively 0.3%, 1.0%, 5.0% oleic acid polyglycols 400 solution; Then with its preparation content of taxol, be the paclitaxel solution of 25 mg/ml, in contrast solution respectively; Embodiment compounding pharmaceutical solution according to described in embodiment 19, obtains test solution; Draw respectively 4 milliliters of above-mentioned contrast solutions, test solution, be dispersed in respectively in 100 milliliters of commercially available Emulsions described in embodiment 19, shake up, obtain test sample.With high performance liquid chromatograph, measure respectively this dispersion liquid at the medicament contg of different time points; When measuring content, first with syringe, extract the microporous filter membrane that appropriate dispersion liquid is crossed 0.45 μ m, measure the content of filtrate Chinese medicine, calculate sign percentage composition, with this content, evaluate whether crystallization of medicine; And perusal outward appearance, in Table 6.
Table 6 is containing the preparation dispersion liquid of the present invention of chelating agen (ethylenediaminetetraacetic acid) and the study on the stability (disperseing Emulsion is commercially available Emulsion) that contrasts proprietary preparation dispersion liquid containing oleic acid
Interpretation of result:
By test, drawn, in identical commercially available Emulsion disperse medium, containing the dispersion stable of the present composition of chelating agen (ethylenediaminetetraacetic acid) for up to more than 20 hours, and containing oleic acid control formulation dispersion stable deficiency of time 6 hours, and along with the increase stability of oleic acid reduces; From outward appearance angle, evaluate, dispersion liquid of the present invention is without oil spill phenomenon, and more serious containing the contrast proprietary preparation dispersion liquid oil spill of serial oleic acid, has a large amount of oil stain wall built-ups, chelating agen add beyond thought this problem that solved.Visible preparation scheme of the present invention with contrast patent and compare and there is significant advantage and beyond thought effect.Therefore further embodied, to contain chelating agen be the feature that the present invention has substantive excellent results.
5, contain the present invention and the contrast test that contains surfactant patent working scheme of chelating agen (citric acid)
At publication (Chinese patent: show 200410025522.3), this patent is mainly comprised of paclitaxel, Tween 80, polyvidone, lecithin, solvent for injection, the embodiment close with the present invention is embodiment 3, i.e. paclitaxel 1.8g, phosphatidase 12 2g, propylene glycol 40g, dehydrated alcohol to 100 milliliter.According to this scheme compounding pharmaceutical solution, in contrast solution; Embodiment compounding pharmaceutical solution according to described in embodiment 20, obtains test solution; Draw respectively 4 milliliters of above-mentioned contrast solutions, test solution, be dispersed in respectively in 100 milliliters of commercially available Emulsions described in embodiment 20, shake up, obtain test sample.With high performance liquid chromatograph, measure respectively this dispersion liquid at the medicament contg of different time points; When measuring content, first with syringe, extract the microporous filter membrane that appropriate dispersion liquid is crossed 0.45 μ m, measure the content of filtrate Chinese medicine, calculate sign percentage composition, with this content, evaluate whether crystallization of medicine; And perusal outward appearance, the results are shown in Table 7.
Table 7 is containing the preparation dispersion liquid of the present invention of chelating agen (citric acid) and the study on the stability (disperseing Emulsion is commercially available Emulsion) that contrasts proprietary preparation dispersion liquid containing surfactant
Interpretation of result:
By test, drawn, in identical commercially available Emulsion disperse medium, containing the dispersion stable of the present composition of chelating agen (citric acid) for up to more than 20 hours, and containing surfactant contrast proprietary preparation dispersion stable deficiency of time 8 hours; From outward appearance angle, evaluate, present composition dispersion liquid is without oil spill phenomenon, and more serious containing the contrast proprietary preparation dispersion liquid oil spill of surfactant, has a large amount of oil stain wall built-ups, chelating agen add beyond thought this problem that solved.Visible preparation scheme of the present invention with contrast patent and compare and there is significant advantage and beyond thought effect.Therefore further embodied, to contain chelating agen be the feature that the present invention has substantive excellent results.
Advantage of the present invention is:
1. safety is good: not containing any solubilizing agent with toxic and side effects, as polyoxyethylene castor oil, tween 80, dimethyl acetylamide, oleic acid, polyvidone etc., wherein polyoxyethylene castor oil, tween 80 have serious haemolysis and anaphylaxis, and safety is poor; The oral LD of dimethyl acetylamide mice
50for 4.620g/kg, and solvent for injection preferred for this invention is PEG400, nontoxic, nonirritant, the oral LD of its mice
50up to 28.9g/kg, LD on year-on-year basis
506.3 times of dimethyl acetylamide, therefore PEG400 is a kind of safe solvent for injection; R.C. sieve etc. (pharmaceutic adjuvant handbook [M]. original work the 4th edition: 476) show, oleic acid can cause breaking of erythrocyte, there is hemolytic, in Britain, be only allowed in non-injection.Therefore not containing the solubilizing agent with toxic and side effects in preparation of the present invention is also a spotlight of the present invention;
2. good stability: adopt the dispersion stability of solution of the present invention to be greatly improved, extended significantly the stabilization time of dispersion liquid, and the beyond thought deficiency that overcomes dispersion liquid oil spill, further improved dispersion stability.
The specific embodiment
In order further to embody the substantive advantage of the present invention and beyond thought effect, we will realize by following embodiment, but be not limited to following embodiment.
Embodiment 1 paclitaxel injection and assembly packaging
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.5 gram of citric acid, join in appropriate PEG400,85 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains paclitaxel solution.
The preparation of Emulsion:
Take 100 grams of injection soybean oils, 100 grams of pungent tricaprin, heating in water bath to 80 ℃, adds 20 grams of injection soybean phospholipids, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 740 milliliters of waters for injection, add 22.5 grams of 10 grams of PLURONICS F87s, glycerol, be stirred to dissolve, be heated to 80 ℃ and obtain water; Oil phase and water are mixed at 80 ℃ of temperature, with emulsification pretreatment device emulsifying 10 minutes (15000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 12000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.86, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam kettle 15 minutes, obtains Emulsion.After measured, its mean diameter is 148nm, and pH is 7.12.
Above paclitaxel solution and medicinal Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
In use, paclitaxel solution and Emulsion are the ratio of 1: 25 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip, also can add normal saline or glucose solution for injection.
Embodiment 2 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 2.5 grams of Docetaxels, join in appropriate PEG400,90 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 100 grams of injection soybean oils, 100 grams of pungent tricaprin, heating in water bath to 80 ℃, adds 20 grams of injection soybean phospholipids, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 740 milliliters of waters for injection, add 22.5 grams of 0.5 gram of disodiumedetates, 10 grams of PLURONICS F87s, glycerol, be stirred to dissolve, be heated to 80 ℃ water; Oil phase and water are mixed at 80 ℃ of temperature, with emulsification pretreatment device emulsifying 8 minutes (20000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 12000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.56, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Emulsion.After measured, its mean diameter is 140nm, and pH is 7.04.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 25 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 3 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 2.0 grams of paclitaxels, join in 90 grams of PEG400s, 90 ℃ of heated and stirred are dissolved, and obtain paclitaxel solution; Take 1.2 grams of disodiumedetates, with 10 grams of waters for injection, dissolved, obtain chelating agent solution; Chelating agent solution is mixed homogeneously with drug solution, with PEG400, be settled to 100 milliliters; The needle-use activated carbon that adds 0.8 gram adsorbs 120 minutes at the temperature of 30 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 8 minutes, obtains paclitaxel solution.
The preparation of Emulsion:
Take 150 grams of soybean oils, 150 grams of pungent tricaprin, mix, heating in water bath to 60 ℃, adds 12 grams of injection egg yolk lecithin, shears and makes to dissolve, and obtains oil phase; Measure 600 milliliters of waters for injection, add 25 grams of glycerol, be stirred to dissolve, be heated to 60 ℃ and obtain water; Oil phase and water are mixed at 60 ℃ of temperature, with emulsification pretreatment device emulsifying 30 minutes (6000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 22000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 8.00, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtain Emulsion.After measured, its mean diameter is 284.2nm, and pH is 7.64.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 20 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 4 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 2.5 grams of Docetaxels, 0.3 gram of citric acid, join in appropriate PEG400,90 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 45 minutes at the temperature of 25 ℃, then with bag type filter, filters, and with 0.22 μ m filtering with microporous membrane degerming, subpackage, sealing, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 200 grams of injection soybean oils, heating in water bath to 80 ℃, adds 20 grams of injection soybean phospholipids, is stirred to dissolve to obtain oil phase; Measure 700 milliliters of waters for injection, add 22.5 grams of 10 grams of PLURONICS F87s, glycerol, be stirred to dissolve, be heated to 80 ℃ and obtain water; Oil phase and water are mixed at 80 ℃ of temperature, with emulsification pretreatment device emulsifying 15 minutes (10000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 15000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 8.53, with filtering with microporous membrane, subpackage, fill nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Emulsion.After measured, its mean diameter is 181nm, and pH is 8.01.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 25 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 5 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 1.5 grams of paclitaxels, 0.05 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,90 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 1.0 grams adsorbs 20 minutes at the temperature of 50 ℃, then with husky filter stick, filters, and subpackage, sealing, 100 ℃ of sterilizings of flowing steam 45 minutes, obtain paclitaxel solution.
The preparation of Emulsion:
Take 75 grams of soybean oils, 75 grams of pungent tricaprin, heating in water bath to 60 ℃, obtains oil phase; Measure 750 milliliters of waters for injection, add 12 grams of egg yolk lecithin, 22.5 grams of glycerol, stirring makes dispersed, is heated to 60 ℃ and obtains water.Oil phase and water are mixed at 60 ℃ of temperature, with emulsification pretreatment device emulsifying 20 minutes (5000 revs/min of rotating speeds), obtain colostrum, by the further emulsifying of high pressure homogenizer for colostrum (pressure 12000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.50, filters subpackage with bag type filter, fill nitrogen, sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Emulsion.After measured, its mean diameter is 214.5nm, and pH is 6.84.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 80 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 6 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 6 grams of Docetaxels, 0.7 gram of citric acid, join in the mixed solution of 80 grams of PEG400s, 10 grams of dehydrated alcohol, 80 ℃ of heated and stirred are dissolved, and then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.5 gram adsorbs 45 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 50 grams of injection soybean oils, 50 grams of Oleum Bulbus Alliis, heating in water bath to 70 ℃, adds 12 grams of injection egg yolk lecithin, shears and dissolves, and obtains oil phase; Measure 850 milliliters of waters for injection, add 22.5 grams of glycerol, be stirred to dissolve, be heated to 70 ℃ and obtain water; Oil phase and water are mixed at 70 ℃ of temperature, with emulsification pretreatment device emulsifying 5 minutes (30000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 20000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 8.25, with filtering with microporous membrane, subpackage, fill nitrogen, sealing, with 117 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 20 minutes, obtains Emulsion.After measured, its mean diameter is 175.6nm, and pH is 7.53.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 90 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 7 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 7.0 grams of paclitaxels, add 80 grams of PEG400s, 85 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 2 grams adsorbs 70 minutes at the temperature of 30 ℃, then with bag type filter, filters, and subpackage, sealing, 100 ℃ of sterilizings of flowing steam 45 minutes, obtain paclitaxel solution.
The preparation of Emulsion:
100 grams of sad monoglycerides, 50 grams, fish oil, 50 grams of Oleum sesami, 3.0 grams of tocopherols, mix, heating in water bath to 83 ℃, and stirring and evenly mixing, obtains oil phase; Measure 700 milliliters of waters for injection, add 0.8 gram of disodiumedetate, 22.5 grams of glycerol, 20 grams of Ovum Gallus domesticus Flavus lecithins, 15 grams of dimyristoyl phosphatidyl cholines (DMPC), shear and disperse, be heated to 83 ℃, obtain water; Oil phase and water are mixed at 83 ℃ of temperature, with emulsification pretreatment device emulsifying 27 minutes (8000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 21000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.56, with filtering with microporous membrane, subpackage, fill nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Emulsion.After measured, its mean diameter is 261nm, and pH is 7.05.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 40 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 8 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 2.5 grams of Docetaxels, join in the mixed solvent of 60 grams of dehydrated alcohol, 20 grams of Macrogol 200s, 10 grams of propylene glycol, 55 ℃ of heated and stirred are dissolved, and then with dehydrated alcohol, are settled to 100 milliliters; The needle-use activated carbon that adds 0.6 gram adsorbs 50 minutes at the temperature of 55 ℃, then with bag type filter, filters, and subpackage, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 25 grams of Semen Coicis oils, 25 grams of Oleum Fructus Bruceae, mix, heating in water bath to 80 ℃, stirring and evenly mixing, obtains oil phase; Measure 900 milliliters of waters for injection, add 10 grams of egg yolk lecithin, 2 grams of DSPE (DSPE), 0.5 gram of disodiumedetate, 22.5 grams of glycerol, shear and disperse, be heated to 60 ℃ and obtain water; Oil phase and water are mixed at 60 ℃ of temperature, with emulsification pretreatment device emulsifying 13 minutes (20000 revs/min of rotating speeds), obtain colostrum, by the further emulsifying of high pressure homogenizer for colostrum (pressure 20000psi), water for injection is settled to 1000 milliliters, with sodium hydroxide solution, regulating its pH is 7.14, filters subpackage with bag type filter, fill nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan sterilizing 15 minutes, obtains Emulsion.After measured, its mean diameter is 134.5nm, and pH is 6.40.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 50 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 9 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 8 grams of paclitaxels, 0.3 gram of ethylenediaminetetraacetic acid, add in the mixed solvent of appropriate PEG400 and dehydrated alcohol, 70 ℃ add hot shearing dissolving, then with dehydrated alcohol, are settled to 100 milliliters; The needle-use activated carbon that adds 1.5 grams adsorbs 90 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, 100 ℃ of sterilizings of flowing steam 45 minutes, obtain paclitaxel solution.
The preparation of Emulsion:
Take 10 grams of Oleum Curcumae, 90 grams of Oleum Helianthis, 25 grams of capric acid monoglycerides, 25 grams of Sunfat GDC-Ss, 0.5 gram of tocopherol, mix, heating in water bath to 60 ℃, stirring and evenly mixing, obtains oil phase; Measure 800 milliliters of waters for injection, add 6 grams of dipalmitoyl phosphatidyl choline (DPPC), 4 grams of distearoyl phosphatidylcholine (DSPC), 25 grams of glycerol, shear and disperse, be heated to 70 ℃, obtain water; Oil phase and water are mixed at 60 ℃ of temperature, with emulsification pretreatment device emulsifying 6 minutes (30000 revs/min of rotating speeds), obtain colostrum, by the further emulsifying of high pressure homogenizer for colostrum (pressure 10000psi), water for injection is settled to 1000 milliliters, with sodium hydroxide solution, regulating its pH is 8.10, with filtering with microporous membrane, and subpackage, fill nitrogen, sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Emulsion.After measured, its mean diameter is 250nm, and pH is 7.46.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 90 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 10 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 6 grams of Docetaxels, 2.5 grams of malic acids, join in the mixed solvent of 50 grams of Macrogol 200s, 35 grams of Macrogol 600s, 75 ℃ add hot shearing dissolving, then with Macrogol 600, are settled to 100 milliliters; The needle-use activated carbon that adds 0.05 gram adsorbs 120 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, 100 ℃ of sterilizings of flowing steam 45 minutes, obtain Taxotere alcoholic solution.
The preparation of Emulsion:
Take 100 grams of pungent capric acid diglycerides, 30 grams of elemene oils, 34 grams of safflower oils, 36 grams of Trivent OCGs, 5.0 grams of tocopherols, heating in water bath to 75 ℃, add 2.0 grams of injection soybean phospholipids, 3.0 grams of DOPCs (DOPC), 1.0 grams of POPCs (POPC), be stirred to dissolve, obtain oil phase; Measure 730 milliliters of waters for injection, add 21.0 grams of glycerol, be heated to 75 ℃, be stirred to dissolve, obtain water; Oil phase and water are mixed at 75 ℃ of temperature, stirring and emulsifying 25 minutes, obtains colostrum, by the further emulsifying of high pressure homogenizer for colostrum (pressure 15000psi), water for injection is settled to 1000 milliliters, with sodium hydroxide solution, regulating its pH is 7.04, filters subpackage with sintered filter funnel, fill nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 10 minutes, obtains Emulsion.After measured, its mean diameter is 219nm, and pH is 6.58.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 80 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 11 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.05 gram of citric acid, join in appropriate PEG400,85 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.2 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains paclitaxel solution.
The preparation of Emulsion:
Take 10 grams of Herba Artemisiae Annuae oils, 100 grams of Semen Maydis oil, heating in water bath to 60 ℃, adds 20 grams of injection soybean phospholipids, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 810 milliliters of waters for injection, add 25.0 grams of glycerol, be stirred to dissolve, be heated to 60 ℃ and obtain water; Oil phase and water are mixed at 60 ℃ of temperature, with emulsification pretreatment device emulsifying 15 minutes (23000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 15000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 6.88, with filtering with microporous membrane, subpackage, fill nitrogen, sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 45 minutes, obtains Emulsion.After measured, its mean diameter is 232nm, and pH is 6.56.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 30 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 12 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 4.0 grams of Docetaxels, join in 80 grams of PEG400s, 95 ℃ of heated and stirred are dissolved, and obtain Taxotere alcoholic solution; Take 0.8 gram of disodiumedetate, with 8 grams of waters for injection, dissolved, obtain chelating agent solution; Chelating agent solution is mixed homogeneously with Taxotere alcoholic solution, with PEG400, be settled to 100 milliliters; The needle-use activated carbon that adds 1.0 grams adsorbs 20 minutes at the temperature of 60 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 12 minutes, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 50 grams of the pungent tricaprin of injection, 20 grams of soybean oils, 30 grams of Ganoderma spore oils, heating in water bath to 70 ℃, adds 12 grams of injection egg yolk lecithin, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 850 milliliters of waters for injection, add 22.5 grams of glycerol, be stirred to dissolve, be heated to 75 ℃ and obtain water; Oil phase and water are mixed at 75 ℃ of temperature, with emulsification pretreatment device emulsifying 10 minutes (12000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 15000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.81, with filtering with microporous membrane, subpackage, fill nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 10 minutes, obtains Emulsion.After measured, its mean diameter is 208nm, and pH is 7.15.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 70 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 13 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.2 gram of citric acid, join in appropriate PEG400,88 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 15 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains paclitaxel solution.
The preparation of Emulsion:
Take 50 grams of injection soybean oils, 50 grams of pungent tricaprin, heating in water bath to 55 ℃, adds 12 grams of injection Ovum Gallus domesticus Flavus lecithins, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 800 milliliters of waters for injection, add 22.5 grams of glycerol, be stirred to dissolve, be heated to 55 ℃ and obtain water; Oil phase and water are mixed at 55 ℃ of temperature, with emulsification pretreatment device emulsifying 15 minutes (22000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 20000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 6.54, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 12 minutes, obtains Emulsion.After measured, its mean diameter is 179nm, and pH is 6.00.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 50 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 14 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 4.0 grams of Docetaxels, 0.3 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,85 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.1 gram adsorbs 80 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 100 grams of injection soybean oils, 100 grams of pungent tricaprin, heating in water bath to 70 ℃, adds 1.2 grams of injection egg yolk lecithin, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 750 milliliters of waters for injection, add 22.5 grams of glycerol, be stirred to dissolve, be heated to 70 ℃ and obtain water; Oil phase and water are mixed at 70 ℃ of temperature, with emulsification pretreatment device emulsifying 10 minutes (18000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 17000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 6.50, with filtering with microporous membrane, subpackage, fill nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization 12 minutes, obtains Emulsion.After measured, its mean diameter is 227nm, and pH is 6.01.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 60 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 15 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take 6.0 grams of paclitaxels, 1.5 grams of citric acids, join in appropriate PEG400,84 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 2 grams adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and 100 ℃ of sterilizings of flowing steam 45 minutes, obtain paclitaxel solution.
The preparation of Emulsion:
Take 150 grams of the pungent tricaprin of injection, 150 grams of soybean oils, heating in water bath to 75 ℃, adds 20 grams of injection egg yolk lecithin, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 650 milliliters of waters for injection, add 22.5 grams of 10 grams of PLURONICS F87s, glycerol, be stirred to dissolve, be heated to 75 ℃ and obtain water; Oil phase and water are mixed at 75 ℃ of temperature, with emulsification pretreatment device emulsifying 16 minutes (11000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 20000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.50, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Emulsion.After measured, its mean diameter is 400nm, and pH is 7.03.
Above paclitaxel solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 60 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 16 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take 4.0 grams of Docetaxels, 0.05 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,95 ℃ of heated and stirred are dissolved, and with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 1.0 grams adsorbs 30 minutes at the temperature of 25 ℃, with filtering with microporous membrane, then uses 0.22 μ m membrane filtration degerming, subpackage, and sealing, obtains Taxotere alcoholic solution.
The preparation of Emulsion:
Take 100 grams of injection soybean oils, heating in water bath to 70 ℃, adds 12 grams of injection egg yolk lecithin, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 850 milliliters of waters for injection, add 22.5 grams of glycerol, be stirred to dissolve, be heated to 75 ℃ and obtain water; Oil phase and water are mixed at 75 ℃ of temperature, with emulsification pretreatment device emulsifying 10 minutes (12000 revs/min of rotating speeds), obtain colostrum; By the further emulsifying of high pressure homogenizer for colostrum (pressure 17000psi), water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 6.88, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 10 minutes, obtains Emulsion.After measured, its mean diameter is 194nm, and pH is 6.58.
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1: 1 together.
During administration, drug solution and Emulsion are the ratio of 1: 40 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Embodiment 17 paclitaxel injections
The preparation of drug solution:
Take 4.0 grams of paclitaxels, join in 90 grams of PEG400s, 85 ℃ of heated and stirred are dissolved, and obtain paclitaxel solution; Take 0.5 gram of disodiumedetate, with 10 grams of waters for injection, dissolved, obtain chelating agent solution; Chelating agent solution is mixed homogeneously with drug solution, with PEG400, be settled to 100 milliliters; The needle-use activated carbon that adds 0.5 gram adsorbs 45 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: 80BM072, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 15, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 18 paclitaxel injections
The preparation of drug solution:
Take 2.5 grams of paclitaxels, join in appropriate PEG400,80 ℃ add hot shearing dissolving, take 0.5 gram of disodiumedetate, with 10 grams of waters for injection, are dissolved, and obtain chelating agent solution; Chelating agent solution is mixed homogeneously with drug solution, with PEG400, be settled to 100 milliliters; The needle-use activated carbon that adds 0.5 gram adsorbs 45 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 19 paclitaxel injections
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.1 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,85 ℃ of heated and stirred are dissolved, and with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.5 gram adsorbs 45 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 12 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 20 paclitaxel injections
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.3 gram of citric acid, join in appropriate PEG400,85 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then with bag type filter, filters, and subpackage, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 21 paclitaxel injections
The preparation of drug solution:
Take 3.0 grams of paclitaxels, 0.8 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,75 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 1.0 grams adsorbs 15 minutes at the temperature of 60 ℃, then with bag type filter, filters, and subpackage, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 20% long-chain fat Emulsion, [lot number]: F090203C2, [manufacturer]: Kelun Pharm Ind Co., Ltd., Sichuan
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 60, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 22 paclitaxel injections
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.5 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,80 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 2.0 grams adsorbs 15 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: F090203C2, [manufacturer]: Kelun Pharm Ind Co., Ltd., Sichuan
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 23 paclitaxel injections
The preparation of drug solution:
Take 6.0 grams of paclitaxels, 2.0 grams of citric acids, join in appropriate PEG400,80 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 1.2 grams adsorbs 20 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, 100 ℃ of sterilizings of flowing steam 45 minutes, obtain paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 20% long-chain fat Emulsion, [lot number]: 0811212-1, [manufacturer]: Zhejiang Kanglaite Pharmaceutical Co., Ltd
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 100, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 24 Docetaxel injections
The preparation of drug solution:
Take 2.5 grams of Docetaxels, 1.4 grams of citric acids, join in appropriate PEG400,70 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 3 grams adsorbs 15 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtains Taxotere alcoholic solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 25 paclitaxel injections
The preparation of drug solution:
Take 2.5 grams of paclitaxels, 0.8 gram, tartaric acid, join in appropriate PEG400,70 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.06 gram adsorbs 90 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, 100 ℃ of sterilizings of flowing steam 45 minutes, obtain paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 26 paclitaxel injections
The preparation of drug solution:
Take 2.5 grams of paclitaxels, join in 90 grams of PEG400s, 90 ℃ of heated and stirred are dissolved, and obtain paclitaxel solution; Take 1.0 grams of disodiumedetates, with 5 grams of waters for injection, dissolved, obtain chelating agent solution; Chelating agent solution is mixed homogeneously with drug solution, with PEG400, be settled to 100 milliliters; The needle-use activated carbon that adds 0.5 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 12 minutes, obtains paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 30% long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 27 Docetaxel injections
The preparation of drug solution:
Take 3.0 grams of Docetaxels, 0.1 gram of citric acid, join in appropriate PEG400,70 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.7 gram adsorbs 60 minutes at the temperature of 45 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: 8192A181, [manufacturer]: the bright medical joint-stock company of German shellfish
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 40, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 28 Docetaxel injections
The preparation of drug solution:
Take 2.5 grams of Docetaxels, 0.25 gram of ethylenediaminetetraacetic acid, join in appropriate PEG400,80 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
Commercially available Emulsion: [specification]: 250 milliliters: 30% long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Embodiment 29 Docetaxel injections
The preparation of drug solution:
Take 2.5 grams of Docetaxels, 0.25 gram of lactic acid, join in appropriate PEG400,80 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
Commercially available Emulsion: [specification]: 250 milliliters: 30% long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, the ratio that drug solution and commercially available Emulsion volume ratio are 1: 25, is dispersed in drug solution in Emulsion, shake up, and intravenous drip.
Claims (3)
1. a taxane medicine solution, is characterized in that, by following steps, is processed into:
Take 2.5 grams of Docetaxels, join in appropriate PEG400,90 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
2. a preparation method for drug solution claimed in claim 1, is characterized in that, comprises the steps:
Take 2.5 grams of Docetaxels, join in appropriate PEG400,90 ℃ add hot shearing dissolving, then with PEG400, are settled to 100 milliliters; The needle-use activated carbon that adds 0.3 gram adsorbs 30 minutes at the temperature of 25 ℃, then uses filtering with microporous membrane, subpackage, and sealing, with 115 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 30 minutes, obtains Taxotere alcoholic solution.
3. a taxone compositions, formulated by taxane medicine solution claimed in claim 1 and Emulsion two parts medicament, described Emulsion configures and forms by the following method:
Take 100 grams of injection soybean oils, 100 grams of pungent tricaprin, heating in water bath to 80 ℃, adds 20 grams of injection soybean phospholipids, shears and makes to dissolve, and stirring and evenly mixing, obtains oil phase; Measure 740 milliliters of waters for injection, add 22.5 grams of 0.5 gram of disodiumedetates, 10 grams of PLURONICS F87s, glycerol, be stirred to dissolve, be heated to 80 ℃ water; Oil phase and water are mixed at 80 ℃ of temperature, and with emulsification pretreatment device emulsifying 8 minutes, 20000 revs/min of rotating speeds, obtained colostrum; By the further emulsifying of high pressure homogenizer for colostrum, pressure 12000psi, water for injection quantitatively to 1000 milliliter, with sodium hydroxide solution, regulating its pH is 7.56, with bag type filter, filter, subpackage, fills nitrogen, sealing, with 121 ℃ of sterilizings of rotating type high-pressure steam sterilization pan 15 minutes, obtain Emulsion, after measured, its mean diameter is 140nm, and pH is 7.04;
Above Taxotere alcoholic solution and Emulsion, be potted in respectively in plastic bottle or vial, and two kinds of medicines, are packaged in same large packing container with the ratio assembly packaging of 1:1 together;
During administration, drug solution and Emulsion are the ratio of 1:25 by volume, and drug solution is dispersed in Emulsion, shake up, and intravenous drip.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910070932.2A CN102038636B (en) | 2009-10-23 | 2009-10-23 | Taxane medicine solution containing chelating agent and preparation method thereof |
| ARP100103881A AR078737A1 (en) | 2009-10-23 | 2010-10-22 | A TAXAN DRUG SOLUTION THAT INCLUDES A CHEMICAL AGENT AND ITS PREPARATION METHOD |
| PCT/CN2010/077998 WO2011047639A1 (en) | 2009-10-23 | 2010-10-22 | Pharmaceutical solution of taxanes comprising chelating agent and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910070932.2A CN102038636B (en) | 2009-10-23 | 2009-10-23 | Taxane medicine solution containing chelating agent and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102038636A CN102038636A (en) | 2011-05-04 |
| CN102038636B true CN102038636B (en) | 2014-08-13 |
Family
ID=43899846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910070932.2A Expired - Fee Related CN102038636B (en) | 2009-10-23 | 2009-10-23 | Taxane medicine solution containing chelating agent and preparation method thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN102038636B (en) |
| AR (1) | AR078737A1 (en) |
| WO (1) | WO2011047639A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110496103B (en) * | 2018-05-18 | 2022-05-10 | 上海维洱生物医药科技有限公司 | Docetaxel palmitate liposome and preparation method thereof |
| CN112933137A (en) * | 2021-02-22 | 2021-06-11 | 青岛康地恩动物药业有限公司 | Nanoemulsion consisting of oregano essential oil and guanidinoacetic acid and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101094646A (en) * | 2004-09-28 | 2007-12-26 | 陈献 | Low oil emulsion compositions for delivering taxoids and other insoluble drugs |
| CN101288642A (en) * | 2007-11-07 | 2008-10-22 | 中国人民解放军第二军医大学 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5877205A (en) * | 1996-06-28 | 1999-03-02 | Board Of Regents, The University Of Texas System | Parenteral paclitaxel in a stable non-toxic formulation |
| US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
| CN1535679A (en) * | 2003-04-04 | 2004-10-13 | 齐鲁制药厂 | Medicine composition containing taxol substance and its preparation method |
| WO2009047794A2 (en) * | 2007-10-01 | 2009-04-16 | Intas Pharmaceuticals Limited | Taxane derivative composition |
-
2009
- 2009-10-23 CN CN200910070932.2A patent/CN102038636B/en not_active Expired - Fee Related
-
2010
- 2010-10-22 WO PCT/CN2010/077998 patent/WO2011047639A1/en active Application Filing
- 2010-10-22 AR ARP100103881A patent/AR078737A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101094646A (en) * | 2004-09-28 | 2007-12-26 | 陈献 | Low oil emulsion compositions for delivering taxoids and other insoluble drugs |
| CN101288642A (en) * | 2007-11-07 | 2008-10-22 | 中国人民解放军第二军医大学 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102038636A (en) | 2011-05-04 |
| AR078737A1 (en) | 2011-11-30 |
| WO2011047639A1 (en) | 2011-04-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102448441B (en) | Pharmaceutical solution of taxanes comprising ph regulator and preparation method thereof | |
| CN101708314B (en) | Chinese medicinal essential oil injection solution, injection and preparation method thereof | |
| CN101288642B (en) | Taxanes medicine preparation for intravenous injection and preparation method thereof | |
| CN104224711B (en) | Paclitaxel submicron emulsion taking steroid compound as intermediate vector | |
| AU2016258642B2 (en) | Cabazitaxel fat emulsion injection, and preparation method and use thereof | |
| CN109730998A (en) | Miboplatin albumin nano granular composition and its preparation method | |
| CN101524329B (en) | Bicyclo-ethanol submicron emulsion and preparation method thereof | |
| WO2011113301A1 (en) | Self-emulsifying formulation of taxanes and preparation method thereof | |
| CN101708156B (en) | Camptothecin medicament injection solution and injection and preparation method thereof | |
| CN102038636B (en) | Taxane medicine solution containing chelating agent and preparation method thereof | |
| CN105534904B (en) | Docetaxel for Injection composition and preparation method thereof | |
| CN102038634B (en) | Cosolvent-containing taxane medicinal solution and preparation method thereof | |
| CN104644548B (en) | Lecithin is as taxol and its combination of derivative injection medicine and application | |
| TWI511725B (en) | A taxane-containing drug solution containing chelating agent and a preparation method thereof | |
| CN102451157A (en) | Docetaxel submicron emulsion with steroid composite as intermediate carrier | |
| KR20140043573A (en) | The water-insoluble docetaxcel covered with amorphous surfactant and method for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 300410 Tianjin City Hedong District of Beichen Puji Road No. 2 city of the modern Chinese Medicine Applicant after: TASLY HOLDING GROUP Co.,Ltd. Address before: 300410 Tianjin City Hedong District of Beichen Puji Road No. 2 city of the modern Chinese Medicine Applicant before: Tianjin Tasly Group Co.,Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: TIANJIN TASLY GROUP CO., LTD. TO: TASLY HOLDING GROUP CO., LTD. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20110504 Assignee: JIANGSU TASLY DIYI PHARMACEUTICAL Co.,Ltd. Assignor: TASLY HOLDING GROUP Co.,Ltd. Contract record no.: 2015320000357 Denomination of invention: Taxane medicine solution containing chelating agent and preparation method thereof Granted publication date: 20140813 License type: Exclusive License Record date: 20150521 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160728 Address after: 223003 Huaian City, Jiangsu province Qingpu Industrial Park, Chaoyang Road No. 168 Patentee after: JIANGSU TASLY DIYI PHARMACEUTICAL Co.,Ltd. Address before: 300410 Tianjin City Hedong District of Beichen Puji Road No. 2 city of the modern Chinese Medicine Patentee before: TASLY HOLDING GROUP Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140813 Termination date: 20211023 |