CN101422458A - Epothilone freeze-drying composition - Google Patents
Epothilone freeze-drying composition Download PDFInfo
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- CN101422458A CN101422458A CNA2007101651118A CN200710165111A CN101422458A CN 101422458 A CN101422458 A CN 101422458A CN A2007101651118 A CNA2007101651118 A CN A2007101651118A CN 200710165111 A CN200710165111 A CN 200710165111A CN 101422458 A CN101422458 A CN 101422458A
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- China
- Prior art keywords
- freeze
- dried
- epothilones
- epothilone
- solubilizing agent
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- 229930013356 epothilone Natural products 0.000 title claims abstract description 48
- 150000003883 epothilone derivatives Chemical class 0.000 title claims abstract description 13
- 239000000203 mixture Substances 0.000 title claims description 39
- 238000004108 freeze drying Methods 0.000 title claims description 16
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 15
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 14
- -1 12-hydroxy stearic acid ester Chemical class 0.000 claims description 11
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 claims description 11
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 claims description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 9
- BEFZAMRWPCMWFJ-QJKGZULSSA-N epothilone C Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 BEFZAMRWPCMWFJ-QJKGZULSSA-N 0.000 claims description 8
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 7
- 229920002307 Dextran Polymers 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- ULQISTXYYBZJSJ-UHFFFAOYSA-N R-12-HOA Natural products CCCCCCC(O)CCCCCCCCCCC(O)=O ULQISTXYYBZJSJ-UHFFFAOYSA-N 0.000 claims description 7
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 7
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229940114072 12-hydroxystearic acid Drugs 0.000 claims description 6
- 239000000470 constituent Substances 0.000 claims description 5
- BEFZAMRWPCMWFJ-JRBBLYSQSA-N Epothilone C Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C=C\C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C BEFZAMRWPCMWFJ-JRBBLYSQSA-N 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC=CCC1C(C)=CC1=CSC(C)=N1 BEFZAMRWPCMWFJ-UHFFFAOYSA-N 0.000 claims description 4
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 claims description 4
- 229960002014 ixabepilone Drugs 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000010695 polyglycol Substances 0.000 claims description 4
- 229920000151 polyglycol Polymers 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- PFJFPBDHCFMQPN-RGJAOAFDSA-N (1s,3s,7s,10r,11s,12s,16r)-3-[(e)-1-[2-(aminomethyl)-1,3-thiazol-4-yl]prop-1-en-2-yl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CN)=N1 PFJFPBDHCFMQPN-RGJAOAFDSA-N 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000008155 medical solution Substances 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 claims 1
- 229940093181 glucose injection Drugs 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 8
- 229920001304 Solutol HS 15 Polymers 0.000 description 8
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 8
- 102000029749 Microtubule Human genes 0.000 description 6
- 108091022875 Microtubule Proteins 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 210000004688 microtubule Anatomy 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-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
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940119744 dextran 40 Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 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 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 241000490229 Eucephalus Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229940119336 Microtubule stabilizer Drugs 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 150000003885 epothilone B derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 229950007460 patupilone Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012827 research and development Methods 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
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an Epothilone freeze-dried compound which mainly contains the Epothilone, a solubilizer and a freeze-dried excipient; wherein, a preferable solubilizer is Carmowax 12-hydroxyl stearate. The product not only is simple in technique and is stable in quality, but also is low in side effect.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to Epothilones (Epothilones) freeze-dried composition and preparation method thereof.
Background technology
Epothilones is the cytotoxic substance of a class microtubule stabilisation, belong to the 16 membered macrolide compounds that contain 7 chiral centres, its antitumor mechanism and paclitaxel are closely similar, it is a kind of novel microtubule stabilizer, effect with promotion guanosine triphosphate (GTP) (GTP) dependency tubulin polymerization formation microtubule, and microtubule had Stabilization, and suppress the depolymerization of microtubule by the stabilize microtubules assembling process, microtubule fasolculus is arranged unusual, form aster, and then the inhibition cell forms normal mitosis spindle, thereby suppress the growth of tumor cell, even induce its death, (Patupilone EPO906) has entered the clinical III phase and has studied the epothilone B of company of Novartis (Novartis) exploitation.
Because Epothilones is insoluble in water, and unstable in aqueous solution, the injection of exploitation Epothilones should solve the water solublity problem of Epothilones, solves its stability problem again; And lyophilized formulations is selected beyond doubt preferably.
Disclosed the prescription of preparation epothilone freeze-drying preparation in CN99803672.2, the CN200480029613.2 patent application, be mixed with the aqueous solution of 30ml comprising mannitol with 5.0mg epothilones B (epothilone B) and 1500mg, lyophilizing, because Epothilones is insoluble in water, in fact this technical scheme may not realize; This patent has also disclosed and has adopted HP-to prepare the freeze-dried powder of Epothilones as solubilizing agent, but along with going deep into that cyclodextrin is understood, its side effect as the injection pharmaceutic adjuvant has also caused people's attention, and the injection HP-not only can cause nephrotoxicity but also can cause haemolysis.
The ZL02804090.2 Patent publish use tertiary butanol and water dissolve Azaepothilone B with preparation lyophilizing stock solution, when but dried frozen aquatic products is mixed with the intravenous injection medical solution again, after using polyoxyethylene castor oil-anhydrous alcohol solution, re-using lactic acid Ge Linshi solution dilutes, whole operation is very complicated very, and also use polyoxyethylene castor oil, and along with injection polyoxyethylene castor oil adjuvant clinically causes being on the increase of severe allergic reaction incident, at present a lot of insoluble drug injections newly developed have not used polyoxyethylene castor oil as the injection pharmaceutic adjuvant.
Summary of the invention
At above technological deficiency, the invention provides a kind of new epothilone freeze-drying composition, it mainly comprises Epothilones, solubilizing agent and freeze-dried excipient, and wherein solubilizing agent is a polyglycol distearate.
Solubilizing agent of the present invention is not limited to above-mentioned cited, can also be other good to the Epothilones solubilizing effect, that side effect is low solubilizing agent, as Liquid Macrogol/400.
Epothilones of the present invention not only comprises the series compound of Epothilones, also comprises the derivant of Epothilones.
Active constituents of medicine in the epothilone freeze-drying composition of the present invention can also be the macrolides compound of other and Epothilones structural similarity, as paclitaxel and derivant or analog.
Epothilones of the present invention is preferably selected from Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, BMS-247550 and BMS-310705; Wherein, the structural formula of Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A and epothilone d is seen formula I;
R=H, Epothilones A R=H, Epothilone C (-)-Deoxyepothilone A
R=CH
3, epothilone B R=CH
3, epothilone d
I
BMS-247550-" Azaepothilone B " and BMS-310705 are the semi-synthetic epothilone B analog of Shi Guibao (Bristol-Myers Squibb) company exploitation, and its structure is suc as formula shown in the II.
In the epothilone freeze-drying composition of the present invention, the preferred polyglycol distearate of solubilizing agent, polyglycol distearate can be Polyethylene Glycol 12-hydroxy stearic acid ester, can also be polyoxyethylene stearic acid ester; The present invention is Polyethylene Glycol 12-hydroxy stearic acid ester more preferably; Further be preferably the Polyethylene Glycol 12-hydroxy stearic acid ester of Solutol HS 15 models.
Solutol HS 15 is a kind of solubilizing agents by the research and development of BASF (BASF) company, compared better solubilizing effect with polyoxyethylene castor oil, Tween 80, but its solution viscosity is lower, the serum histamine release is low after the intravenous injection, haemolysis is low, the physiological tolerance height meets the standard of modern high-efficiency low-toxicity solubilizing agent, and has passed through the injectable drug application verification.These product are incorporated in the European Pharmacopoeia, and with very fast authorization by American Pharmacopeia.Solutol HS 15 at room temperature outward appearance is light yellowish-white pastel, and freezing point is 25-30 ℃, and main active is the ester that 12-hydroxy stearic acid and Polyethylene Glycol 660 form, and its structure is as follows:
Among the present invention, Solutol HS 15 solubilisings mechanism is the micelle solubilising, the stearic acid of Solutol HS 15 is partly assembled the formation hydrophobic inner core, the hydrophilic long-chain part of Polyethylene Glycol outwards stretches, form hydrophilic outer shell, its with the epothilones medicine and with the drug encapsulation of Epothilones structural similarity in hydrophobic inner core, thereby realize solubilising.
The HLB value of Solutol HS 15 is 14-16 among the present invention, and critical micelle concentration is 0.005-0.02%.
In the epothilone freeze-drying composition solid constituent of the present invention, the quality percentage composition of Epothilones is 0.1%-2%; The quality percentage composition of solubilizing agent is 10-90%; Surplus partly is a freeze-dried excipient.
Wherein, the quality percentage composition of solubilizing agent of the present invention in the freeze-dried composition solid constituent is preferably 40-60%.
Freeze-dried excipient can be selected the freeze-dried excipient of this area routine for use, is preferably selected from mannitol, lactose, trehalose, sucrose, sorbitol and the dextran one or more; Further be preferably selected from mannitol, dextran and the trehalose one or more.
Concrete active component difference according to Epothilones, and as required, can also add an amount of buffer solution in the present composition, as, the pH value scope is in the phosphate buffered solution of 5-7, after making Epothilones form solution like this, in freeze dried process, keep near neutral, to improve the stability of Epothilones in aqueous solution.
Needs according to practical situation, in the Epothilones freeze-dried composition of the present invention, can also add the oxidative degradation of proper quantity of antioxidant, but antioxidant can be selected from the intravenous injection antioxidant that uses known in the art such as sodium sulfite, vitamin E under nearly neutrality with the inhibition Epothilones.
Epothilone freeze-drying composition of the present invention can adopt this area routine techniques to be prepared, but preferably adopt following technology to be prepared: Epothilones is dissolved in the solubilizing agent, add water for injection again or/and buffer solution and freeze-dried excipient, be mixed with clear solution, by 0.2 μ m and the more filter membrane aseptic filtration of small-bore, packing, lyophilizing are promptly then.
The present invention can make the freeze-dried composition of the Epothilones of different size according to the actual needs, as 1mg, 2mg, 3mg, 4mg, 5mg or 10mg etc., but is not limited to herein actual enumerating.
Preferred for preparation wherein of the present invention contains the lyophilizing stock solution that Epothilones reaches the above concentration of 1mg/ml, and according to specification packing appropriate volume lyophilizing stock solution in medicinal glass bottle, carry out lyophilizing then.
When freeze-dried composition of the present invention carries out the parenteral administration clinically, as intravenously administrable, before administration, epothilone freeze-drying composition of the present invention can be mixed with Pharmaceutical composition solution, be specially: it is dissolved under aseptic condition in water for injection or the medicinal solvent of aqueous again, for example normal saline, 5% glucose, G/NS, lactic acid Ge Linshi solution etc.; Immediately or in the short time, in 6 hours, use this Pharmaceutical composition solution of preparation again then.
Epothilone freeze-drying composition of the present invention has not only reduced the side effect of prior art products to the generation of human body, and has steady quality, the characteristics that solubility property is good.
Freeze-dried composition of the present invention can be 2-30 ℃ of stable down the storage 24-36 month, and the freeze-dried composition of lay up period does not have the sign of obvious degradation, and its solubility property is also unaffected.
The specific embodiment
The invention will be further elaborated below in conjunction with specific embodiment, but be not construed as limiting the invention.
Embodiment 1
The 5.0mg epothilone B is dissolved among the 500mg Solutol HS 15, adds 10mM then, the NaH of pH7.0
2PO4-Na
2HPO
4The mannitol of buffer solution and 500mg, be mixed with the 5ml settled solution, this solution passes through the filter membrane in 0.2 μ m aperture, aseptic filtration, and filtrate fill under aseptic condition is in the bottle of 10ml to volume, add the lyophilizing plug under aseptic, lyophilization after lyophilizing is finished, makes cryodesiccation chamber's pressure rise to atmospheric pressure at the aseptic drying nitrogen of aseptic feeding down, compress plug under aseptic so that bubble-tight sterile sealing to be provided, roll lid, label, adorn 2-30 ℃ of storage behind the box.
Before facing administration, prepare again with 5ml water for injection or the medicinal solvent of other aqueous, through intravenously administrable.
Embodiment 2
The 5.0mg epothilone B is dissolved among the 500mg Solutol HS 15, the mannitol that adds water for injection and 500mg then, be mixed with the 5ml settled solution, this solution is by the filter membrane in 0.2 μ m aperture, aseptic filtration, filtrate fill under aseptic condition is in the bottle of 10ml to volume, add the lyophilizing plug under aseptic, lyophilization, after lyophilizing is finished,, make cryodesiccation chamber's pressure rise to atmospheric pressure at the aseptic drying nitrogen of aseptic feeding down, compress plug under aseptic so that bubble-tight sterile sealing to be provided, roll lid, label, adorn 2-30 ℃ of storage behind the box.
Again prepare with 5ml water for injection or the medicinal solvent of other aqueous before facing administration, through intravenously administrable.
Embodiment 3-11
According to the method for embodiment 2, prepare freeze-dried composition of the present invention with the prescription in the table 1.
Table 1
| Embodiment | Epothilone B (mg) | SolutolHS15 (mg) | Freeze-dried excipient (mg) | Water for injection (ml) |
| 3 | 5.0 | 500 | Trehalose (two water) 500 | To 5.0 |
| 4 | 5.0 | 250 | Trehalose (two water) 1000 | To 5.0 |
| 5 | 5.0 | 250 | Trehalose (two water) 2000 | To 5.0 |
| 6 | 5.0 | 500 | Dextran 20 150 | To 5.0 |
| 7 | 5.0 | 500 | Dextran 20 50 | To 5.0 |
| 8 | 10.0 | 450 | Dextran 20 50 | To 5.0 |
| 9 | 5.0 | 500 | Dextran 40 150 | To 5.0 |
| 10 | 5.0 | 500 | Dextran 40 50 | To 5.0 |
| 11 | 10.0 | 450 | Dextran 40 50 | To 5.0 |
Embodiment 12-13
According to the method for embodiment 2, prepare freeze-dried composition of the present invention with the prescription in the table 2.
Table 2
| Embodiment | Epothilones A (mg) | SolutolHS15 (mg) | Freeze-dried excipient (mg) | Water for injection (ml) |
| 12 | 5.0 | 500 | Mannitol 500 | To 5.0 |
| 13 | 10.0 | 500 | Mannitol 500 | To 5.0 |
Claims (11)
1, epothilone freeze-drying composition is characterized in that, it mainly comprises Epothilones, solubilizing agent and freeze-dried excipient, and wherein solubilizing agent is a polyglycol distearate.
2, freeze-dried composition according to claim 1 is characterized in that, solubilizing agent is a Polyethylene Glycol 12-hydroxy stearic acid ester.
3, freeze-dried composition according to claim 2 is characterized in that, solubilizing agent is the Polyethylene Glycol 12-hydroxy stearic acid ester of SolutolHS 15 models.
4, according to the arbitrary described freeze-dried composition of claim 1-3, it is characterized in that Epothilones is selected from one or more among Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, BMS-247550 and the BMS-310705.
5, freeze-dried composition according to claim 4 is characterized in that, in the freeze-dried composition solid constituent, the quality percentage composition of Epothilones is 0.1-2%; The quality percentage composition of solubilizing agent is 10-90%; Surplus is a freeze-dried excipient.
6, freeze-dried composition according to claim 5 is characterized in that, in the freeze-dried composition solid constituent, the quality percentage composition of solubilizing agent is 40-60%.
7, freeze-dried composition according to claim 6 is characterized in that, freeze-dried excipient is selected from one or more in mannitol, lactose, trehalose, sucrose, sorbitol and the dextran.
8, freeze-dried composition according to claim 7 is characterized in that, freeze-dried excipient is selected from one or more in mannitol, trehalose and the dextran.
9, the preparation method of freeze-dried composition according to claim 8, it is characterized in that, Epothilones is dissolved in the solubilizing agent, add water for injection again or/and buffer solution and freeze-dried excipient, be mixed with clear solution, by 0.2 μ m or the more filter membrane aseptic filtration of small-bore, packing, lyophilization are promptly then.
10, a kind of Pharmaceutical composition, it is characterized in that the medical solution that described Pharmaceutical composition is to use each described freeze-dried composition of water for injection or normal saline or 5% glucose injection or G/NS or Lactated Ringer'S Solution redissolution claim 1-3 or claim 5-8 to obtain.
11, compositions according to claim 10 is characterized in that, prepares the purposes in the medicine that is suitable for the parenteral administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101651118A CN101422458A (en) | 2007-10-29 | 2007-10-29 | Epothilone freeze-drying composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101651118A CN101422458A (en) | 2007-10-29 | 2007-10-29 | Epothilone freeze-drying composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926772A (en) * | 2010-08-02 | 2010-12-29 | 南京农业大学 | Veterinary BCG polysaccharide nucleic acid lipid composition and freeze-dried preparation thereof |
| CN103908432A (en) * | 2013-01-02 | 2014-07-09 | 博瑞生物医药技术(苏州)有限公司 | Ixabepilone albumin freeze-dried composition and preparation method thereof |
| CN104739782A (en) * | 2015-04-03 | 2015-07-01 | 海南通用康力制药有限公司 | Doxycycline hydrochloride lyophilized powder injection and preparation method thereof |
-
2007
- 2007-10-29 CN CNA2007101651118A patent/CN101422458A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926772A (en) * | 2010-08-02 | 2010-12-29 | 南京农业大学 | Veterinary BCG polysaccharide nucleic acid lipid composition and freeze-dried preparation thereof |
| CN103908432A (en) * | 2013-01-02 | 2014-07-09 | 博瑞生物医药技术(苏州)有限公司 | Ixabepilone albumin freeze-dried composition and preparation method thereof |
| CN103908432B (en) * | 2013-01-02 | 2018-09-21 | 博瑞生物医药（苏州）股份有限公司 | A kind of freeze-dried composition and preparation method thereof of Ipsapirone albumin |
| CN104739782A (en) * | 2015-04-03 | 2015-07-01 | 海南通用康力制药有限公司 | Doxycycline hydrochloride lyophilized powder injection and preparation method thereof |
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