WO2009084801A1 - Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same - Google Patents
Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same Download PDFInfo
- Publication number
- WO2009084801A1 WO2009084801A1 PCT/KR2008/006021 KR2008006021W WO2009084801A1 WO 2009084801 A1 WO2009084801 A1 WO 2009084801A1 KR 2008006021 W KR2008006021 W KR 2008006021W WO 2009084801 A1 WO2009084801 A1 WO 2009084801A1
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- WO
- WIPO (PCT)
- Prior art keywords
- composition
- block copolymer
- taxane
- amphiphilic block
- adjusting agent
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 110
- 239000000693 micelle Substances 0.000 title claims abstract description 82
- 229920000469 amphiphilic block copolymer Polymers 0.000 title claims abstract description 52
- 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 44
- 229940123237 Taxane Drugs 0.000 title claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 title description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 32
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- 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 29
- 229960003668 docetaxel Drugs 0.000 claims description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 23
- 229920001577 copolymer Polymers 0.000 claims description 23
- 238000004108 freeze drying Methods 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 19
- 229930012538 Paclitaxel Natural products 0.000 claims description 14
- 229960001592 paclitaxel Drugs 0.000 claims description 14
- 229920000642 polymer Polymers 0.000 claims description 14
- 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 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 229920000359 diblock copolymer Polymers 0.000 claims description 10
- 238000001556 precipitation Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000001110 calcium chloride Substances 0.000 claims description 9
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- 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 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 4
- 239000004626 polylactic acid Substances 0.000 claims description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- TYLVGQKNNUHXIP-MHHARFCSSA-N 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)C=4C=CC=CC=4)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 TYLVGQKNNUHXIP-MHHARFCSSA-N 0.000 claims description 2
- 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
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229930006000 Sucrose Natural products 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
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims 2
- 229960004275 glycolic acid Drugs 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 20
- 229940079593 drug Drugs 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 19
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 229920001400 block copolymer Polymers 0.000 description 15
- 239000002245 particle Substances 0.000 description 11
- 229920000382 poly(ethylene glycol) methyl ether-block-poly(L-lactide-co-glycolide) Polymers 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000002296 dynamic light scattering Methods 0.000 description 6
- 239000012456 homogeneous solution Substances 0.000 description 6
- 229960001855 mannitol Drugs 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 239000011369 resultant mixture Substances 0.000 description 6
- 238000000935 solvent evaporation Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000004971 Cross linker Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229920006030 multiblock copolymer Polymers 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000011258 core-shell material Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 125000005313 fatty acid group Chemical group 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 229920001308 poly(aminoacid) Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical group CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229920000428 triblock copolymer Polymers 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/17—Amines; Quaternary ammonium compounds
- C08K5/175—Amines; Quaternary ammonium compounds containing COOH-groups; Esters or salts thereof
Definitions
- Example embodiments of the present invention relate to an amphiphilic block copolymer micelle composition containing taxane and a process for preparing the same.
- the block copolymer is an A-B type diblock copolymer polymerized from a hydrophilic segment (A) and a hydrophobic segment (B).
- polyethylene oxide is used as the hydrophilic segment (A) and a polyaminoacid or hydrophobic group-bonded polyaminoacid is used as the hydrophobic segment (B).
- Such drugs as Adriamycin or indomethacin can be physically encapsulated within the cores of the polymeric micelles formed from the block copolymer, so that the block copolymer micelles can be used as drug delivery systems.
- the polymeric micelles formed from the block copolymer cause many problems in the case of in vivo applications, since they cannot be hydrolyzed in vivo but are degraded only by enzymes, have poor biocompatibility, and cause immune responses, or the like.
- diblock or multiblock copolymers comprising polyalkylene glycol as a hydrophilic polymer and polylactic acid as a hydrophobic polymer are known to those skilled in the art. More particularly, acrylic acid derivatives are bonded to the end groups of such diblock or multiblock copolymers to form copolymers. The resultant copolymers are subjected to crosslinking to stabilize the polymeric micelles.
- a so-called solvent evaporation process has been known as a method for preparing a polymer micelle composition.
- the solvent evaporation process can be applied as a large-scale process by which taxane derivatives, which are hardly soluble in water, can be encapsulated within amphiphilic block copolymer micelles.
- utilization of the solvent evaporation process is limited with respect to the selection of a solvent, because the solvent should be an organic solvent in which both taxane and the polymer can be dissolved, and should have such a low boiling point that it can be volatilized via evaporation.
- the organic solvent should be a pharmaceutically acceptable solvent, whose residue does not adversely affect the human body.
- the solvent evaporation process essentially includes a step of exposing reagents to high temperature for a long period of time, and thus it may cause such problems as degradation of pharmaceutically active ingredients or decreased pharmacological effects. Disclosure of Invention Technical Problem
- a taxane-containing amphiphilic block copolymer micelle composition comprising taxane, an amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block, and an osmolality adjusting agent.
- a process for preparing a taxane-containing amphiphilic block copolymer micelle composition comprising: (a) dissolving taxane and an amphiphilic block copolymer into an organic solvent; and (b) adding an aqueous solution containing an osmolality adjusting agent thereto to form polymeric micelles.
- the taxane-containing amphiphilic block copolymer micelle composition according to one embodiment disclosed herein has excellent stability so that it can prevent rapid release of a drug. Additionally, the method for preparing the composition according to another embodiment disclosed herein avoids a need for a separate step of removing an organic solvent, thereby maximizing a desired pharmacological effect and reducing the number of preparation steps and preparation time.
- Fig. 1 is the H NMR spectrum of the diblock copolymer [mPEG-PLA] obtained from Preparation Example 1 ;
- Fig. 2 is the 1 H NMR spectrum of the diblock copolymer [mPEG-PLGA] obtained from Preparation Example 2.
- the taxane-containing amphiphilic block copolymer micelle composition may comprise taxane, an amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block, and an osmolality adjusting agent.
- the taxane-containing amphiphilic block copolymer micelle composition has excellent biodegradability and biocompatibility, and provides a polymeric micelle structure having relatively improved stability.
- the taxane may be present in an amount of Q 1-30 wt%
- the amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block may be present in an amount of 20-98 wt%, based on the total dry weight of the micelle composition.
- the osmolality adjusting agent may be present in an amount of Q 1-30 wt% based on the total dry weight of the composition.
- the taxane may be in an anhydrous or hydrated state, or amorphous or crystalline state. Additionally, the taxane may be extracted from natural plants, or may be obtained by semi-synthesis or plant cell cultivation. In one embodiment, the taxane may be present in the composition in an amount of Q 1-30 wt%, specifically Q5-15 wt%, and more specifically 1-7 wt% based on the total dry weight of the composition.
- the taxane includes paclitaxel, docetaxel, 7-epipaclitaxel, t - acetyl paclitaxel, 10-desacetyl-paclitaxel, lO-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, lO-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel or a mixture thereof.
- paclitaxel or docetaxel may be used.
- the amphiphilic block copolymer may comprise a hydrophilic block (A) and a hydrophobic block (B) linked with each other in the form of A-B, A- B-A or B-A-B structure. Additionally, the amphiphilic block copolymer may form core-shell type polymeric micelles in its aqueous solution state, wherein the hydrophobic block forms the core and the hydrophilic block forms the shell.
- the hydrophilic block (A) of the amphiphilic block copolymer may be polyethylene glycol (PEG) or monomethoxypolyethylene glycol (mPEG). Particularly, it may be mPEG.
- the hydrophilic block (A) may have a weight average molecular weight of 330-20,000 daltons, specifically 1,000-5,000 daltons, and more specifically 1,000-2,300 daltons.
- the hydrophobic block (B) of the amphiphilic block copolymer may be a water- insoluble, biodegradable polymer.
- the hydrophobic block (B) may be polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA).
- the hydrophobic block (B) may have a weight average molecular weight of 500-20,000 daltons, specifically 1,000-5,000 daltons, and more specifically 1,000-2,500 daltons.
- Hydroxyl end groups of the hydrophobic block (B) may be protected with fatty acid groups, and particular examples of the fatty acid groups include acetate, propionate, butyrate, stearate, palmitate groups, and the like.
- amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be present in the composition in an amount of 20-98 wt%, specifically 65-98 wt%, and more specifically 80-98 wt% based on the total dry weight of the composition.
- the hydrophilic block (A) and the hydrophobic block (B) may be present in the amphiphilic block copolymer in such a ratio that the copolymer comprises 40-70 wt%, specifically 50-60 wt% of the hydrophilic block (A) based on the weight of the copolymer.
- the hydrophilic block (A) is present in a proportion less than 40%, the polymer has undesirably low solubility to water, resulting in difficulty in forming micelles.
- the hydrophilic block (A) is present in a proportion greater than 70%, the polymer becomes too hydrophilic to form stable polymeric micelles, and thus the composition may not be used as a composition for solubilizing taxane.
- the osmolality adjusting agent functions to improve the stability of the taxane- containing amphiphilic block copolymer micelle composition. Particularly, the osmolality adjusting agent significantly improves the stability of the composition in its aqueous solution state.
- One possible mechanism of the function of the osmolality adjusting agent is as follows.
- the degree of encapsulation of a drug within a polymeric micelle structure is in proportion to the fraction of cores formed from the hydrophobic block of the polymer in an aqueous solution. Additionally, the stability of the polymeric micelles depends on the dynamic equilibrium state formed by the polymeric micelles in an aqueous solution, i.e., on the equilibrium constant between the polymeric micelle state and the unimer state dissolved in water.
- the hydrophilic blocks of the polymer micelles may be surrounded with a great amount of water molecules upon the encapsulation of the drug, and thus the interaction between the water molecules and the hydrophilic blocks may weaken the hydrophobic interaction between hydrophobic blocks of the micelles, thereby destabilizing the micelles in a dynamic equilibrium state.
- Addition of the osmolality adjusting agent causes an electrostatic attraction force between the osmolality adjusting agent and water, resulting in dissociation of water molecules from the hydrophilic blocks of the polymeric micelles.
- the hydrophobic interaction between the hydrophobic blocks increases relatively, so that stable micelle structures can be formed.
- the osmolality adjusting agent is not removed during the preparation of the composition according to one embodiment disclosed herein but remains in the finished composition. Through the stabilization effect realized by the osmolality adjusting agent, the taxane-containing amphiphilic block copolymer micelle composition has excellent stability.
- the osmolality adjusting agent is pharmaceutically acceptable one and may be selected from any osmolality adjusting agents as long as it does not cause hemolysis upon the contact with blood.
- the osmolality adjusting agent may be an electrolyte, specifically an inorganic salt.
- the osmolality adjusting agent may be at least one selected from the group consisting of sodium chloride, calcium chloride, sodium sulfate and magnesium chloride. More particularly, the osmolality adjusting agent may be sodium chloride or calcium chloride. Especially, it may be sodium chloride.
- the osmolality adjusting agent may be present in the composition in an amount of Q 1-3) wt%, specifically Q5-20 wt%, and more specifically 1-10 wt%, based on the total dry weight of the composition.
- a lyophilized composition comprising the taxane- containing amphiphilic block copolymer micelle composition.
- the lyophilized composition may further comprise a lyophilization aid.
- the lyophilization aid may be at least one selected from the group consisting of lactose, mannitol, sorbitol and sucrose.
- the lyophilization aid is added for the lyophilized composition to maintain a cake form.
- the lyophilization aid serves to help the amphiphilic block copolymer micelle composition to form homogeneously in short time during the reconstitution of the lyophilized composition.
- the lyophilization aid may be used in an amount of 1-90 wt%, and more particularly 10-60 wt%, based on the total dry weight of the lyophilized composition.
- the lyophilized composition may comprise Q 1-15 wt% of taxane based on the total dry weight of the composition, upon the reconstitution in an aqueous solution.
- the amphiphilic block copolymer may be present at a concentration of 10-150 mg/mL
- the osmolality adjusting agent may be present at a concentration of 5-30 mg/mL (specifically, 10-20 mg/mL)
- the lyophilization aid may be present at a concentration of 1-100 mg/mL.
- the lyophilized composition can have a controlled micelle particle size in a range of 1-400 nm, and more particularly 5-200 nm in an aqueous solution, depending on the molecular weight of the copolymer.
- the taxane-containing amphiphilic block copolymer micelle composition may be formulated into the form of an aqueous solution, powder or tablet.
- the composition may be an injection formulation.
- the composition may be reconstituted with distilled water for injection, 0.9% physiological saline, 5% aqueous dextrose solution, and the like. When the composition is reconstituted, at least 95% of taxane is stable for 12 houis or more without precipitation.
- the method for preparing the taxane- containing amphiphilic block copolymer micelle composition may comprise:
- the method may further comprise, after step (b):
- drug precipitation may be prevented by using an osmolality adjusting agent and a minimized amount of organic solvent.
- the composition needs to be dried at a high temperature of 6CPC or higher under reduced pressure for at least 12 houis.
- reduced-pressure, high-temperature drying conditions may cause degradation of a drug.
- the method for preparing the taxane-containing amphiphilic block copolymer micelle composition uses a minimized amount of organic solvent so that the finished composition can be directly subjected to lyophilization while avoiding a need for a separate step of removing the organic solvent.
- the taxane-containing amphiphilic block copolymer micelle composition containing the osmolality adjusting agent and using a minimized amount of organic solvent can provide a lyophilized composition which is free from precipitation of taxane for 12 homs or more when reconstituted into an injection formulation.
- the organic solvent in step (a) may include at least one selected from the group consisting of acetone, ethanol, methanol, ethyl acetate, acetonitrile, methylene chloride, chloroform, acetic acid and dioxane.
- the organic solvent may be used in an amount of Q5-30 wt%, specifically Q5-15 wt%, and more specifically 1-10 wt% based on the weight of the resultant micelle composition.
- Q 5 wt% there may be a difficulty in dissolving a drug.
- the organic solvent is used in an amount greater than 30 wt%, drug precipitation may occur upon the reconstitution of the lyophilized composition.
- the osmolality of the aqueous solution containing the osmolality adjusting agent may be adjusted to 30-15,000 m ⁇ sm/kg, specifically 100-5,000 mOsm/kg, and more specifically 200-2,500 mOsm/kg.
- the osmolality of the aqueous solution is less than 30 mOsm/kg, drug precipitation may occur during the preparation of the composition.
- the osmolality is greater than 15,000 mOsm/kg, phase separation may occur in the polymer.
- the osmolality adjusting agent may be at least one selected from the group consisting of sodium chloride, calcium chloride, sodium sulfate and magnesium chloride.
- the osmolality adjusting agent may be used in an amount of Q 1-50 wt% based on the total dry weight of the micelle composition.
- Step (b) may be performed at a temperature of 25 0 C or lower.
- the method for preparing the taxane-containing amphiphilic block copolymer micelle composition may further comprise sterilizing the aqueous polymeric micelle solution obtained from step (c) with a sterilization filter, before step (d) of carrying out lyophilization.
- the taxane-containing amphiphilic block copolymer micelle composition according to one embodiment disclosed herein may be orally or parenterally administered in the form of an aqueous solution or powder.
- Parenteral administration includes administration via intravascular, intramuscular, subcutaneous, intraperitoneal, nasal, rectal, ophthalmic, pulmonary or other routes.
- Oral administration includes administration in the form of tablets or capsules, or aqueous solution itself.
- the lyophilized composition according to one embodiment disclosed herein causes little variation in the concentration of docetaxel in a reconstituted composition over time. However, when no osmolality adjusting agent is added, docetaxel concentration decreases after the lapse of one hour.
- the copolymer monomethoxylpoly ethylene glycol-polylactide (mPEG-PLA), had a number average molecular weight of 2,000-1,765 daltons. Analysis of the copolymer performed by H-NMR revealed that the copolymer was an A-B type diblock copolymer (see Fig. 1).
- a block copolymer was obtained by reacting monomethoxypolyethylene glycol
- Example 1 Preparation of mPEG-PLA Block Copolymer Micelle Composition Containing Sodium Chloride and Docetaxel
- aqueous solutions each containing 09 wt% and 1.8 wt% of sodium chloride and having an osmolality of 300 mOsm/kg and 600 mOsm/kg were prepared in separate containers.
- the osmolality was measured by using a commercially available osmometer (Gonotech GmbH, OSMOMAT030).
- Each aqueous solution was added to the ethanol solution comprising the copolymer in an amount of 4 mL, and the resultant mixture was agitated at 4CPC for 10 minutes to form an aqueous polymeric micelle solution.
- the lyophilized composition was subjected to liquid chromatography as follows to determine the content of docetaxel. Additionally, particle size was measured by a dynamic light scattering (DLS) method. The results are shown in the following Table 1.
- Liquid Chromatography [66] 1) Column: a stainless steel column having a length of 250 mm and an inner diameter of 4.6 mm and packed with pentafluorophenyl-coated particles having a particle diameter of 5 ⁇ m and a pore diameter of 300 A.
- aqueous solutions each containing 09 wt% and 1.8 wt% of calcium chloride and having an osmolality of 230 mOsm/kg and 460 mOsm/kg were prepared in separate containers. Each aqueous solution was added to the ethanol solution comprising the copolymer in an amount of 4 mL, and the resultant mixture was agitated at 4CPC for 10 minutes to form an aqueous polymeric micelle solution.
- Example 3 Preparation of mPEG-PLGA Block Copolymer Micelle Composition Containing Sodium Chloride and Docetaxel
- mPEG-PLGA number average molecular weight: 5,000-4,000 daltons
- the lyophilized composition was subjected to the liquid chromatography as described in Example 1 to determine the content of docetaxel. Additionally, particle size was measured by a DLS method.
- Fiist 100 mg of the amphiphilic block copolymer, mPEG-PLGA (number average molecular weight: 5,000-4,000 daltons), obtained from Preparation Example 2 was completely dissolved into 02 mL of acetone at 5CPC to provide a clear acetone solution comprising the copolymer.
- the acetone solution was cooled to 25 0 C, and 40 mg of paclitaxel was added thereto and the resultant solution was agitated until paclitaxel was completely dissolved.
- the lyophilized composition was subjected to high-performance liquid chromatography (HPLC) to determine the content of docetaxel. Additionally, particle size was measured by a DLS method.
- HPLC high-performance liquid chromatography
- the lyophilized composition was subjected to HPLC to determine the content of docetaxel. Additionally, particle size was measured by a DLS method.
- Example 1 The sodium chloride-containing polymeric micelle compositions according to Example 1 were compared with the polymeric micelle composition containing no inorganic salt according to Comparative Example 1 in terms of the stability of the aqueous solution at 37 0 C.
- Example 1 was diluted with distilled water for injection to a docetaxel concentration of 1 mg/mL. While each diluted solution was left at 37 0 C, concentration of docetaxel contained in each micelle structure was measured over time. The results are shown in the following Table 3.
- compositions according to Example 1 cause no precipitation of docetaxel even after the lapse of 12 houis, while the composition according to Comparative Example 1 shows an amount of docetaxel precipitation of 59% after the lapse of 12 hours.
- addition of sodium chloride may increase the docetaxel retainability of a micelle composition by about at least two times.
- a higher ratio of the amount of the inorganic salt to that of the amphiphilic block copolymer provides the micelle composition with higher stability.
Abstract
A taxane-containing amphiphilic block copolymer micelle composition, including taxane, an amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block, and an osmolality adjusting agent, is discribed. Also described are a method for preparing the same composition. The composition has excellent stability so that it can prevent rapid release of a drug and can improve a desired pharmacological effect. Additionally, the method enables highly efficient preparation of the composition.
Description
Description
AMPHIPHILIC BLOCK COPOLYMER MICELLE COMPOSITION CONTAINING TAXANE AND MANUFACTURING PROCESS OF THE SAME
Technical Field
[1] Example embodiments of the present invention relate to an amphiphilic block copolymer micelle composition containing taxane and a process for preparing the same. Background Art
[2] Submicronic particulate drug delivery systems using biodegradable polymers have been studied for the purpose of carrying out intravenous administration of drugs. Recently, it has been reported that nanoparticle systems and polymeric micelle systems using biodegradable polymers are useful technological systems that can modify the in vivo distribution of a drug to reduce undesired side effects and can provide improved efficiency. Additionally, because such systems enable targeted drug delivery, they can achieve controlled drug release to target organs, tissues or cells. In fact, such systems are known to have excellent compatibility with body fluids and to improve the solubilization ability of a hardly soluble drug and the bioavailability of a drug.
[3] Recently, there has been reported a method for preparing block copolymer micelles by chemically bonding a drug to a block copolymer comprising a hydrophilic segment and a hydrophobic segment. The block copolymer is an A-B type diblock copolymer polymerized from a hydrophilic segment (A) and a hydrophobic segment (B). In the above-mentioned block copolymer, polyethylene oxide is used as the hydrophilic segment (A) and a polyaminoacid or hydrophobic group-bonded polyaminoacid is used as the hydrophobic segment (B). Such drugs as Adriamycin or indomethacin can be physically encapsulated within the cores of the polymeric micelles formed from the block copolymer, so that the block copolymer micelles can be used as drug delivery systems. However, the polymeric micelles formed from the block copolymer cause many problems in the case of in vivo applications, since they cannot be hydrolyzed in vivo but are degraded only by enzymes, have poor biocompatibility, and cause immune responses, or the like.
[4] Therefore, many attempts have been made to develop core -shell type drug delivery systems having improved biodegradability and biocompatibility.
[5] For example, diblock or multiblock copolymers comprising polyalkylene glycol as a hydrophilic polymer and polylactic acid as a hydrophobic polymer are known to those skilled in the art. More particularly, acrylic acid derivatives are bonded to the end groups of such diblock or multiblock copolymers to form copolymers. The resultant copolymers are subjected to crosslinking to stabilize the polymeric micelles. However, methods for preparing such diblock or multiblock copolymers have difficulties in introducing cross linkers to the hydrophobic segments of A-B or A-B-A type diblock or triblock copolymers for the polymers to form stable structures via crosslinMng. Additionally, the crosslinkers used in the above methods may not ensure safety in the human body because the crosslinkers have not been applied in the human body as yet. Furthermore, the crosslinked polymers cannot be degraded in vivo, and thus cannot be applied for in vivo use.
[6] As another example, a so-called solvent evaporation process has been known as a method for preparing a polymer micelle composition. The solvent evaporation process can be applied as a large-scale process by which taxane derivatives, which are hardly soluble in water, can be encapsulated within amphiphilic block copolymer micelles. However, utilization of the solvent evaporation process is limited with respect to the selection of a solvent, because the solvent should be an organic solvent in which both taxane and the polymer can be dissolved, and should have such a low boiling point that it can be volatilized via evaporation. In addition, the organic solvent should be a pharmaceutically acceptable solvent, whose residue does not adversely affect the human body. Further, the solvent evaporation process essentially includes a step of exposing reagents to high temperature for a long period of time, and thus it may cause such problems as degradation of pharmaceutically active ingredients or decreased pharmacological effects. Disclosure of Invention Technical Problem
[7] Therefore, in an effort to solve the above-described problems associated with the related art, there is provided a taxane-containing amphiphilic block copolymer micelle composition having improved stability.
[8] There is also provided a process for preparing a taxane-containing amphiphilic block copolymer micelle composition via simplified steps in short time. Technical Solution
[9] In an aspect, there is provided a taxane-containing amphiphilic block copolymer
micelle composition comprising taxane, an amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block, and an osmolality adjusting agent. [10] In another aspect, there is provided a process for preparing a taxane-containing amphiphilic block copolymer micelle composition, comprising: (a) dissolving taxane and an amphiphilic block copolymer into an organic solvent; and (b) adding an aqueous solution containing an osmolality adjusting agent thereto to form polymeric micelles.
Advantageous Effects
[11] The taxane-containing amphiphilic block copolymer micelle composition according to one embodiment disclosed herein has excellent stability so that it can prevent rapid release of a drug. Additionally, the method for preparing the composition according to another embodiment disclosed herein avoids a need for a separate step of removing an organic solvent, thereby maximizing a desired pharmacological effect and reducing the number of preparation steps and preparation time. Brief Description of Drawings
[12] Description will now be given in detail with reference to certain example embodiments of a taxane-containing amphiphilic block copolymer micelle composition and a process for preparing the same illustrated in the accompanying drawings which are given hereinbelow by way of illustration only and thus are not limitative, wherein:
[13] Fig. 1 is the H NMR spectrum of the diblock copolymer [mPEG-PLA] obtained from Preparation Example 1 ; and
[14] Fig. 2 is the 1H NMR spectrum of the diblock copolymer [mPEG-PLGA] obtained from Preparation Example 2. Mode for the Invention
[15] Hereinafter, reference will now be made in detail to various embodiments, examples of which are illustrated in the accompanying drawings and described below. While the invention will be described in conjunction with example embodiments, it will be understood that the present description is not intended to be limitative.
[16] The taxane-containing amphiphilic block copolymer micelle composition according to one embodiment disclosed herein may comprise taxane, an amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block, and an osmolality adjusting agent. The taxane-containing amphiphilic block copolymer micelle composition has excellent biodegradability and biocompatibility, and provides a polymeric micelle structure having relatively improved stability.
[17] In the composition according to one embodiment disclosed herein, the taxane may be
present in an amount of Q 1-30 wt%, and the amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block may be present in an amount of 20-98 wt%, based on the total dry weight of the micelle composition. Additionally, the osmolality adjusting agent may be present in an amount of Q 1-30 wt% based on the total dry weight of the composition.
[18] The taxane may be in an anhydrous or hydrated state, or amorphous or crystalline state. Additionally, the taxane may be extracted from natural plants, or may be obtained by semi-synthesis or plant cell cultivation. In one embodiment, the taxane may be present in the composition in an amount of Q 1-30 wt%, specifically Q5-15 wt%, and more specifically 1-7 wt% based on the total dry weight of the composition.
[19] In one embodiment, the taxane includes paclitaxel, docetaxel, 7-epipaclitaxel, t - acetyl paclitaxel, 10-desacetyl-paclitaxel, lO-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, lO-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel or a mixture thereof. Particularly, paclitaxel or docetaxel may be used.
[20] In one embodiment, the amphiphilic block copolymer may comprise a hydrophilic block (A) and a hydrophobic block (B) linked with each other in the form of A-B, A- B-A or B-A-B structure. Additionally, the amphiphilic block copolymer may form core-shell type polymeric micelles in its aqueous solution state, wherein the hydrophobic block forms the core and the hydrophilic block forms the shell.
[21] In one embodiment, the hydrophilic block (A) of the amphiphilic block copolymer may be polyethylene glycol (PEG) or monomethoxypolyethylene glycol (mPEG). Particularly, it may be mPEG. The hydrophilic block (A) may have a weight average molecular weight of 330-20,000 daltons, specifically 1,000-5,000 daltons, and more specifically 1,000-2,300 daltons.
[22] The hydrophobic block (B) of the amphiphilic block copolymer may be a water- insoluble, biodegradable polymer. In one embodiment, the hydrophobic block (B) may be polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA). In another embodiment, the hydrophobic block (B) may have a weight average molecular weight of 500-20,000 daltons, specifically 1,000-5,000 daltons, and more specifically 1,000-2,500 daltons. Hydroxyl end groups of the hydrophobic block (B) may be protected with fatty acid groups, and particular examples of the fatty acid groups include acetate, propionate, butyrate, stearate, palmitate groups, and the like. The amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be present in the composition in an amount of 20-98 wt%, specifically
65-98 wt%, and more specifically 80-98 wt% based on the total dry weight of the composition.
[23] In another embodiment, the hydrophilic block (A) and the hydrophobic block (B) may be present in the amphiphilic block copolymer in such a ratio that the copolymer comprises 40-70 wt%, specifically 50-60 wt% of the hydrophilic block (A) based on the weight of the copolymer. When the hydrophilic block (A) is present in a proportion less than 40%, the polymer has undesirably low solubility to water, resulting in difficulty in forming micelles. On the other hand, when the hydrophilic block (A) is present in a proportion greater than 70%, the polymer becomes too hydrophilic to form stable polymeric micelles, and thus the composition may not be used as a composition for solubilizing taxane.
[24] The osmolality adjusting agent functions to improve the stability of the taxane- containing amphiphilic block copolymer micelle composition. Particularly, the osmolality adjusting agent significantly improves the stability of the composition in its aqueous solution state. One possible mechanism of the function of the osmolality adjusting agent is as follows.
[25] The degree of encapsulation of a drug within a polymeric micelle structure is in proportion to the fraction of cores formed from the hydrophobic block of the polymer in an aqueous solution. Additionally, the stability of the polymeric micelles depends on the dynamic equilibrium state formed by the polymeric micelles in an aqueous solution, i.e., on the equilibrium constant between the polymeric micelle state and the unimer state dissolved in water.
[26] Although a large amount of poorly soluble drug can be encapsulated within a polymeric micelle structure, the hydrophilic blocks of the polymer micelles may be surrounded with a great amount of water molecules upon the encapsulation of the drug, and thus the interaction between the water molecules and the hydrophilic blocks may weaken the hydrophobic interaction between hydrophobic blocks of the micelles, thereby destabilizing the micelles in a dynamic equilibrium state. Addition of the osmolality adjusting agent causes an electrostatic attraction force between the osmolality adjusting agent and water, resulting in dissociation of water molecules from the hydrophilic blocks of the polymeric micelles. As a result, the hydrophobic interaction between the hydrophobic blocks, which otherwise would participate in loose interaction, increases relatively, so that stable micelle structures can be formed. In addition, the osmolality adjusting agent is not removed during the preparation of the composition according to one embodiment disclosed herein but remains in the finished
composition. Through the stabilization effect realized by the osmolality adjusting agent, the taxane-containing amphiphilic block copolymer micelle composition has excellent stability.
[27] The osmolality adjusting agent is pharmaceutically acceptable one and may be selected from any osmolality adjusting agents as long as it does not cause hemolysis upon the contact with blood. In one embodiment, the osmolality adjusting agent may be an electrolyte, specifically an inorganic salt. Preferably, the osmolality adjusting agent may be at least one selected from the group consisting of sodium chloride, calcium chloride, sodium sulfate and magnesium chloride. More particularly, the osmolality adjusting agent may be sodium chloride or calcium chloride. Especially, it may be sodium chloride. In another embodiment, the osmolality adjusting agent may be present in the composition in an amount of Q 1-3) wt%, specifically Q5-20 wt%, and more specifically 1-10 wt%, based on the total dry weight of the composition.
[28] In another aspect, there is provided a lyophilized composition comprising the taxane- containing amphiphilic block copolymer micelle composition.
[29] The lyophilized composition may further comprise a lyophilization aid. In one embodiment, the lyophilization aid may be at least one selected from the group consisting of lactose, mannitol, sorbitol and sucrose. The lyophilization aid is added for the lyophilized composition to maintain a cake form. In addition, the lyophilization aid serves to help the amphiphilic block copolymer micelle composition to form homogeneously in short time during the reconstitution of the lyophilized composition. In another embodiment, the lyophilization aid may be used in an amount of 1-90 wt%, and more particularly 10-60 wt%, based on the total dry weight of the lyophilized composition.
[30] In one embodiment, the lyophilized composition may comprise Q 1-15 wt% of taxane based on the total dry weight of the composition, upon the reconstitution in an aqueous solution. Additionally, upon the reconstitution, the amphiphilic block copolymer may be present at a concentration of 10-150 mg/mL, the osmolality adjusting agent may be present at a concentration of 5-30 mg/mL (specifically, 10-20 mg/mL), and the lyophilization aid may be present at a concentration of 1-100 mg/mL. In another embodiment, the lyophilized composition can have a controlled micelle particle size in a range of 1-400 nm, and more particularly 5-200 nm in an aqueous solution, depending on the molecular weight of the copolymer.
[31] In one embodiment, the taxane-containing amphiphilic block copolymer micelle composition may be formulated into the form of an aqueous solution, powder or tablet.
In another embodiment, the composition may be an injection formulation. For example, the composition may be reconstituted with distilled water for injection, 0.9% physiological saline, 5% aqueous dextrose solution, and the like. When the composition is reconstituted, at least 95% of taxane is stable for 12 houis or more without precipitation.
[32] In still another aspect, there is provided a method for preparing the taxane-containing amphiphilic block copolymer micelle composition.
[33] According to one embodiment disclosed herein, the method for preparing the taxane- containing amphiphilic block copolymer micelle composition may comprise:
[34] (a) dissolving taxane and an amphiphilic block copolymer into an organic solvent; and
[35] (b) adding an aqueous solution containing an osmolality adjusting agent thereto to form polymeric micelles.
[36] In another embodiment, the method may further comprise, after step (b):
[37] (c) adding a lyophilization aid to the polymeric micelles; and
[38] (d) carrying out lyophilization.
[39] When taxane is encapsulated with a micelle composition by using an organic solvent via a solvent evaporation process, rapid drug precipitation may occur in the taxane- containing micelle composition after the composition is reconstituted in injection water and is left at room temperature. This is because the organic solvent used in the solvent evaporation process remains in the composition.
[40] Therefore, according to one embodiment of the method disclosed herein, drug precipitation may be prevented by using an osmolality adjusting agent and a minimized amount of organic solvent. To minimize the amount of the organic solvent still remaining in the finished composition, the composition needs to be dried at a high temperature of 6CPC or higher under reduced pressure for at least 12 houis. However, such reduced-pressure, high-temperature drying conditions may cause degradation of a drug. Thus, the method for preparing the taxane-containing amphiphilic block copolymer micelle composition according to one embodiment disclosed herein uses a minimized amount of organic solvent so that the finished composition can be directly subjected to lyophilization while avoiding a need for a separate step of removing the organic solvent.
[41] The taxane-containing amphiphilic block copolymer micelle composition containing the osmolality adjusting agent and using a minimized amount of organic solvent according to one embodiment disclosed herein can provide a lyophilized composition
which is free from precipitation of taxane for 12 homs or more when reconstituted into an injection formulation.
[42] In one embodiment, the organic solvent in step (a) may include at least one selected from the group consisting of acetone, ethanol, methanol, ethyl acetate, acetonitrile, methylene chloride, chloroform, acetic acid and dioxane. The organic solvent may be used in an amount of Q5-30 wt%, specifically Q5-15 wt%, and more specifically 1-10 wt% based on the weight of the resultant micelle composition. When the organic solvent is used in an amount less than Q 5 wt%, there may be a difficulty in dissolving a drug. On the other hand, when the organic solvent is used in an amount greater than 30 wt%, drug precipitation may occur upon the reconstitution of the lyophilized composition.
[43] In step (b), the osmolality of the aqueous solution containing the osmolality adjusting agent may be adjusted to 30-15,000 mθsm/kg, specifically 100-5,000 mOsm/kg, and more specifically 200-2,500 mOsm/kg. When the osmolality of the aqueous solution is less than 30 mOsm/kg, drug precipitation may occur during the preparation of the composition. On the other hand, when the osmolality is greater than 15,000 mOsm/kg, phase separation may occur in the polymer. In one example embodiment, the osmolality adjusting agent may be at least one selected from the group consisting of sodium chloride, calcium chloride, sodium sulfate and magnesium chloride. In addition, the osmolality adjusting agent may be used in an amount of Q 1-50 wt% based on the total dry weight of the micelle composition. Step (b) may be performed at a temperature of 250C or lower.
[44] In one embodiment, the method for preparing the taxane-containing amphiphilic block copolymer micelle composition may further comprise sterilizing the aqueous polymeric micelle solution obtained from step (c) with a sterilization filter, before step (d) of carrying out lyophilization.
[45] The taxane-containing amphiphilic block copolymer micelle composition according to one embodiment disclosed herein may be orally or parenterally administered in the form of an aqueous solution or powder. Parenteral administration includes administration via intravascular, intramuscular, subcutaneous, intraperitoneal, nasal, rectal, ophthalmic, pulmonary or other routes. Oral administration includes administration in the form of tablets or capsules, or aqueous solution itself.
[46] In addition, the lyophilized composition according to one embodiment disclosed herein causes little variation in the concentration of docetaxel in a reconstituted composition over time. However, when no osmolality adjusting agent is added,
docetaxel concentration decreases after the lapse of one hour.
[47]
[48] The following examples are not intended to be limitative.
[49]
[50] Preparation Example 1 : Synthesis of Monomethoxypolyethylene glycol-Polylactide
(mPEG-PLA) Block Copolymer (A-B Type)
[51] First, 5.0 g of monomethoxypolyethylene glycol (number average molecular weight:
2,000 daltons) was introduced into a 100 mL two-neck round-bottom flask, and was heated to 13CPC under reduced pressure (1 mmHg) for 3-4 houis to remove water therefrom. Next, the flask was purged with nitrogen gas, and stannous octoate (Sn(Oct)
2 ) was added thereto as a reaction catalyst using a syringe in an amount of Q 1 wt%
(IQ 13 mg, 25 mmol) based on the weight of d- and 1-lactides. After the reaction mixture was agitated for 30 minutes, it was subjected to depressurization (1 mmHg) at 13CPC for 1 hour to remove the solvent (toluene) in which the catalyst was dissolved. Then, IQ 13 g of purified lactide was added thereto, and the resultant mixture was heated at 13CPC for 18 houis. After heating, the resultant polymer was dissolved into methylene chloride, and was added to diethyl ether to cause precipitation of the polymer. The resultant polymer was dried in a vacuum oven for 48 houis.
[52] The copolymer, monomethoxylpoly ethylene glycol-polylactide (mPEG-PLA), had a number average molecular weight of 2,000-1,765 daltons. Analysis of the copolymer performed by H-NMR revealed that the copolymer was an A-B type diblock copolymer (see Fig. 1).
[53]
[54] Preparation Example 2: Synthesis of Monomethoxypolvethylene glycol-
PolyQactic-co-glycolic acid) (mPEG-PLGA) Block Copolymer (A-B Type)
[55] A block copolymer was obtained by reacting monomethoxypolyethylene glycol
(number average molecular weight: 5,000 daltons), lactide and glycolide in the presence of stannous octoate as a catalyst at 12CPC for 12 houis in the same manner as Preparation Example 1.
[56] The copolymer, monomethoxypolyethylene glycol-poly(lactic-co-glycolic acid)
(mPEG-PLGA), had a number average molecular weight of 5,000-4,000 daltons and was an A-B type copolymer. Analysis of the copolymer performed by H-NMR revealed that the copolymer was an A-B type diblock copolymer (see Fig. X).
[57]
[58] Example 1 : Preparation of mPEG-PLA Block Copolymer Micelle Composition
Containing Sodium Chloride and Docetaxel
[59] First, 760 mg of the amphiphilic block copolymer, mPEG-PLA (number average molecular weight: 2,000-1,765 daltons), obtained from Preparation Example 1 was completely dissolved into Q2 mL of ethanol at 6CPC to provide a clear ethanol solution comprising the copolymer. The ethanol solution was cooled to 250C, and 20 mg of docetaxel was added thereto and the resultant solution was agitated until docetaxel was completely dissolved.
[60] Next, aqueous solutions each containing 09 wt% and 1.8 wt% of sodium chloride and having an osmolality of 300 mOsm/kg and 600 mOsm/kg were prepared in separate containers. The osmolality was measured by using a commercially available osmometer (Gonotech GmbH, OSMOMAT030). Each aqueous solution was added to the ethanol solution comprising the copolymer in an amount of 4 mL, and the resultant mixture was agitated at 4CPC for 10 minutes to form an aqueous polymeric micelle solution.
[61] Then, 100 mg of d-mannitol was dissolved into each solution, and the resultant solution was filtered through a filter with a pore size of 200 nm to remove undissolved docetaxel, followed by lyophilization.
[62] The lyophilized composition was subjected to liquid chromatography as follows to determine the content of docetaxel. Additionally, particle size was measured by a dynamic light scattering (DLS) method. The results are shown in the following Table 1.
[63] [Table 1] [64]
[65] Liquid Chromatography [66] 1) Column: a stainless steel column having a length of 250 mm and an inner diameter of 4.6 mm and packed with pentafluorophenyl-coated particles having a particle diameter of 5 μm and a pore diameter of 300 A.
[67] 2) Mobile Phase: acetonitrile: methanol: water = 26:32:420 [68] 3) Flow Rate: 1.5 mL/min [69] 4) Loading Amount: 20 ;d [70] 5) Detector: UV absorption spectrometer (measurement wavelength: 232 nm)
[71] [72] Example 2: Preparation of mPEG-PLA Block Copolymer Micelle Composition Containing Calcium Chloride and Paclitaxel
[73] First, 100 mg of the amphiphilic block copolymer, mPEG-PLA (number average molecular weight: 2,000-1,765 daltons), obtained from Preparation Example 1 was completely dissolved into Q 1 mL of ethanol at 6CPC to provide a clear ethanol solution comprising the copolymer. The ethanol solution was cooled to 250C, and 20 mg of paclitaxel was added thereto and the resultant solution was agitated until paclitaxel was completely dissolved.
[74] Next, aqueous solutions each containing 09 wt% and 1.8 wt% of calcium chloride and having an osmolality of 230 mOsm/kg and 460 mOsm/kg were prepared in separate containers. Each aqueous solution was added to the ethanol solution comprising the copolymer in an amount of 4 mL, and the resultant mixture was agitated at 4CPC for 10 minutes to form an aqueous polymeric micelle solution.
[75] Then, 39 mg of d-mannitol was dissolved into each solution, and the resultant solution was filtered through a filter with a pore size of 200 nm to remove undissolved paclitaxel, followed by lyophilization.
[76] The lyophilized composition was subjected to the liquid chromatography as described in Example 1 to determine the content of paclitaxel. Additionally, particle size was measured by a DLS method. The results are shown in the following Table 2.
[77] [Table 2] [78]
[79] Example 3: Preparation of mPEG-PLGA Block Copolymer Micelle Composition Containing Sodium Chloride and Docetaxel [80] First, 760 mg of the amphiphilic block copolymer, mPEG-PLGA (number average molecular weight: 5,000-4,000 daltons), obtained from Preparation Example 2 was completely dissolved into 02 mL of acetone at 5CPC to provide a clear acetone solution comprising the copolymer. The acetone solution was cooled to 250C, and 40 mg of docetaxel was added thereto and the resultant solution was agitated until docetaxel was completely dissolved.
[81] Next, 8 mL of an aqueous solution containing Q 9 wt% of sodium chloride and having an osmolality of 300 mOsm/kg was added to the acetone solution comprising the copolymer and further containing the drug, and the resultant mixture was agitated at 250C for 20 minutes to form a homogeneous solution. Once the homogeneous solution was formed, 200 mg of d-mannitol was dissolved into the solution to provide a clear aqueous polymeric micelle solution. Finally, the aqueous polymeric micelle solution was filtered through a filter with a pore size of 200 nm to remove undissolved docetaxel, followed by lyophilization.
[82] The lyophilized composition was subjected to the liquid chromatography as described in Example 1 to determine the content of docetaxel. Additionally, particle size was measured by a DLS method.
[83] Docetaxel content: 101. 3 wt%.
[84] Particle size: 35 nm.
[85]
[86] Example 4: Preparation of mPEG-PLGA Block Copolymer Micelle Composition
Containing Calcium Chloride and Paclitaxel
[87] Fiist, 100 mg of the amphiphilic block copolymer, mPEG-PLGA (number average molecular weight: 5,000-4,000 daltons), obtained from Preparation Example 2 was completely dissolved into 02 mL of acetone at 5CPC to provide a clear acetone solution comprising the copolymer. The acetone solution was cooled to 250C, and 40 mg of paclitaxel was added thereto and the resultant solution was agitated until paclitaxel was completely dissolved.
[88] Next, 8 mL of an aqueous solution containing 09 wt% of calcium chloride and having an osmolality of 230 mOsm/kg was added to the acetone solution comprising the copolymer and further containing the drug, and the resultant mixture was agitated at 250C for 20 minutes to form a homogeneous solution. Once the homogeneous solution was formed, 53 mg of d-mannitol was dissolved into the solution to provide a clear aqueous polymeric micelle solution. Finally, the aqueous polymeric micelle solution was filtered through a filter with a pore size of 200 nm to remove undissolved paclitaxel, followed by lyophilization.
[89] The lyophilized composition was subjected to high-performance liquid chromatography (HPLC) to determine the content of docetaxel. Additionally, particle size was measured by a DLS method.
[90] Docetaxel content: 101. 1 wt%.
[91] Particle size: 35 nm.
[92]
[93] Comparative Example 1: Preparation of mPEG-PLA Block Copolymer Micelle
Composition Containing No Inorganic Salt
[94] First, 760 mg of the amphiphilic block copolymer, mPEG-PLA (number average molecular weight: 2,000-1,765 daltons), obtained from Preparation Example 1 was completely dissolved into 02 mL of ethanol at 6CPC to provide a clear ethanol solution comprising the copolymer. The ethanol solution was cooled to 250C, and 20 mg of docetaxel was added thereto and the resultant solution was agitated until docetaxel was completely dissolved.
[95] Next, 4 mL of distilled water for injection (osmolality: 0 mOsm/kg) was added to the ethanol solution comprising the copolymer, and the resultant mixture was agitated at 4CPC for 10 minutes to form a homogeneous solution. Once the homogeneous solution was formed, 100 mg of d-mannitol was dissolved into the solution to provide a clear aqueous polymeric micelle solution. Finally, the aqueous polymeric micelle solution was filtered through a filter with a pore size of 200 nm to remove undissolved docetaxel, followed by lyophilization.
[96] The lyophilized composition was subjected to HPLC to determine the content of docetaxel. Additionally, particle size was measured by a DLS method.
[97] Docetaxel content: 10Q3 wt%.
[98] Particle size: 18 nm.
[99]
[100] Experimental Example 1 : Stability Test
[101] The sodium chloride-containing polymeric micelle compositions according to Example 1 were compared with the polymeric micelle composition containing no inorganic salt according to Comparative Example 1 in terms of the stability of the aqueous solution at 370C.
[102] Each of the lyophilized compositions according to Example 1 and Comparative
Example 1 was diluted with distilled water for injection to a docetaxel concentration of 1 mg/mL. While each diluted solution was left at 370C, concentration of docetaxel contained in each micelle structure was measured over time. The results are shown in the following Table 3.
[103] [Table 3]
[104]
[105] As can be seen from the results of Table 3, the compositions according to Example 1 cause no precipitation of docetaxel even after the lapse of 12 houis, while the composition according to Comparative Example 1 shows an amount of docetaxel precipitation of 59% after the lapse of 12 hours. It can be seen from the above results that addition of sodium chloride may increase the docetaxel retainability of a micelle composition by about at least two times. Additionally, it can be also seen that a higher ratio of the amount of the inorganic salt to that of the amphiphilic block copolymer provides the micelle composition with higher stability.
[106] Description has been given in detail with reference to example embodiments. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the taxane- containing amphiphilic block copolymer micelle composition and the method for preparing the same, the scope of which is defined in the accompanying claims and their equivalents.
Claims
[1] A taxane-containing amphiphilic block copolymer micelle composition, comprising taxane, an amphiphilic block copolymer containing a hydrophilic block (A) and a hydrophobic block (B), and an osmolality adjusting agent.
[2] The composition as defined in claim 1, wherein the taxane-containing amphiphilic block copolymer micelle composition comprises Q 1-30 wt% of taxane, 20-98 wt% of an amphiphilic block copolymer containing a hydrophilic block and a hydrophobic block, and Q 1-30 wt% of an osmolality adjusting agent, based on the total dry weight of the composition.
[3] The composition as defined in claim 1, wherein the amphiphilic block copolymer containing a hydrophilic block (A) and a hydrophobic block (B) is an A-B, A- B-A or B-A-B type block copolymer.
[4] The composition as defined in claim 1, wherein the taxane is paclitaxel, docetaxel, 7-epipaclitaxel, t- acetyl paclitaxel, 10-desacetyl-paclitaxel, lO-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, lO-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel or a mixture thereof.
[5] The composition as defined in claim 1, wherein the hydrophilic block (A) has a weight average molecular weight of 300-20,000 daltons, and the hydrophobic block (B) has a weight average molecular weight of 500-20,000 daltons.
[6] The composition as defined in claim 1, wherein the hydrophilic block (A) is polyethylene glycol or monomethoxypolyethylene glycol, and the hydrophobic block (B) is polylactic acid(PLA) or a copolymer of polylactic acid and gly colic acid(PLGA).
[7] The composition as defined in claim 1, wherein the osmolality adjusting agent is an inorganic salt.
[8] The composition as defined in claim 7, wherein the inorganic salt is one or more selected from the group consisting of sodium chloride, calcium chloride, sodium sulfate and magnesium chloride.
[9] The composition as defined in claim 1, wherein the amphiphilic block copolymer micelle composition is a lyophilized composition further comprising a lyophilization aid.
[10] The composition as defined in claim 9, wherein the lyophilized composition is characterized that at least 95% of taxane is stable for 12 houis without pre-
cipitation, when the composition is reconstituted with distilled water for injection, 09% physiological saline and 5% aqueous dextrose solution. [11] The composition as defined in claim 9, wherein the lyophilization aid is used in an amount of 1-90 wt% based on the total dry weight of the lyophilized composition. [12] The composition as defined in claim 9, wherein the lyophilization aid is one or more selected from the group consisting of lactose, mannitol, sorbitol and sucrose. [13] A method for preparing a taxane-containing amphiphilic block copolymer micelle composition, comprising: dissolving taxane and an amphiphilic block copolymer into an organic solvent to provide a polymer solution; and adding an aqueous solution containing an osmolality adjusting agent to the polymer solution to form polymeric micelles. [14] The method as defined in claim 13, further comprising, after adding an aqueous solution containing an osmolality adjusting agent to the polymer solution to form polymeric micelles: adding a lyophilization aid to the polymeric micelles; and carrying out lyophilization. [15] The method as defined in claim 13, wherein the organic solvent is one or more selected from the group consisting of acetone, ethanol, methanol, ethyl acetate, acetonitrile, methylene chloride, chloroform, acetic acid and dioxane. [16] The method as defined in claim 13, wherein the organic solvent is used in an amount of Q5-30 wt% based on the weight of the micelle composition. [17] The method as defined in claim 13, wherein the aqueous solution has an osmolality of 30-15,000 mOsm/kg. [18] The method as defined in claim 13, wherein the osmolality adjusting agent is one or more selected from the group consisting of sodium chloride, calcium chloride, sodium sulfate and magnesium chloride.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2709993A CA2709993C (en) | 2007-12-31 | 2008-10-13 | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same |
| JP2010540552A JP2011509322A (en) | 2007-12-31 | 2008-10-13 | Taxane-containing amphiphilic block copolymer micelle composition and production method thereof |
| US12/810,473 US20100286075A1 (en) | 2007-12-31 | 2008-10-13 | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same |
| AU2008344184A AU2008344184B2 (en) | 2007-12-31 | 2008-10-13 | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same |
| CN200880123622.6A CN101910274B (en) | 2007-12-31 | 2008-10-13 | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same |
| BRPI0821616A BRPI0821616B8 (en) | 2007-12-31 | 2008-10-13 | micellar composition of amphiphilic block copolymer containing taxane and method for preparing the same |
| US13/960,177 US9801818B2 (en) | 2007-12-31 | 2013-08-06 | Method for stabilizing amphiphilic block copolymer micelle composition containing poorly water-soluble drug |
| US14/717,641 US9795562B2 (en) | 2007-12-31 | 2015-05-20 | Method for stabilizing amphiphilic block copolymer micelle composition containing poorly water-soluble drug |
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| KR20070141181 | 2007-12-31 | ||
| KR10-2007-0141181 | 2007-12-31 | ||
| KR10-2008-0098521 | 2008-10-08 | ||
| KR1020080098521A KR101024742B1 (en) | 2007-12-31 | 2008-10-08 | Amphiphilic Block Copolymer Micelle Composition Containing Taxane and Manufacturing Process of The Same |
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| US12/810,473 A-371-Of-International US20100286075A1 (en) | 2007-12-31 | 2008-10-13 | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same |
| US13/960,177 Continuation-In-Part US9801818B2 (en) | 2007-12-31 | 2013-08-06 | Method for stabilizing amphiphilic block copolymer micelle composition containing poorly water-soluble drug |
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