TWI458501B - Dopc之穩定結晶改質物 - Google Patents
Dopc之穩定結晶改質物 Download PDFInfo
- Publication number
- TWI458501B TWI458501B TW098118813A TW98118813A TWI458501B TW I458501 B TWI458501 B TW I458501B TW 098118813 A TW098118813 A TW 098118813A TW 98118813 A TW98118813 A TW 98118813A TW I458501 B TWI458501 B TW I458501B
- Authority
- TW
- Taiwan
- Prior art keywords
- dopc
- crystalline
- aprotic solvent
- acetate
- group
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title description 20
- 238000012986 modification Methods 0.000 title description 12
- 230000004048 modification Effects 0.000 title description 12
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 84
- 238000000034 method Methods 0.000 claims description 19
- 150000002632 lipids Chemical class 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 238000002844 melting Methods 0.000 claims description 11
- 230000008018 melting Effects 0.000 claims description 11
- 238000001228 spectrum Methods 0.000 claims description 11
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- 239000002502 liposome Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002105 nanoparticle Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000000824 cytostatic agent Substances 0.000 claims description 3
- 239000004530 micro-emulsion Substances 0.000 claims description 3
- 239000002773 nucleotide Substances 0.000 claims description 3
- 125000003729 nucleotide group Chemical group 0.000 claims description 3
- 229960005486 vaccine Drugs 0.000 claims description 3
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 230000001085 cytostatic effect Effects 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical group 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 230000004913 activation Effects 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 7
- -1 for example Chemical class 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000003607 modifier Substances 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000002178 crystalline material Substances 0.000 description 3
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- RBPWQIKZHBYIEY-PXCYNBOKSA-N [(2r)-2,3-bis[(z)-octadec-9-enoxy]propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC RBPWQIKZHBYIEY-PXCYNBOKSA-N 0.000 description 2
- 239000013590 bulk material Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002518 glial effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethyl hydrogen phosphate Chemical compound C[N+](C)(C)CCOP(O)([O-])=O YHHSONZFOIEMCP-UHFFFAOYSA-N 0.000 description 1
- MRNWDGJVCQLVOX-UHFFFAOYSA-N 4,4,4-triphenylbutane-1,2,3-triol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(O)C(O)CO)C1=CC=CC=C1 MRNWDGJVCQLVOX-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
- C07F9/103—Extraction or purification by physical or chemical treatment of natural phosphatides; Preparation of compositions containing phosphatides of unknown structure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
- C30B29/54—Organic compounds
- C30B29/58—Macromolecular compounds
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/08—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by cooling of the solution
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Epidemiology (AREA)
- Metallurgy (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Description
本發明係關於DOPC之結晶改質物,其製備方法及其用於製備醫藥組合物之用途。
以上及以下DOPC表示自然生成的1,2-二油醯基-sn-甘油基-3-磷酸膽鹼,以及1,2-二油醯基-sn-甘油基-3-磷脂醯膽鹼,1,2-二油醯基-sn-甘油基-3-磷醯膽鹼,(R)-2,3-雙(油醯氧基)丙基-2-(三甲銨基)乙基磷酸鹽,1,2-二油醯基-L-α-卵磷脂,或(R)-DOPC,其非自然生成的對映結構體,2,3-二油醯基-sn-甘油基-1-磷酸膽鹼,外消旋(R,S)-DOPC,及上述對映結構體的其他混合物。
CAS號:4235-95-4(R態)及84366-67-6(S態)
脂質體係包含兩性物質之合成的多層囊泡(球狀封閉薄膜),通常為天然脂質,其中親水物質可囊封入含水內部且親脂性物質亦可併入脂質薄膜內部。
具體而言,該等可在化妝品及藥品中,尤其在皮膚醫學中使用。尤其,其中嵌入有維生素、輔酶、護膚劑及遮光劑。通常局部應用脂質體。
但,脂質體在製藥技術中越來越重要,因為脂質體的非經腸胃給藥比以自由溶解形式使用活性化合物更能實現更特異的器官分佈。
因此,US 2006/0067998 A1揭示了一種方法,其中投與包含薑黃素或薑黃素衍生物作為活性物質的膠質狀包囊調配物用於治療或預防癌症疾病。合適的調配物包含基於脂質的膠質系統及聚合膠質系統,諸如,例如,脂質體、奈米顆粒、微粒或由嵌段聚合物形成的共聚物微胞。
如果包含入DNA、RNA或蛋白質,則可得到脂質複合體(lipoplexes)。
奈米顆粒(奈米部分)係與脂質體大約相同大小的顆粒,但其不含水相,而係在其等內部為油相或實心。其等特別適用於親脂物質的囊封。
微乳劑係膠質分散的單相系統,其包含水性、類脂質及類界面活性劑的組分。其等具有1-500nm的顆粒大小且行為方式與液體相似。
上述應用中之溶解作用非常重要,尤其與一般為低溶解性的類胜肽活性化合物、核苷酸、疫苗及其他生物製藥有關時尤其重要。
此外,可減緩該等活性化合物在體內之降解且以此方式可實現持續釋放的效果。
(R)-DOPC係屬於自然生成的兩性離子磷酸膽鹼之類。含兩性離子脂質之脂質體單獨或與其它磷酸膽鹼或其他不帶電的類脂質化合物結合而具有中性表面。
但,DOPC為主之脂質體及脂質複合體滲透細胞且以此將包含於其內的活性化合物運送至細胞內部(轉染)的能力特別重要。該等脂質體經常包含帶電脂質,特別係陽離子脂質。但,其中僅由DOPC組成之脂質複合體的應用亦已由例如在美國國家癌症研究所期刊(Journal of the National Cancer Institute)(2008),100,359-372中由Sood等人出版。
所有該等性質亦使DOPC用於癌症治療極受矚目。由於該等性質,其提供投與RNA、DNA或包含於DOPC脂質體中之習知細胞抑制劑的可能性。
醫藥,尤其是非經腸胃的應用對活性化合物的品質與純度及使用的助劑具有極高的要求。因此,就有關方面而言,關於該等化合物之製備、製備再現性及副產品基本信息有非常嚴格的規定。在非經腸胃投與物質的情況下,另外需要嚴格避免及控制由致病微生物及內毒素引起的微生物雜質。
DOPC在室溫下不穩定且因此本身難以製備成可接受的純度,因此其適用於製備醫藥調配物。
與所有載有油酸基團的脂質例如天然磷脂POPC及DOPE一樣,DOPC非常易氧化。但,該等不飽和脂肪酸衍生物的氧化產物通常具有高毒性。
本文中要求合適的製備及提純方法。DOPC係例如呈冷凍乾產物或蠟狀固體形式且因此產業上以極大困難度才能得到適當的品質。
克服不穩定性的習知方法,諸如,例如,添加生育酚或還原型L-谷胱甘肽形式的抗氧化劑,極大地限制DOPC的總體可用性,因為不能排除隨後欲包埋的活性化合物的相互作用。在製備、儲藏及使用期間完全排除氧氣實際係不可能的或僅可藉由極大地努力而實現。
因此,製造商通常建議於-20℃下在保護性氣體中儲藏凍乾的DOPC且僅保證約12個月的保存期。儘管對蠟狀DOPC保證較長的保存期,但仍需要加入抗氧化劑,且同樣必須在-20℃下儲藏。
凍乾的及蠟狀DOPC均具有非常高的無定形含量。
除了其易氧化性,該無定形DOPC亦係極易吸濕且在正常大氣濕度水準下在極短的時間內潮解,生成油膜。另,極難以將蠟狀DOPC粉碎且,與凍乾的DOPC一樣,極難以稱量。此使該化合物之處理更加困難。
文獻僅揭示製備無定形DOPC之各種合成途徑:Ichihara等人之Chemistry and Physics of Lipids(2005),137(1-2),94-99,概述由sn-甘油基-3-磷酸膽鹼(GPC)合成DOPC。
Roodsari等人之Journal of Organic Chemistry(1999),64(21),7727-7737,描述自三苯甲基甘油開始DOPC之總合成。
許多關於DOPC合成及用途的其他出版物已出現,但均未描述結晶材料。
Lewis等人之Biochemistry(1988),27(3),880-7及Biochemistry(1989),28(2),541-8已報導凍乾的DOPC。
Baer與Kindler於Biochemistry(1962),1(3),518-21中提出蠟狀DOPC。
Lekim、Biedermann及Ghyczy之DE2647395,概括地描述藉由結晶作用純化GPC酯,但未詳細描述DOPC的結晶作用。
外消旋DOPC可由外消旋起始物質以類似於對映結構體製程之方式獲得。
另,諸多出版物完全未給出DOPC之熔點。
本發明之目的因此係提供一種高純度DOPC,如果可能,提供呈結晶形式之高純度DOPC。本發明之進一步目的係對該化合物提供長的保存期及良好的處理性質,以使其可用於製備醫藥調配物製劑。此外,對用於製備穩定形式DOPC之可以產業規模實施之可再現製程有強烈需求。
令人驚訝地,經由實驗已發現具有高化學純度及極佳穩定性之外消旋及對映結構的純結晶DOPC均可以簡單的方法得到。以此方法得到的該等結晶產品在室溫下及在保護性氣體中實際上可無限時間地穩定。
結晶DOPC亦製造為具有改良收濕性的易處理鬆散材料。
其因此適合作為製備醫藥形式的成分或起始材料。
本發明據此係關於DOPC對映結構體之穩定結晶改質物及具有相同結晶形式之該等對映結構體的混合物。
該等穩定結晶改質物可係以結晶及部分結晶形式。在40℃及75%相對大氣濕度下隔絕空氣儲藏12個月後及在25℃及60%相對大氣濕度下儲藏18個月後(未添加抗氧化劑,此態樣參見表1),基於初始值,該等具有之前從未達到的純度>98%及之前從未達到的穩定性>99%。該等DOPC結晶改質物具有每當量DOPC小於1當量水或結晶溶劑含量。
對映異構上純的DOPC係例如類型1結晶改質物且在X射線粉末繞射測量中呈現中間窄光譜帶(此態樣參見圖1及表2)。各種結晶改質物之選定的2θ值係3.6、5.3、18.3、19.3及21.7(類型1),其等用Cu Kα射線測量。源自該等值之各自光譜帶可發生細微差別,倘若選擇不同的儀器或記錄方法,諸如反射或投射,或毛細狀或窗口狀,或倘若關於大氣濕度或溫度之不同記錄條件起重要作用。
該等結晶改質物之某些具有非常高之結晶含量,其熔化焓明顯大於48J/g。該等結晶改質物之熔點通常係高於60℃(圖9)。
另,根據本發明之結晶改質物係製造為易處理的鬆散材料(圖4)。在偏振顯微鏡下結晶特徵變得清楚(圖6)。
結晶DOPC對映異構體之混合物,諸如,例如,外消旋結晶亦可具有相同的XRD光譜。
本發明進一步關於製備DOPC結晶改質物之方法,其特徵為DOPC由非質子介質而結晶。可用於此目的之非質子介質係非質子溶劑或其混合物。該非質子介質亦可包含小比例的質子溶劑,諸如,例如,水。在特別情況下,在合適條件下亦可存在有25重量%質子溶劑。本文中可直接自反應溶液實施DOPC之結晶過程,無需事先純化。結晶DOPC同樣可由無定形的、部分結晶或結晶材料之再結晶而得到。
具體而言,合適的非質子溶劑係,酯類,諸如,例如,四氫呋喃、甲基四氫呋喃及二噁烷,酯類,諸如,例如,甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸異丙酯、乙酸丁酯、乙酸異丁酯、碳酸二甲酯、碳酸二乙酯及1,3-二氧雜環戊-2-酮,酮類,諸如,例如,丙酮、2-丁酮、甲基異丁基酮、甲基異丙基酮,及腈,諸如,例如,乙腈。
質子溶劑添加物通常由下列所組成:醇類,例如,甲醇、乙醇、正丙醇、異丙醇、正丁醇、異丁醇、2-丁醇、第三丁醇、3-甲基-1-丁醇,乙二醇、甲氧乙醇、乙氧乙醇,水或其混合物。
通常尤其藉由將已製備溶液緩慢冷卻至低於30℃之溫度實施DOPC改質物的結晶。該結晶自發形成或經由接種相對應的DOPC結晶改質物而形成。
各種DOPC結晶改質物可轉變成另一者。可藉由在升溫下溫度處理單離的該等結晶改質物或藉由在結晶條件下長時間攪拌該等之懸浮液實現該等轉變。
使用無定形或部分結晶之DOPC作為所述製程中之再結晶的起始材料基本上可獲得具有先前從未達到之純度及先前從未達到之穩定性的結晶DOPC。
本發明亦關於結晶DOPC用於製備醫藥調配物之用途,因為結晶DOPC之固體形式在既定條件下具有極佳穩定性且在實際無限制的時間內具有恆定且非常良好的品質。
本發明因此亦進一步關於由使用所請DOPC形式而得之醫藥組合物。其等可呈例如脂質體、脂質複合體、微乳劑及奈米顆粒形式,且包含例如選自胜肽、核苷酸、疫苗及細胞抑制劑之群的活性化合物。
本說明書可使熟習此項技術者在全部範圍內使用本發明。因此推測即使無進一步建議,熟習此項技術者亦可在最廣範圍內利用上述描述。本描述因此使熟習此項技術者可在全部範圍內使用及實施本發明。
在有任何不清楚的情況下,自然應利用所引用的出版物及專利文獻。因此,將該等文件視為本描述之部分揭示內容。
為更好理解及闡明本發明,給出以下在本發明保護範圍之內的實例。該等實例亦用於闡明可能的變體。但,由於所描述的發明原理之總體有效性,該等實例不適用於將本發明之保護範圍減小至僅限於該等。
在實例及描述及在申請專利範圍中給出的溫度始終為℃。除非另有指示,否則含量數據係以重量%表示。
進而不待言,對熟習此項技術者而言在給出的實例及其餘的描述中,組合物中存在的組分量通常只加到基於組合物整體為100重量%或100莫耳%,且不可超過此,即使可由所指示的百分數範圍產生更大值。除非另有指示,否則%數據係重量%,但比例除外,其係以體積數據表示。
200g無定形(R)-DOPC在25℃下溶解於1700ml乙腈中。以0.1℃/min將該溶液冷卻至-10℃。於10℃開始結晶。當結晶完成時,藉由過濾分離該產品且在真空中乾燥。結晶(R)-DOPC之產量係180g(90%)。
以相同的方法可得到結晶改質物(R,S)-及(S)-DOPC。
20.0g DOPC在35℃下溶解於100ml乙酸乙酯中。迅速冷卻該溶液至20℃且然後以0.01℃/min之速率冷卻至-10℃,其間開始結晶。過濾該結晶物且在室溫下於真空中乾燥。產量係19.6g結晶DOPC(理論之98.1%)。在5℃/min之加熱速率下,該產品呈現71℃之熔點及49.4J/g之熔化焓。
為測定結晶DOPC之穩定性,在25℃及60%相對濕度下及在40℃及75%相對濕度下,排除空氣,將該等物質與比較樣品一起儲藏。定期測量DOPC殘留量並以與初始值相比較加以表示。
藉由HPLC測量DOPC純度及含量。
對於類型1結晶改質物,發現下列值:
為瞭解DOPC結晶改質物之特徵,記錄該等物質之X射線粉末繞射圖型(XRD繞射光譜)。為了比較目的,亦記錄凍乾的及蠟狀DOPC變體之X射線粉末繞射圖型(XRD繞射光譜)。
對於類型1的DOPC結晶改質物,得到脂質的具有中間窄光譜帶的相對高分辨率光譜。該光譜顯示高結晶含量。在偏振顯微鏡下未看見無定形組分。
圖1(類型1)中可見一說明性光譜。為比較,在類似條件下同樣記錄自商業上獲得的無定形樣品之光譜且如圖2(凍乾的)及圖3(蠟狀的)所示。
表2列舉類型1的DOPC結晶改質物之選定2θ值:
類型1的DOPC結晶改質物係作為粒狀鬆散材料(圖4)而生產,而市售DOPC樣品係作為凍乾產物或蠟塊(圖5)而得到。
在偏振顯微鏡下,類型1的DOPC結晶改質物明顯證明為結晶材料(圖6),而凍乾的及蠟狀比較材料(圖8)顯現為無定形。
差示掃描量熱法(DSC)測量同樣顯示類型1的DOPC結晶改質物(圖9)與凍乾的(圖10)及蠟狀比較材料(圖11)之間的明顯差別。
圖1顯示類型1的DOPC之XRD光譜。
圖2顯示凍乾DOPC之XRD光譜。
圖3顯示蠟狀DOPC之XRD光譜。
圖4顯示類型1的DOPC結晶。
圖5顯示蠟狀DOPC。
圖6顯示偏振顯微鏡下之類型1的DOPC結晶。
圖7顯示偏振顯微鏡下之凍乾DOPC。
圖8顯示偏振顯微鏡下之蠟狀DOPC。
圖9顯示類型1的DOPC之熔化行為。
圖10顯示凍乾DOPC之熔化行為。
圖11顯示蠟狀DOPC之熔化行為。
(無元件符號說明)
Claims (23)
- 一種結晶性DOPC,其具有2θ值3.6、5.3、7.1、8.8、11.0、12.3、15.3、17.6、18.3、19.3、20.4、21.1、21.7、22.8及26.4中之5個值。
- 如請求項1之結晶性DOPC,其係結晶性(R)-DOPC或結晶性(S)-DOPC。
- 如請求項1之結晶性DOPC,其係結晶性(R)-DOPC及結晶性(S)-DOPC之混合物。
- 如請求項1之結晶性DOPC,其係結晶性(R)-DOPC。
- 如請求項1至4中任一項之結晶性DOPC,其具有2θ值3.6、5.3、18.3、19.3及21.7。
- 如請求項5之結晶性DOPC,其具有2θ值3.6、5.3、7.1、12.3、17.6、18.3、19.3、21.1、21.7及22.8。
- 如請求項6之結晶性DOPC,其具有根據圖1之光譜。
- 如請求項1至4中任一項之結晶性DOPC,其具有高於60℃之熔點及大於48J/g之熔化焓。
- 一種製備如請求項1至8中任一項之結晶性DOPC之方法,其特徵為DOPC之結晶作用係在一或多種非質子溶劑中實施。
- 如請求項9之方法,其特徵為所使用之非質子溶劑係醚。
- 如請求項10之方法,其特徵為所使用之非質子溶劑係四氫呋喃、甲基四氫呋喃或二噁烷。
- 如請求項9之方法,其特徵為所使用之非質子溶劑係 酮。
- 如請求項12之方法,其特徵為所使用之非質子溶劑係丙酮、2-丁酮、甲基異丁基酮或甲基異丙基酮。
- 如請求項9之方法,其特徵為所使用之非質子溶劑係腈。
- 如請求項14之方法,其特徵為所使用之非質子溶劑係乙腈。
- 如請求項9之方法,其特徵為所使用之非質子溶劑係選自甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸異丙酯、乙酸丁酯、乙酸異丁酯、碳酸二甲酯、碳酸二乙酯及1,3-二氧雜環戊-2-酮或其混合物之群的酯。
- 如請求項10至16中任一項之方法,其特徵為使用與選自甲醇、乙醇、正丙醇、異丙醇、正丁醇、異丁醇、2-丁醇、第三丁醇、3-甲基-1-丁醇、乙二醇、甲氧乙醇、乙氧乙醇或其混合物之群之醇混合的非質子介質。
- 如請求項9之方法,其特徵為直接自反應溶液實施該結晶作用,而未經事先純化。
- 如請求項9之方法,其特徵為實施無定形或結晶性(R,S)-、(R)-或(S)-DOPC之再結晶。
- 一種如請求項1至8中任一項之結晶性DOPC之用途,其係單獨或視需要與其他脂質混合而作為用於製備藥品之成分。
- 一種醫藥組合物,其包含單獨的如請求項1至8中任一項之結晶性DOPC或其混合物,或視需要連同醫藥活性化 合物、助劑或溶劑。
- 如請求項21之醫藥組合物,其特徵為所使用的醫藥活性化合物係選自胜肽、核苷酸、疫苗及細胞抑制劑之群的活性化合物。
- 如請求項21之醫藥組合物,其特徵為其包含脂質體、脂質複合體、奈米顆粒或微乳劑。
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CL2009001370A1 (es) | 2010-06-25 |
JP2011523951A (ja) | 2011-08-25 |
TW201012485A (en) | 2010-04-01 |
DK2280691T3 (da) | 2022-10-31 |
CA2726871C (en) | 2016-10-11 |
NZ590274A (en) | 2012-07-27 |
EP2280691A1 (de) | 2011-02-09 |
EP2280691B1 (de) | 2022-08-03 |
AU2009254310B2 (en) | 2014-05-22 |
RU2543046C2 (ru) | 2015-02-27 |
WO2009146779A1 (de) | 2009-12-10 |
BRPI0913347A2 (pt) | 2015-11-24 |
IL209476A (en) | 2016-08-31 |
JP2015013867A (ja) | 2015-01-22 |
JP5972323B2 (ja) | 2016-08-17 |
ES2933098T3 (es) | 2023-02-01 |
IL209476A0 (en) | 2011-01-31 |
KR20160047597A (ko) | 2016-05-02 |
PT2280691T (pt) | 2022-10-28 |
AU2009254310A1 (en) | 2009-12-10 |
CA2726871A1 (en) | 2009-12-10 |
CN102056592B (zh) | 2013-03-27 |
RU2010154508A (ru) | 2012-07-20 |
US20110086091A1 (en) | 2011-04-14 |
KR20110022660A (ko) | 2011-03-07 |
US8513446B2 (en) | 2013-08-20 |
KR101820967B1 (ko) | 2018-01-22 |
BRPI0913347B1 (pt) | 2023-11-21 |
CN102056592A (zh) | 2011-05-11 |
MX2010013246A (es) | 2010-12-21 |
ZA201100141B (en) | 2011-10-26 |
JP5947541B2 (ja) | 2016-07-06 |
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