JP7387330B2 - Bortezomib storage container - Google Patents
Bortezomib storage container Download PDFInfo
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- JP7387330B2 JP7387330B2 JP2019147507A JP2019147507A JP7387330B2 JP 7387330 B2 JP7387330 B2 JP 7387330B2 JP 2019147507 A JP2019147507 A JP 2019147507A JP 2019147507 A JP2019147507 A JP 2019147507A JP 7387330 B2 JP7387330 B2 JP 7387330B2
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- bortezomib
- container
- ultraviolet absorbing
- absorbing film
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims description 52
- 229960001467 bortezomib Drugs 0.000 title claims description 50
- 238000002834 transmittance Methods 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 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 13
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 7
- 239000012931 lyophilized formulation Substances 0.000 claims description 6
- 239000006097 ultraviolet radiation absorber Substances 0.000 claims description 5
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012964 benzotriazole Substances 0.000 claims description 4
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 15
- -1 mannitol ester Chemical class 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 229920006300 shrink film Polymers 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000006096 absorbing agent Substances 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012790 adhesive layer Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005229 chemical vapour deposition Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000001782 photodegradation Methods 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000004447 silicone coating Substances 0.000 description 2
- 229920002545 silicone oil Polymers 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000011146 sterile filtration Methods 0.000 description 2
- 229940099039 velcade Drugs 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920006257 Heat-shrinkable film Polymers 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009876 antimalignant effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000005620 boronic acid group Chemical group 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- NJPPVKZQTLUDBO-UHFFFAOYSA-N novaluron Chemical compound C1=C(Cl)C(OC(F)(F)C(OC(F)(F)F)F)=CC=C1NC(=O)NC(=O)C1=C(F)C=CC=C1F NJPPVKZQTLUDBO-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000176 photostabilization Effects 0.000 description 1
- 238000000623 plasma-assisted chemical vapour deposition Methods 0.000 description 1
- 229920003216 poly(methylphenylsiloxane) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 229920000306 polymethylpentene Polymers 0.000 description 1
- 239000011116 polymethylpentene Substances 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000007740 vapor deposition Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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- Packages (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ボルテゾミブを含有する凍結乾燥製剤を保存するための容器に関する。 The present invention relates to containers for storing lyophilized formulations containing bortezomib.
ボルテゾミブ(一般名)は、下記式:
特許文献2には、ボルテゾミブをマンニトールと共に凍結乾燥することで凍結乾燥した化合物を製造する方法、同製造方法で得られる組成物、および同製造方法で得られるボルテゾミブのマンニトールエステルが記載されている。アルキルボロン酸はアルコール共存下、エステルとの平衡状態を取り、水が少なくなればエステルになり、水が多くなるとエステルが加水分解されてアルキルボロン酸がフリー化されるとの性質を有している。特許文献2の発明はこの性質を利用したものであり、市販のベルケイド(登録商標)凍結乾燥製剤に応用されている。 Patent Document 2 describes a method for producing a freeze-dried compound by freeze-drying bortezomib together with mannitol, a composition obtained by the production method, and a mannitol ester of bortezomib obtained by the production method. In the coexistence of alcohol, alkylboronic acids maintain an equilibrium state with esters, and when water decreases, they become esters, and when water increases, the esters are hydrolyzed and the alkylboronic acids are freed. There is. The invention of Patent Document 2 utilizes this property and is applied to a commercially available Velcade (registered trademark) freeze-dried preparation.
ボルテゾミブは光によって分解することが知られているが、光安定性についての詳細な知見は少ないことが現状である。従来、ボルテゾミブを含有する凍結乾燥製剤は、透明なガラス容器(例えば、バイアル)に充填されているが、光によるボルテゾミブの分解防止のため、さらに紙製の個包装箱に入れて遮光保存される必要があった。 Although bortezomib is known to be degraded by light, there is currently little detailed knowledge about its photostability. Conventionally, lyophilized preparations containing bortezomib are packed in transparent glass containers (e.g. vials), but to prevent bortezomib from being degraded by light, they are further stored in individual paper packaging boxes to protect them from light. There was a need.
本発明は、ボルテゾミブを含有する凍結乾燥製剤を保存するための容器であって、ボルテゾミブの光分解を抑制できる容器を提供することを目的とする。 An object of the present invention is to provide a container for storing a lyophilized preparation containing bortezomib, which can suppress photodegradation of bortezomib.
本発明者らは、鋭意検討を行った結果、特定の紫外線領域の光線が、ボルテゾミブの分解を促進することを見出した。そこで、所望の紫外線吸収性を有するフィルムで容器を包装することにより、上記課題を解決できることを見出し、本発明を完成させた。 As a result of extensive research, the present inventors found that light in a specific ultraviolet region promotes the decomposition of bortezomib. Therefore, the inventors have discovered that the above-mentioned problems can be solved by wrapping the container with a film having desired ultraviolet absorbing properties, and have completed the present invention.
すなわち、本発明は、
〔1〕ボルテゾミブを含有する凍結乾燥製剤が充填され、200~360nmの波長の光透過率が10%以下の紫外線吸収性フィルムで包装された容器、
〔2〕前記紫外線吸収性フィルムにおいて、420~700nmの波長の光透過率が70%以上である、〔1〕記載の容器、
〔3〕前記紫外線吸収性フィルムの波長380nmにおける光透過率に対する波長420nmにおける光透過率の比率が5.0以上である、〔1〕または〔2〕記載の容器、
〔4〕前記紫外線吸収性フィルムにおいて、320~360nmの波長の光透過率が5%以下である、〔1〕~〔3〕のいずれかに記載の容器、
〔5〕前記紫外線吸収性フィルムが、ベンゾトリアゾール系紫外線吸収剤またはトリアジン系紫外線吸収剤を含有または塗工した紫外線吸収性フィルムである、〔1〕~〔4〕のいずれかに記載の容器、
〔6〕前記凍結乾燥製剤が、ボルテゾミブとD-マンニトールとの凍結乾燥製剤である、〔1〕~〔5〕のいずれかに記載の容器、
〔7〕ボルテゾミブを含有する溶液を容器に充填し凍結乾燥する工程、および前記容器を200~360nmの波長の光透過率が10%以下である紫外線吸収性フィルムで包装する工程を含む、ボルテゾミブの光安定化方法、に関する。
That is, the present invention
[1] A container filled with a freeze-dried preparation containing bortezomib and packaged with an ultraviolet absorbing film with a light transmittance of 10% or less in the wavelength range of 200 to 360 nm;
[2] The container according to [1], wherein the ultraviolet absorbing film has a light transmittance of 70% or more at a wavelength of 420 to 700 nm;
[3] The container according to [1] or [2], wherein the ratio of the light transmittance at a wavelength of 420 nm to the light transmittance at a wavelength of 380 nm of the ultraviolet absorbing film is 5.0 or more;
[4] The container according to any one of [1] to [3], wherein the ultraviolet absorbing film has a light transmittance of 5% or less at a wavelength of 320 to 360 nm;
[5] The container according to any one of [1] to [4], wherein the ultraviolet absorbing film is an ultraviolet absorbing film containing or coated with a benzotriazole-based ultraviolet absorber or a triazine-based ultraviolet absorber,
[6] The container according to any one of [1] to [5], wherein the lyophilized preparation is a lyophilized preparation of bortezomib and D-mannitol;
[7] A method for producing bortezomib, which comprises a step of filling a container with a solution containing bortezomib and freeze-drying it, and a step of packaging the container with an ultraviolet absorbing film having a light transmittance of 10% or less in the wavelength range of 200 to 360 nm. Relating to a photostabilization method.
本発明の容器の使用により、ボルテゾミブの分解を促進する有害な波長領域の光線が遮断される(すなわち、ボルテゾミブの光分解を抑制できる)ので、当該容器内に充填されたボルテゾミブを含有する凍結乾燥製剤を長期間安定に保存することができる。 By using the container of the present invention, the harmful wavelength range of light that promotes the degradation of bortezomib is blocked (i.e., the photodegradation of bortezomib can be suppressed), so the lyophilization containing bortezomib filled in the container is The formulation can be stored stably for a long period of time.
また、好ましい態様においては、容器の外側から内容物を視認することができ、この容器内でボルテゾミブを含有する凍結乾燥製剤を生理食塩水に溶かして患者に投与する前の溶解状態の確認や異物混入等の検査が容易である。さらに、集積体単位の遮光処理と異なり、容器をひとつずつ紫外線吸収性フィルムで包装しているので、カートンから取り出して照明器具からの光が当たる場所に放置されても、光による影響を受けない。 In addition, in a preferred embodiment, the contents can be visually checked from the outside of the container, and the lyophilized preparation containing bortezomib can be dissolved in physiological saline to confirm the dissolution state before administering to the patient. Easy to inspect for contamination, etc. Furthermore, unlike light-shielding treatment for individual aggregates, each container is individually wrapped in UV-absorbing film, so even if it is taken out of the carton and left in a place exposed to light from lighting equipment, it will not be affected by light. .
本発明の一実施形態であるボルテゾミブ保存用容器の作製手順について、以下に詳細に説明する。但し、以下の記載は本発明を説明するための例示であり、本発明の技術的範囲をこの記載範囲にのみ限定する趣旨ではない。なお、本明細書において、「~」を用いて数値範囲を示す場合、その両端の数値を含むものとする。 A procedure for producing a container for storing bortezomib, which is an embodiment of the present invention, will be described in detail below. However, the following description is an illustration for explaining the present invention, and is not intended to limit the technical scope of the present invention only to this described range. Note that in this specification, when a numerical range is indicated using "~", the numerical values at both ends thereof are included.
(ボルテゾミブを含有する凍結乾燥製剤)
本実施形態に係るボルテゾミブを含有する凍結乾燥製剤は、例えば以下の方法で製造することができる。
(lyophilized formulation containing bortezomib)
The lyophilized preparation containing bortezomib according to the present embodiment can be produced, for example, by the following method.
ボルテゾミブ、および必要に応じて薬学上許容される添加剤を、水または水と有機溶媒との混合溶媒に加えて溶解させる。ボルテゾミブと薬学上許容される添加剤とを分けてそれぞれ溶媒に溶解させ、その後混合することもできる。得られた溶液の容量を水で一定量に調整した後、滅菌ろ過をして、一定量のボルテゾミブとなるように容器に充填して、凍結乾燥を行うことで、本実施形態に係るボルテゾミブを含有する凍結乾燥製剤を得る。 Bortezomib and, if necessary, a pharmaceutically acceptable additive are added to and dissolved in water or a mixed solvent of water and an organic solvent. Bortezomib and a pharmaceutically acceptable excipient can also be separately dissolved in a solvent and then mixed. After adjusting the volume of the obtained solution to a certain amount with water, it is sterilized and filtered, filled into a container so that a certain amount of bortezomib is obtained, and freeze-dried to obtain the bortezomib according to this embodiment. Obtain a lyophilized formulation containing:
添加剤としては、例えば、マンニトール、ソルビトール、キシリトール、エリスリトール、グルコース、スクロース、フルクトース、トレハロース等が挙げられ、D-マンニトールが好ましい。D-マンニトールを添加した場合、上記の凍結乾燥製剤の製造方法により、ボルテゾミブのボロン酸部分が、D-マンニトールエステルを形成し、ボルテゾミブの熱安定性が向上する。 Examples of the additive include mannitol, sorbitol, xylitol, erythritol, glucose, sucrose, fructose, trehalose, etc., with D-mannitol being preferred. When D-mannitol is added, the boronic acid moiety of bortezomib forms a D-mannitol ester by the above-described method for producing a lyophilized preparation, and the thermal stability of bortezomib is improved.
有機溶媒としては、例えば、水と混和性があり、凍結乾燥で除去される有機溶媒が挙げられる。具体的には、メタノール、エタノール、2-プロパノール、t-ブタノール等の低級アルコール;1,4-ジオキサン、テトラヒドロフラン等のエーテル;アセトン、2-ブタノン、メチルイソブチルケトン等のケトン;アセトニトリル等が挙げられる。好ましくは低級アルコールが挙げられ、エタノール、2-プロパノール、およびt-ブタノールがより好ましく、t-ブタノールが特に好ましい。 Examples of organic solvents include organic solvents that are miscible with water and are removed by freeze-drying. Specifically, lower alcohols such as methanol, ethanol, 2-propanol, and t-butanol; ethers such as 1,4-dioxane and tetrahydrofuran; ketones such as acetone, 2-butanone, and methyl isobutyl ketone; and acetonitrile. . Preferred are lower alcohols, more preferred are ethanol, 2-propanol, and t-butanol, and particularly preferred is t-butanol.
有機溶媒の使用量は、ボルテゾミブが溶解するに十分な量であって、その後の凍結乾燥に過剰な負担をかけない程度の量であれば特に制限されないが、ボルテゾミブ3mgに対して通常0.03~3mLの範囲であり、0.05~1mLが好ましく、0.07~0.5mLがより好ましい。 The amount of organic solvent used is not particularly limited as long as it is sufficient to dissolve bortezomib and does not impose an excessive burden on the subsequent freeze-drying, but it is usually 0.03 mg per 3 mg of bortezomib. 3 mL, preferably 0.05 to 1 mL, more preferably 0.07 to 0.5 mL.
混合溶媒の組成は、混合溶媒が含水アルコールである場合、通常1~50%のアルコールを含有し、3~30%が好ましく、5~20%がより好ましい。 When the mixed solvent is a hydrous alcohol, the composition of the mixed solvent usually contains 1 to 50% alcohol, preferably 3 to 30%, and more preferably 5 to 20%.
滅菌ろ過は、無菌ろ過膜を用いて、例えば0.22ミクロンフィルターを用いて実施することができる。続いて、滅菌ろ過された溶液を一定量のボルテゾミブとなるように容器に充填して、凍結乾燥を行う。凍結乾燥は、例えば、-25℃~-50℃で凍結させて、減圧下、乾燥することができる。圧力としては、例えば、真空度3~10Pa等が挙げられる。 Sterile filtration can be performed using a sterile filtration membrane, such as a 0.22 micron filter. Subsequently, the sterilized and filtered solution is filled into a container to give a certain amount of bortezomib, and freeze-dried. Freeze-drying can be carried out, for example, by freezing at -25°C to -50°C and drying under reduced pressure. Examples of the pressure include a degree of vacuum of 3 to 10 Pa.
以下の構造式で示される不純物が、後記する光安定性試験において増加することが確認された。
光安定性試験においては、上記の不純物A、B、D、およびEの増加に注目して、凍結乾燥製剤の光安定性を評価した。本実施形態に係る紫外線吸収性フィルムを包装した容器にボルテゾミブを含有する凍結乾燥製剤を保存することにより、上記の不純物の増加を顕著に抑制することができる。 In the photostability test, the photostability of the lyophilized formulation was evaluated by focusing on the increase in impurities A, B, D, and E mentioned above. By storing the freeze-dried preparation containing bortezomib in a container packaged with the ultraviolet absorbing film according to the present embodiment, the increase in impurities described above can be significantly suppressed.
ボルテゾミブを含有する凍結乾燥製剤は、例えば多発性骨髄腫の治療に用いられる。例えば、静脈内投与するための注射液を調製する場合は、ボルテゾミブ3mgを含有する容器に、生理食塩水3.0mLを加えて溶解させて、患者に適用する。例えば、皮下投与するための注射液を調製する場合は、ボルテゾミブ3mgを含有する容器に、生理食塩水1.2mLを加えて溶解させて、患者に適用する。 Lyophilized formulations containing bortezomib are used, for example, in the treatment of multiple myeloma. For example, when preparing an injection solution for intravenous administration, 3.0 mL of physiological saline is added to a container containing 3 mg of bortezomib, dissolved, and applied to the patient. For example, when preparing an injection solution for subcutaneous administration, 1.2 mL of physiological saline is added to a container containing 3 mg of bortezomib, dissolved, and applied to the patient.
(紫外線吸収性フィルム)
本実施形態に係る紫外線吸収性フィルムは、波長360nm以下の紫外光をほとんど透過させないため、紫外線によるボルテゾミブの分解を抑制することができる。一方、波長420nm以上の可視光の透過率が高いため、内容物の状態を目視により容易に確認することができる。
(UV absorbing film)
The ultraviolet absorbing film according to the present embodiment hardly transmits ultraviolet light having a wavelength of 360 nm or less, so that decomposition of bortezomib due to ultraviolet light can be suppressed. On the other hand, since the transmittance of visible light having a wavelength of 420 nm or more is high, the state of the contents can be easily confirmed visually.
本明細書において「X~Ynmの波長の光透過率」とは、「X~Ynmの波長の全範囲における光透過率」を意味する。また、光透過率は、市販の分光光度計を用いて測定することができる。 In this specification, "light transmittance in the wavelength range of X to Y nm" means "light transmittance in the entire wavelength range of X to Y nm". Moreover, the light transmittance can be measured using a commercially available spectrophotometer.
紫外線吸収性フィルムの200~360nmの波長の光透過率は、ボルテゾミブの分解を抑制する観点から、10%以下が好ましく、5%以下がより好ましく、3%以下がさらに好ましく、2%以下が特に好ましい。 The light transmittance of the ultraviolet absorbing film at a wavelength of 200 to 360 nm is preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, particularly 2% or less, from the viewpoint of suppressing the decomposition of bortezomib. preferable.
紫外線吸収性フィルムの320~360nmの波長の光透過率は、ボルテゾミブの分解を抑制する観点から、5%以下が好ましく、3%以下がより好ましく、2%以下がさらに好ましく、1%以下が特に好ましい。 The light transmittance of the ultraviolet absorbing film at a wavelength of 320 to 360 nm is preferably 5% or less, more preferably 3% or less, even more preferably 2% or less, particularly 1% or less, from the viewpoint of suppressing the decomposition of bortezomib. preferable.
紫外線吸収性フィルムの360~380nmの波長の光透過率は、ボルテゾミブの分解を抑制する観点から、10%以下が好ましく、5%以下がより好ましく、3%以下がさらに好ましく、2%以下が特に好ましい。 The light transmittance of the ultraviolet absorbing film at a wavelength of 360 to 380 nm is preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, particularly 2% or less, from the viewpoint of suppressing the decomposition of bortezomib. preferable.
紫外線吸収性フィルムの420~700nmの波長の光透過率は、内部の視認性の観点から、70%以上が好ましく、75%以上がより好ましく、80%以上がさらに好ましく、85%以上が特に好ましい。この構成によれば、ボルテゾミブを含有する凍結乾燥製剤が充填された容器の外側から内容物を視認することが可能となるため、この容器に生理食塩水を投入して、凍結乾燥製剤の溶解状態を確認しながら、上述の注射液の調製を行うことが可能となる。 The light transmittance of the ultraviolet absorbing film at a wavelength of 420 to 700 nm is preferably 70% or more, more preferably 75% or more, even more preferably 80% or more, and particularly preferably 85% or more, from the viewpoint of internal visibility. . According to this configuration, it is possible to visually check the contents from the outside of the container filled with the lyophilized preparation containing bortezomib, so physiological saline is poured into this container and the lyophilized preparation is dissolved. It becomes possible to prepare the above-mentioned injection solution while checking the following.
紫外線の不透過性と内部の視認性とを両立させる観点から、紫外線吸収性フィルムの波長380nmにおける光透過率に対する波長420nmにおける光透過率の比率は、5.0以上が好ましく、6.0以上がより好ましく、7.0以上がさらに好ましい。 From the viewpoint of achieving both ultraviolet opacity and internal visibility, the ratio of the light transmittance at a wavelength of 420 nm to the light transmittance at a wavelength of 380 nm of the ultraviolet absorbing film is preferably 5.0 or more, and 6.0 or more. is more preferable, and 7.0 or more is even more preferable.
紫外線吸収性フィルムのヘイズ値は、透明性の観点から、40%以下が好ましく、30%以下がより好ましく、25%以下がさらに好ましい。 From the viewpoint of transparency, the haze value of the ultraviolet absorbing film is preferably 40% or less, more preferably 30% or less, and even more preferably 25% or less.
紫外線吸収性フィルムの厚みは、紫外線透過を抑制する観点から、20μm以上が好ましく、30μm以上がより好ましく、40μm以上がさらに好ましく、50μm以上が特に好ましい。一方、内部の視認性の観点からは、200μm以下が好ましく、150μm以下がより好ましく、100μm以下がさらに好ましく、80μm以下が特に好ましい。 The thickness of the ultraviolet absorbing film is preferably 20 μm or more, more preferably 30 μm or more, even more preferably 40 μm or more, particularly preferably 50 μm or more, from the viewpoint of suppressing ultraviolet light transmission. On the other hand, from the viewpoint of internal visibility, the thickness is preferably 200 μm or less, more preferably 150 μm or less, even more preferably 100 μm or less, and particularly preferably 80 μm or less.
紫外線吸収性フィルムとしては、複雑な形状をした容器に対して密着性を高く維持した状態で包装することができるシュリンクフィルム(熱収縮性フィルム)が好適に用いられるが、特に限定されない。 As the ultraviolet absorbing film, a shrink film (heat-shrinkable film) that can be used to package a container having a complicated shape while maintaining high adhesion is suitably used, but is not particularly limited.
紫外線吸収性フィルム(好ましくは紫外線吸収性シュリンクフィルム)には、紫外線吸収剤を含有または塗工することが好ましい。紫外線吸収剤としては、例えば、サリチル酸系、ベンゾフェノン系、ベンゾトリアゾール系、トリアジン系、およびシアノアクリレート系等の紫外線吸収剤が挙げられるが、360nm付近において強い紫外線吸収能を示すベンゾトリアゾール系紫外線吸収剤およびトリアジン系紫外線吸収剤が好ましい。 The ultraviolet absorbing film (preferably the ultraviolet absorbing shrink film) preferably contains or is coated with an ultraviolet absorber. Examples of UV absorbers include salicylic acid-based, benzophenone-based, benzotriazole-based, triazine-based, and cyanoacrylate-based UV absorbers, including benzotriazole-based UV absorbers that exhibit strong UV absorption ability around 360 nm. and triazine ultraviolet absorbers are preferred.
紫外線吸収性フィルム(好ましくは紫外線吸収性シュリンクフィルム)は、その片面に粘着剤層を形成することが好ましい。粘着剤層を形成する粘着剤としては、例えば、アクリル系、ロジン系、ゴム系、ビニル系等の粘着剤が挙げられるが、経時接着力変化が少なく、透明性に優れる点から、アクリル系粘着剤が好ましい。 The ultraviolet absorbing film (preferably the ultraviolet absorbing shrink film) preferably has an adhesive layer formed on one side thereof. Examples of the adhesive that forms the adhesive layer include acrylic, rosin, rubber, and vinyl adhesives, but acrylic adhesives have less change in adhesive strength over time and have excellent transparency. Agents are preferred.
粘着剤層には、遮光性物質を含有していてもよい。遮光性物質としては、紫外線遮光性および透明性の観点から、酸化チタン、酸化亜鉛等の金属酸化物が好ましく、平均粒子径が0.01~0.1μmの超微粒子金属酸化物がより好ましい。 The adhesive layer may contain a light-shielding substance. The light-shielding substance is preferably a metal oxide such as titanium oxide or zinc oxide from the viewpoint of ultraviolet light-shielding property and transparency, and more preferably an ultrafine metal oxide having an average particle diameter of 0.01 to 0.1 μm.
シュリンクフィルムとしては、カレンダ加工、Tダイ法、インフレーション法、ロール延伸法、テンター延伸法、チューブラー延伸法等により一軸または二軸延伸(同時二軸または逐次二軸延伸)されたシュリンクフィルムが好適に用いられる。 Suitable shrink films are shrink films that have been uniaxially or biaxially stretched (simultaneous biaxial or sequential biaxial stretching) by calender processing, T-die method, inflation method, roll stretching method, tenter stretching method, tubular stretching method, etc. used for.
シュリンクフィルムの基材としては、透明性に優れている樹脂が好ましく、例えば、ポリエステル(ポリエチレンテレフタレート、ポリブチレンテレフタレート等)、ポリエチレン、ポリスチレン、ポリプロピレン、塩化ビニル等が挙げられる。なかでも、透明性と熱収縮性能の観点から、ポリエステル、ポリエチレン、ポリプロピレンおよびポリスチレンが好ましい。 The base material for the shrink film is preferably a resin with excellent transparency, such as polyester (polyethylene terephthalate, polybutylene terephthalate, etc.), polyethylene, polystyrene, polypropylene, vinyl chloride, and the like. Among these, polyester, polyethylene, polypropylene, and polystyrene are preferred from the viewpoint of transparency and heat shrinkage performance.
<容器>
本実施形態に係る容器は、密封可能であり、内容物の無菌性を保つことができる容器であればどのような形態であってもよいが、一般的に注射用製剤や注射剤の充填に用いられるバイアルやアンプルが好ましい。また、凍結乾燥品用の溶解液(例えば、注射用蒸留水や生理食塩液等)と共にシリンジに充填してプレフィルドシリンジ(ダブルチャンバー型シリンジ)とすることも可能である。
<Container>
The container according to this embodiment may have any form as long as it can be sealed and maintain the sterility of the contents, but it is generally used for filling injectable preparations and injections. Vials and ampoules used are preferred. Further, it is also possible to prepare a prefilled syringe (double chamber type syringe) by filling a syringe with a solution for lyophilized products (for example, distilled water for injection, physiological saline, etc.).
容器の材質は特に限定されないが、例えば、バイアルやアンプルであればガラス材質やプラスチック材質のものが、例えば、ダブルチャンバー型シリンジであればプラスチック材質のものが好ましい。また、これらの材質を組み合わせて、例えば、内表面をプラスチック材質で被覆したガラス容器や、内表面をガラス材質で被覆したプラスチック容器も用いることができる。 The material of the container is not particularly limited, but for example, a glass or plastic material is preferable for a vial or an ampoule, and a plastic material is preferable for a double chamber syringe. Further, by combining these materials, for example, a glass container whose inner surface is coated with a plastic material or a plastic container whose inner surface is coated with a glass material can also be used.
ガラス材質は、医薬品の充填用容器に使用可能なガラス材質であれば特に限定されない。ガラス容器の内表面は、シリコンでコーティングしてもよい。シリコンのコーティングは、シリコン系コーティング剤(例えば、ジメチルシリコンオイル、メチルフェニルシリコンオイル、メチルハイドロゲンシリコンオイル等)等を用いて、かかる容器の内表面を、加熱蒸着法、プラズマ強化化学蒸着法、プラズマパルス化学蒸着法等の公知の方法で処理することにより行われる。また、ガラス容器の内表面を、二酸化ケイ素で処理することもできる。二酸化ケイ素の処理は、公知の方法、例えば、シリコート処理、波状プラズマ化学的気相法処理等の公知の方法によって行われる。 The glass material is not particularly limited as long as it can be used for containers for filling pharmaceuticals. The inner surface of the glass container may be coated with silicone. Silicone coating can be achieved by coating the inner surface of the container with a silicone coating agent (e.g., dimethyl silicone oil, methylphenyl silicone oil, methyl hydrogen silicone oil, etc.) using a heating vapor deposition method, plasma enhanced chemical vapor deposition method, or plasma deposition method. This is carried out by processing using a known method such as pulsed chemical vapor deposition. The inner surface of the glass container can also be treated with silicon dioxide. The treatment of silicon dioxide is carried out by known methods such as silicoating, wave plasma chemical vapor deposition, and the like.
プラスチック材質は、医薬品の充填用容器に使用可能なプラスチック材質であれば特に限定されず、例えば、ポリエチレン、ポリプロピレン、ポリスチレン、ポリメチルペンテン、ポリエステル、ポリアミド、ポリカーボネート、または環状オレフィン系化合物もしくは架橋多環式炭化水素化合物の重合体樹脂等を使用することができる。 The plastic material is not particularly limited as long as it can be used for containers for filling pharmaceuticals, and examples include polyethylene, polypropylene, polystyrene, polymethylpentene, polyester, polyamide, polycarbonate, or cyclic olefin compounds or crosslinked polycyclics. Polymer resins of formula hydrocarbon compounds, etc. can be used.
容器がバイアルである場合は、ガラスバイアルが好ましく、シリコンで内表面をコーティングしたガラスバイアルがより好ましい。また、破ビンを防止するため、樹脂製プロテクター等からなる台座を設置してもよい。 When the container is a vial, a glass vial is preferred, and a glass vial whose inner surface is coated with silicone is more preferred. Furthermore, in order to prevent the bottle from breaking, a pedestal made of a resin protector or the like may be installed.
容器がバイアルである場合は、前記のボルテゾミブを含有する溶液を充填し、凍結乾燥に付した後に開口部をゴム栓、所望によってアルミニウム製のキャップ等を組み合わせて密封される。 If the container is a vial, it is filled with the solution containing bortezomib, freeze-dried, and then the opening is sealed with a rubber stopper, optionally an aluminum cap, or the like.
前記紫外線吸収性シュリンクフィルムの容器への被覆は、常法により、加熱炉にシュリンクフィルムを装着した容器を通過させることにより行うことができる。 The ultraviolet absorbing shrink film can be coated on the container by a conventional method by passing the container equipped with the shrink film through a heating furnace.
本発明を実施例に基づいて説明するが、本発明は、実施例にのみ限定されるものではない。 Although the present invention will be explained based on examples, the present invention is not limited only to the examples.
[実施例1]
(凍結乾燥製剤の調製)
注射用水およびt-ブタノールの混合溶媒に、ボルテゾミブ200mg、D-マンニトール2000mgを加えて溶解し、注射用水で全量を100mLに定容した。得られた溶液を、無菌ろ過フィルターを用いてろ過し、1.5mLずつバイアルに充填した。次いで、バイアルにゴム栓を半打栓し、凍結乾燥機に入れて凍結乾燥処理を施した。乾燥終了後、窒素を用いて復圧し、全打栓してから、アルミキャップを巻き締めした。その後、バイアルを厚さ50μmの紫外線吸収性フィルム(光透過率 200nm:約1%、320nm:約2%、360nm:約3%、380nm:約10%、420nm:約85%)でシュリンク包装した。
[Example 1]
(Preparation of lyophilized preparation)
200 mg of bortezomib and 2000 mg of D-mannitol were added and dissolved in a mixed solvent of water for injection and t-butanol, and the total volume was made up to 100 mL with water for injection. The resulting solution was filtered using a sterile filter, and 1.5 mL each was filled into vials. Next, the vial was partially capped with a rubber stopper, placed in a freeze dryer, and subjected to freeze-drying treatment. After drying, the pressure was restored using nitrogen, the entire container was capped, and then an aluminum cap was tightened. Thereafter, the vial was shrink wrapped in a 50 μm thick ultraviolet absorbing film (light transmittance: 200 nm: approximately 1%, 320 nm: approximately 2%, 360 nm: approximately 3%, 380 nm: approximately 10%, 420 nm: approximately 85%). .
(光安定性試験)
凍結乾燥製剤の充填および紫外線吸収性フィルムによるシュリンク包装が完了したバイアルを光安定性装置に入れ、光源にD65ランプを用いて、照射強度3000lux/hrの散光下に置いた。総照度120万lux・hrの光に曝露した後、バイアルを試験装置より取り出した。その後、バイアルに水6mLおよびアセトニトリル4mLを加えて内容物を溶解させ、試料溶液とした。調製された溶液の安定性は、下記の方法により確認した。D65ランプの分光分布を図1に示す。
(Photostability test)
The vial, which had been filled with the freeze-dried preparation and shrink-wrapped with an ultraviolet absorbing film, was placed in a photostabilizer and placed under diffused light with an irradiation intensity of 3000 lux/hr using a D65 lamp as a light source. After exposure to light with a total illuminance of 1.2 million lux·hr, the vial was removed from the test apparatus. Thereafter, 6 mL of water and 4 mL of acetonitrile were added to the vial to dissolve the contents, forming a sample solution. The stability of the prepared solution was confirmed by the following method. Figure 1 shows the spectral distribution of the D65 lamp.
各試料溶液の各類縁物質および総類縁物質量をHPLC法で測定した。HPLC法の条件は次のとおりである。
検出器:紫外吸光光度計(測定波長:270nm)
カラム:内径4.6mm、長さ15cmのステンレス管に3.5μmの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填した。
カラム温度:40℃付近の一定温度
移動相流量:毎分0.9mL
サンプル注入量:20μL
移動相:溶液AおよびBから構成される。
溶液A:水/ギ酸混液(1000:1)にトリエチルアミンを加えてpH3.0に調整する。この液860mLにテトラヒドロフラン140mLを加える.
溶液B:アセトニトリル/テトラヒドロフラン混液(43:7)
移動相の送液:溶液Aおよび溶液Bの混合比を次のように変えて濃度勾配制御する。
Each related substance and the total amount of related substances in each sample solution were measured by HPLC method. The conditions for the HPLC method are as follows.
Detector: Ultraviolet absorption photometer (measurement wavelength: 270 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was filled with 3.5 μm octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 40°C Mobile phase flow rate: 0.9mL/min
Sample injection volume: 20μL
Mobile phase: composed of solutions A and B.
Solution A: Add triethylamine to a water/formic acid mixture (1000:1) to adjust the pH to 3.0. Add 140 mL of tetrahydrofuran to 860 mL of this liquid.
Solution B: Acetonitrile/tetrahydrofuran mixture (43:7)
Transfer of mobile phase: Control the concentration gradient by changing the mixing ratio of solution A and solution B as follows.
各検体のピーク面積を自動積分法により測定し、面積百分率法によりそれらの量を求め、各類縁物質量および総類縁物質を求めた(表2)。なお、総類縁物質とは、不純物A、不純物B、不純物D、および不純物Eを含むすべての不純物を合わせたものである。 The peak area of each sample was measured by automatic integration method, and the amount thereof was determined by area percentage method, and the amount of each related substance and total related substances were determined (Table 2). Note that the total related substances are the sum of all impurities including impurity A, impurity B, impurity D, and impurity E.
[比較例1]
紫外線吸収性シュリンクフィルムを包装していないバイアルに凍結乾燥製剤を充填した以外は、実施例1と同様の方法で光安定性試験を実施した。
[Comparative example 1]
A photostability test was carried out in the same manner as in Example 1, except that the lyophilized preparation was filled into a vial that was not wrapped in a UV-absorbing shrink film.
表2の結果より、本発明の紫外線吸収性フィルムで包装された容器の使用により、ボルテゾミブを含有する凍結乾燥製剤の光安定性が顕著に改善されていることがわかる。 The results in Table 2 show that the photostability of the lyophilized formulation containing bortezomib is significantly improved by using the container packaged with the ultraviolet absorbing film of the present invention.
本発明の容器は、ボルテゾミブの分解を促進する有害な波長領域の光線を遮断し、かつ好ましい態様においては容器の外側から内容物を視認できることから、ボルテゾミブの充填用容器として有用である。 The container of the present invention is useful as a container for filling bortezomib because it blocks light in the harmful wavelength range that promotes the decomposition of bortezomib, and in a preferred embodiment, the contents can be viewed from the outside of the container.
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JP2005013469A (en) | 2003-06-26 | 2005-01-20 | Kaito Kagaku Kogyo Kk | Packaging material for prefilled syringe |
JP3109486U (en) | 2004-12-20 | 2005-05-19 | 株式会社大塚製薬工場 | Packaging for drugs containing photodegradable components |
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JP2008195829A (en) | 2007-02-13 | 2008-08-28 | Fujifilm Corp | Polyester film and bottle label produced by using the same |
JP4162491B2 (en) | 2001-01-25 | 2008-10-08 | アメリカ合衆国 | Boronic acid compound preparation |
JP5086497B1 (en) | 2011-03-31 | 2012-11-28 | ナノキャリア株式会社 | Pharmaceutical composition comprising a block copolymer containing a boronic acid compound |
JP2017001995A (en) | 2015-06-12 | 2017-01-05 | 東和薬品株式会社 | Freeze-dried preparation |
JP6462922B1 (en) | 2018-02-26 | 2019-01-30 | 岩田硝子工業株式会社 | Glass container |
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JP2015066896A (en) * | 2013-09-30 | 2015-04-13 | 積水フィルム株式会社 | Multilayered film for use in heat-shrinkable packaging |
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JP4162491B2 (en) | 2001-01-25 | 2008-10-08 | アメリカ合衆国 | Boronic acid compound preparation |
JP2007507567A (en) | 2003-05-26 | 2007-03-29 | チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド | Highly compatible and non-migrating polymeric UV-absorbers |
JP2005013469A (en) | 2003-06-26 | 2005-01-20 | Kaito Kagaku Kogyo Kk | Packaging material for prefilled syringe |
JP3109486U (en) | 2004-12-20 | 2005-05-19 | 株式会社大塚製薬工場 | Packaging for drugs containing photodegradable components |
JP2008195829A (en) | 2007-02-13 | 2008-08-28 | Fujifilm Corp | Polyester film and bottle label produced by using the same |
JP5086497B1 (en) | 2011-03-31 | 2012-11-28 | ナノキャリア株式会社 | Pharmaceutical composition comprising a block copolymer containing a boronic acid compound |
JP2017001995A (en) | 2015-06-12 | 2017-01-05 | 東和薬品株式会社 | Freeze-dried preparation |
JP6462922B1 (en) | 2018-02-26 | 2019-01-30 | 岩田硝子工業株式会社 | Glass container |
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