JP2009506030A - アセチルシステイン組成物及びその使用 - Google Patents
アセチルシステイン組成物及びその使用 Download PDFInfo
- Publication number
- JP2009506030A JP2009506030A JP2008527905A JP2008527905A JP2009506030A JP 2009506030 A JP2009506030 A JP 2009506030A JP 2008527905 A JP2008527905 A JP 2008527905A JP 2008527905 A JP2008527905 A JP 2008527905A JP 2009506030 A JP2009506030 A JP 2009506030A
- Authority
- JP
- Japan
- Prior art keywords
- composition
- acetylcysteine
- edta
- pharmaceutically acceptable
- aqueous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 89
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 title claims abstract description 84
- 229960004308 acetylcysteine Drugs 0.000 title claims abstract description 73
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960005489 paracetamol Drugs 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000003002 pH adjusting agent Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 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 claims description 5
- 239000008121 dextrose Substances 0.000 claims description 4
- 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 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims 2
- 239000002738 chelating agent Substances 0.000 abstract description 38
- 230000000747 cardiac effect Effects 0.000 abstract description 5
- GYCMBHHDWRMZGG-UHFFFAOYSA-N Methylacrylonitrile Chemical compound CC(=C)C#N GYCMBHHDWRMZGG-UHFFFAOYSA-N 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 206010063837 Reperfusion injury Diseases 0.000 abstract description 4
- 239000003172 expectorant agent Substances 0.000 abstract description 4
- 208000017169 kidney disease Diseases 0.000 abstract description 4
- 229940066491 mucolytics Drugs 0.000 abstract description 4
- 238000001356 surgical procedure Methods 0.000 abstract description 4
- 230000035987 intoxication Effects 0.000 abstract description 3
- 231100000566 intoxication Toxicity 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 208000007788 Acute Liver Failure Diseases 0.000 abstract 1
- 206010000804 Acute hepatic failure Diseases 0.000 abstract 1
- 231100000836 acute liver failure Toxicity 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000002253 acid Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 229960001484 edetic acid Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
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- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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- VKZRWSNIWNFCIQ-WDSKDSINSA-N (2s)-2-[2-[[(1s)-1,2-dicarboxyethyl]amino]ethylamino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NCCN[C@H](C(O)=O)CC(O)=O VKZRWSNIWNFCIQ-WDSKDSINSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229940022720 acetadote Drugs 0.000 description 2
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- 229940009662 edetate Drugs 0.000 description 2
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- 231100000234 hepatic damage Toxicity 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
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- 150000007529 inorganic bases Chemical class 0.000 description 2
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- 230000008818 liver damage Effects 0.000 description 2
- 230000007056 liver toxicity Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
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- 229960003330 pentetic acid Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
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- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 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
- FCKYPQBAHLOOJQ-NXEZZACHSA-N 2-[[(1r,2r)-2-[bis(carboxymethyl)amino]cyclohexyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)[C@@H]1CCCC[C@H]1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-NXEZZACHSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-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
- 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 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- FCKYPQBAHLOOJQ-UHFFFAOYSA-N Cyclohexane-1,2-diaminetetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)C1CCCCC1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 1
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021027 Hypomagnesaemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Natural products SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 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 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000007379 Muscle Hypotonia Diseases 0.000 description 1
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000000172 allergic effect Effects 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
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- JHECKPXUCKQCSH-UHFFFAOYSA-J calcium;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O JHECKPXUCKQCSH-UHFFFAOYSA-J 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
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- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 229940126534 drug product Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229940058180 edetate dipotassium anhydrous Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000000396 hypokalemic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- HWGNBUXHKFFFIH-UHFFFAOYSA-I pentasodium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O HWGNBUXHKFFFIH-UHFFFAOYSA-I 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
- -1 salt disodium edetate Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
A.定義
本発明をより容易に理解できるために、一定の用語を最初に定義する。更なる定義は詳細な説明全体にわたって記載される。
本発明者らは、キレート剤を必要とすることなく、周囲条件で少なくとも1年間及び加速条件(40℃)で6ヵ月間の、溶液中で医薬上許容される安定性を有するアセチルシステインの液体組成物を製造できることを見出した。この安定性は、アセチルシステインの一般的に不安定な性質を考えると驚くべきことである。
20キログラムのアセチルシステインを約60リットルの注射用脱気水に加え、この溶液を混合した。水酸化ナトリウム溶液を加えてpHを約 6.5〜7.0 に調節し、溶解するまで混合した。十分な量の注射用脱気水を加えて20%溶液にした(総体積100リットル)。酸素を窒素で置き換えることにより空気への暴露を最小限にした。この溶液を 0.2 ミクロン滅菌フィルターに通した。生成物をバイアル又はアンプルに充填し、上部空間を窒素で置き換えることにより酸素への暴露を最小限にした。
10kgのアセチルシステインを約60リットルの注射用脱気水に加え、混合する。水酸化ナトリウム溶液を加えてpHを約 6.5〜7.0 に調節し、溶解するまで混合を続ける。十分な量の注射用脱気水を加えて10%溶液にする(総体積100リットル)。酸素を窒素又は他の医薬上不活性なガスで置き換えることにより空気への暴露を最小限にする。この溶液を 0.2 ミクロンの又は他の滅菌フィルターに通す。生成物をバイアル又はアンプルに充填し、上部空間を窒素又は他の医薬上不活性なガスで置き換えることにより酸素への暴露を最小限にする。
アセチルシステイン溶液の安定性にEDTAが必要であるかどうかを決定するために、異なる濃度のエデト酸二ナトリウムを含有する三つの溶液を製造した。0.05% のエデト酸二ナトリウムを含有する溶液、この量の 40% 、すなわち 0.02% のエデト酸二ナトリウムを含有する溶液、及びエデト酸二ナトリウムを含有しない(0.00%)溶液を調べた。これら三つの溶液は実施例1に記載したのと同様の方法を用いて製造した。簡単に述べると、もしあれば、エデト酸二ナトリウムを、必要な脱気水の約 60% に加え、溶解するまで混合した。次いでアセチルシステインを加え、溶解するまで混合した。pHを水酸化ナトリウムで約 6.8 に調節し、脱気水を目標レベルまで加えた。窒素を用いて溶液をパージした。次いで生成物を 0.2 ミクロンのフィルターに通して潜在的な微生物汚染を除去し、バイアルに充填した。
Claims (32)
- アセチルシステインを含む水性医薬組成物であって、該組成物がEDTA又はその医薬上許容される塩を実質的に含まない上記組成物。
- アセチルシステインを含む水性医薬組成物であって、該組成物が0.05%w/v未満のEDTA又はその医薬上許容される塩を含有する上記組成物。
- 組成物が 0.02%w/v未満のEDTA又はその医薬上許容される塩を含有する、請求項2に記載の水性医薬組成物。
- 組成物がEDTA又はその医薬上許容される塩を含有しない、請求項3に記載の水性医薬組成物。
- 組成物のpHが6〜8である、請求項1又は2に記載の水性医薬組成物。
- 組成物のpHが6.5〜7.0である、請求項5に記載の水性医薬組成物。
- 組成物のpHが6.8である、請求項6に記載の水性医薬組成物。
- 組成物が25℃で少なくとも12ヵ月間安定である、請求項1又は2に記載の水性医薬組成物。
- 組成物が40℃で少なくとも6ヵ月間安定である、請求項1又は2に記載の水性医薬組成物。
- 脱気水に溶解した10〜400mg/mLのアセチルシステインからなる、pHがpH調節剤で6〜8に調節されている水性医薬組成物。
- 治療を必要とする患者に有効量のアセチルシステインの水性組成物を投与することを含むアセトアミノフェン過剰摂取の治療方法であって、該組成物がEDTA又はその医薬上許容される塩を実質的に含まない、上記方法。
- 治療を必要とする患者に有効量のアセチルシステインの水性組成物を投与することを含むアセトアミノフェン過剰摂取の治療方法であって、該組成物が0.05%w/v未満のEDTA又はその医薬上許容される塩を含有する上記方法。
- 組成物が0.02%w/v未満のEDTA又はその医薬上許容される塩を含有する、請求項12に記載の方法。
- 組成物がEDTA又はその医薬上許容される塩を含有しない、請求項13に記載の方法。
- 組成物のpHが6〜8である、請求項11又は12に記載の方法。
- 組成物のpHが6.5〜7.0である、請求項15に記載の方法。
- 組成物のpHが6.8である、請求項16に記載の方法。
- 投与が静脈内注射、経口又は吸入により行われる、請求項11又は12に記載の方法。
- 投与が静脈内注射により行われる、請求項18に記載の方法。
- 組成物を投与の前にデキストロース及び塩化ナトリウムの少なくとも一方の水溶液中で混合する、請求項11又は12に記載の方法。
- 組成物を投与の前に5%w/vデキストロース水溶液中で混合する、請求項20に記載の方法。
- 組成物を投与の前に0.45%又は0.90%w/v塩化ナトリウム水溶液中で混合する、請求項20に記載の方法。
- アセチルシステインを脱気水に溶解すること、及び、6〜8のpHを得るために塩基性物質を添加することを含む水性アセチルシステイン医薬組成物の製造方法であって、該組成物がEDTA又はその医薬上許容される塩を実質的に含まない上記方法。
- アセチルシステインを脱気水に溶解すること、及び、6〜8のpHを得るために塩基性物質を添加することを含む水性アセチルシステイン医薬組成物の製造方法であって、該組成物が0.05%w/v未満のEDTA又はその医薬上許容される塩を含有する上記方法。
- 溶液を滅菌フィルターに通すこと及び不活性雰囲気下に充填することを更に含む、請求項23又は24に記載の方法。
- 組成物が0.02%w/v未満のEDTA又はその医薬上許容される塩を含有する、請求項24に記載の方法。
- 組成物がEDTA又はその医薬上許容される塩を含有しない、請求項26に記載の方法。
- 組成物のpHが6.5〜7.0である、請求項23又は24に記載の方法。
- 組成物のpHが6.8である、請求項28に記載の方法。
- 組成物が25℃で少なくとも6ヵ月間安定である、請求項23又は24に記載の方法。
- 組成物が40℃で少なくとも6ヵ月間安定である、請求項23又は24に記載の方法。
- 塩基性物質が水酸化ナトリウムである、請求項23又は24に記載の方法。
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JP2014509619A (ja) * | 2011-04-01 | 2014-04-21 | イアソマイ エービー | N−アセチル−l−システインを含む新規な組み合わせおよびその使用 |
JP2016065074A (ja) * | 2011-04-01 | 2016-04-28 | イアソマイ エービー | N−アセチル−l−システインを含む新規な組み合わせおよびその使用 |
US9795582B2 (en) | 2011-04-01 | 2017-10-24 | Iasomai Ab | Combination comprising N-acetyl-L-cysteine and its use |
US10300038B2 (en) | 2011-04-01 | 2019-05-28 | Iasomai Ab | Combination comprising N-acetyl-L-cysteine and its use |
US11207287B2 (en) | 2011-04-01 | 2021-12-28 | Iasomai Ab | Combination comprising N-acetyl-L-cysteine and its use |
JP2017504615A (ja) * | 2013-12-23 | 2017-02-09 | サムヤン バイオファーマシューティカルズ コーポレイション | パロノセトロンを含有する薬学組成物 |
US9877959B2 (en) | 2013-12-23 | 2018-01-30 | Samyang Biopharmaceuticals Corporation | Pharmaceutical composition containing palonosetron |
JP2018503689A (ja) * | 2015-01-27 | 2018-02-08 | フローレンゲイル・エル・エル・シー | 治癒性局所用組成物 |
JP2020502096A (ja) * | 2016-12-15 | 2020-01-23 | ザンボン ソシエタ ペル アチオニ | 抗バクテリア剤(antibacterial agent)として使用するためのn−アセチルシステイン |
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WO2007024311A1 (en) | 2007-03-01 |
CN101242824A (zh) | 2008-08-13 |
CN101242824B (zh) | 2011-07-20 |
NZ566100A (en) | 2012-01-12 |
KR20080047398A (ko) | 2008-05-28 |
US20170042850A1 (en) | 2017-02-16 |
HK1123972A1 (zh) | 2009-07-03 |
US20130165516A1 (en) | 2013-06-27 |
EP1928449B1 (en) | 2015-09-16 |
AU2006282030B2 (en) | 2011-07-07 |
CA2619441C (en) | 2015-07-14 |
US8399445B2 (en) | 2013-03-19 |
PH12012501687A1 (en) | 2015-04-20 |
US8653061B2 (en) | 2014-02-18 |
US8148356B2 (en) | 2012-04-03 |
PH12012501687B1 (en) | 2015-04-20 |
US20070049640A1 (en) | 2007-03-01 |
US20120309832A1 (en) | 2012-12-06 |
EP1928449A1 (en) | 2008-06-11 |
US8952065B2 (en) | 2015-02-10 |
CN102266316A (zh) | 2011-12-07 |
AU2006282030A1 (en) | 2007-03-01 |
KR101408336B1 (ko) | 2014-06-20 |
US20150196519A1 (en) | 2015-07-16 |
US20140128470A1 (en) | 2014-05-08 |
JP5303272B2 (ja) | 2013-10-02 |
US20180055801A1 (en) | 2018-03-01 |
CA2619441A1 (en) | 2007-03-01 |
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