JP7438802B2 - Palonosetron-containing composition - Google Patents
Palonosetron-containing composition Download PDFInfo
- Publication number
- JP7438802B2 JP7438802B2 JP2020051745A JP2020051745A JP7438802B2 JP 7438802 B2 JP7438802 B2 JP 7438802B2 JP 2020051745 A JP2020051745 A JP 2020051745A JP 2020051745 A JP2020051745 A JP 2020051745A JP 7438802 B2 JP7438802 B2 JP 7438802B2
- Authority
- JP
- Japan
- Prior art keywords
- palonosetron
- concentration
- composition
- edetate
- mass
- 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.)
- Active
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- 239000000203 mixture Substances 0.000 title claims description 139
- 229960002131 palonosetron Drugs 0.000 title claims description 107
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 title claims description 107
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 183
- 235000015165 citric acid Nutrition 0.000 claims description 100
- 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 description 40
- 229940009662 edetate Drugs 0.000 claims description 26
- 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 24
- 235000010355 mannitol Nutrition 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 17
- 150000007513 acids Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 229930195725 Mannitol Natural products 0.000 claims description 16
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 16
- 239000000594 mannitol Substances 0.000 claims description 16
- 239000001509 sodium citrate Substances 0.000 claims description 15
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 15
- 239000012929 tonicity agent Substances 0.000 claims description 15
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 14
- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 claims description 14
- 229960003359 palonosetron hydrochloride Drugs 0.000 claims description 14
- 229940037001 sodium edetate Drugs 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 12
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 11
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- 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
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- 239000007951 isotonicity adjuster 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 3
- 150000003892 tartrate salts Chemical class 0.000 claims 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
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- 239000007788 liquid Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000003002 pH adjusting agent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
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- 239000013065 commercial product Substances 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
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- 150000005846 sugar alcohols Chemical class 0.000 description 4
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 230000001687 destabilization Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000003978 infusion fluid Substances 0.000 description 3
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- 239000007924 injection Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000008057 potassium phosphate buffer Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
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- 150000001735 carboxylic acids Chemical class 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 150000004820 halides Chemical class 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
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- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
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- 210000001367 artery Anatomy 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate 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
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
- 229940043276 diisopropanolamine Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229910001629 magnesium chloride 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 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
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000012756 surface treatment agent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Description
本発明は、パロノセトロン類を含有する組成物等に関する。 The present invention relates to compositions containing palonosetrons.
パロノセトロン（パロノセトロン塩酸塩）は、５－ＨＴ３受容体拮抗薬であり、「アロキシ静注０．７５ｍｇ」が市販されている（非特許文献１）。 Palonosetron (palonosetron hydrochloride) is a 5-HT 3 receptor antagonist, and "aloxy intravenous injection 0.75 mg" is commercially available (Non-Patent Document 1).
本発明の目的は、新規なパロノセトロン組成物（パロノセトロン製剤、パロノセトロン水性組成物）を提供することにある。 An object of the present invention is to provide a novel palonosetron composition (palonosetron preparation, palonosetron aqueous composition).
上記の通り、パロノセトロンには、市販品として「アロキシ静注０．７５ｍｇ」が知られている。この市販品は、１瓶（５ｍＬ）中に、パロノセトロン塩酸塩０．８４ｍｇ（パロノセトロンとして０．７５ｍｇ）、Ｄ－マンニトール２０７．５ｍｇ、エデト酸ナトリウム水和物２．５ｍｇ、クエン酸ナトリウム水和物１８．５ｍｇ、クエン酸水和物７．８ｍｇを含む、ｐＨ４．５～５．５、浸透圧比約１の製剤である。 As mentioned above, "Aloxy intravenous injection 0.75 mg" is known as a commercially available product for palonosetron. This commercial product contains 0.84 mg of palonosetron hydrochloride (0.75 mg as palonosetron), 207.5 mg of D-mannitol, 2.5 mg of sodium edetate hydrate, and sodium citrate hydrate in one bottle (5 mL). It is a formulation containing 18.5 mg of citric acid hydrate and 7.8 mg of citric acid hydrate, with a pH of 4.5 to 5.5 and an osmotic pressure ratio of approximately 1.
この製剤は、そのまま又は希釈して使用されるが、いずれの使用態様においても高濃度化することで、保管（省スペース）、取扱性等の点で有利となりうる。一方、製剤は、有効成分の機能や安定性等を考慮して厳密に設定されたものであり、仮に高濃度化するとしても、各成分の配合量は維持すべきものと考えられる。 This preparation can be used as it is or diluted, but in any usage mode, increasing the concentration can be advantageous in terms of storage (space saving), ease of handling, and the like. On the other hand, formulations are strictly determined in consideration of the functions and stability of the active ingredients, and even if the concentration is increased, the amount of each ingredient should be maintained.
このような観点から、本発明者は、各成分の配合量を変化させず（すなわち、媒体たる水の量を変更して）、パロノセトロンを高濃度で含む製剤を調製した。
しかしながら、このような製剤では、意外なことに、各成分の配合量が同じであるにもかかわらず、安定性（保存安定性）が低下する等の不都合を生じる場合があった。しかも、このような不都合が生じる理由は全くわからず、その解決には困難を極めた。
From this point of view, the present inventor prepared a formulation containing palonosetron at a high concentration without changing the blending amount of each component (ie, by changing the amount of water as a medium).
However, unexpectedly, such formulations sometimes have disadvantages such as decreased stability (storage stability) even though the amounts of each component are the same. Moreover, the reason for such inconveniences was completely unknown, and it was extremely difficult to solve them.
このような中、本発明者は、意外なことに、製剤を構成する特定成分の配合割合を選択することで、パロノセトロンを特定濃度に高濃度化しても、安定性の低下等を抑制ないし改善しうること等を見出し、さらに検討を重ね、本発明を完成させるに至った。 Under these circumstances, the present inventor surprisingly found that by selecting the blending ratio of specific components that make up the formulation, it is possible to suppress or improve the stability of palonosetron even if the concentration is increased to a specific level. After discovering what could be done, and conducting further studies, the present invention was completed.
すなわち、本発明は、下記の発明等に関する。
［１］
パロノセトロン類及びクエン酸類を含有し、
パロノセトロン類の濃度が、パロノセトロンとして０．２ｍｇ／ｍＬ以上、
クエン酸類の濃度が８．５ｍｇ／ｍＬ以下である、組成物。
［２］
パロノセトロン類及びクエン酸類を含有し、
パロノセトロン類の濃度が、パロノセトロンとして０．２ｍｇ／ｍＬ以上、
クエン酸類の割合が、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して３０質量部以下である、組成物。
［３］
パロノセトロン類及びクエン酸類を含有し、
パロノセトロン類の濃度が、パロノセトロンとして０．２ｍｇ／ｍＬ以上、
クエン酸類の濃度が８．５ｍｇ／ｍＬ以下、
クエン酸類の割合が、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して３０質量部以下である、組成物。
［４］
パロノセトロン類がパロノセトロン塩酸塩であり、パロノセトロン類の濃度が、パロノセトロンとして０．２５～０．５ｍｇ／ｍＬである［１］～［３］のいずれかに記載の組成物。
［５］
パロノセトロン類がパロノセトロン塩酸塩であり、クエン酸類の割合が、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して２５質量部以下である、
［１］～［４］のいずれかに記載の組成物。
［６］
クエン酸類が、クエン酸及びクエン酸塩である、［１］～［５］のいずれかに記載の組成物。
［７］
クエン酸類がクエン酸及びクエン酸塩であり、クエン酸の濃度が２．９ｍｇ／ｍＬ以下、クエン酸塩の濃度が６．５ｍｇ／ｍＬ、クエン酸類の割合がパロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して１～２５質量部である、［１］～［６］のいずれかに記載の組成物。
［８］
クエン酸類が、クエン酸及びクエン酸ナトリウムであり、クエン酸の濃度が０．５～２．２ｍｇ／ｍＬ、クエン酸塩の濃度が１～５ｍｇ／ｍＬ、クエン酸類の割合がパロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して２～２０質量部であるである、［１］～［７］のいずれかに記載の組成物。
［９］
さらに、エデト酸類を含む、［１］～［８］のいずれかに記載の組成物。
［１０］
さらに、エデト酸類を含み、エデト酸類がエデト酸ナトリウム（二ナトリウム）であり、エデト酸類の濃度が０．１ｍｇ／ｍＬ以上である、［１］～［９］のいずれかに記載の組成物。
［１１］
さらに、エデト酸を含み、エデト酸類がエデト酸ナトリウム（二ナトリウム）であり、エデト酸類の濃度が０．２～３ｍｇ／ｍＬである、［１］～［１０］のいずれかに記載の組成物。
［１２］
さらに、等張化剤を含む、［１］～［１１］のいずれかに記載の組成物。
［１３］
さらに、等張化剤を含み、等張化剤がマンニトールである、［１］～［１２］のいずれかに記載の組成物。
［１４］
さらに、等張化剤を含み、等張化剤の濃度が２０～６０ｍｇ／ｍＬである、［１］～［１３］のいずれかに記載の組成物。
［１５］
ｐＨが４～６である、［１］～［１４］のいずれかに記載の組成物。
［１６］
さらに、エデト酸類及び等張化剤を含み、
パロノセトロン類がパロノセトロン塩酸塩、クエン酸類がクエン酸及びクエン酸ナトリウム、等張化剤がマンニトール、エデト酸類がエデト酸ナトリウム（二ナトリウム）であり、
パロノセトロン類の濃度が、パロノセトロンとして０．３～０．４５ｍｇ／ｍＬ、
クエン酸の濃度が１～２ｍｇ／ｍＬ、
クエン酸塩の濃度が２．５～４．５ｍｇ／ｍＬ、
クエン酸類の割合がパロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して１．５～２０質量部、
エデト酸類の濃度が０．８～２ｍｇ／ｍＬ、
等張化剤の濃度が、３０～５０ｍｇ／ｍＬ、
ｐＨが、４．５～５．５である、［１］～［１５］のいずれかに記載の組成物。
［１７］
全量が５ｍＬ未満の製剤である、［１］～［１６］のいずれかに記載の組成物。
［１８］
全量３ｍＬ以下のシリンジ製剤である、［１］～［１７］のいずれかに記載の組成物。
［１９］
パロノセトロン類及びクエン酸類を含有し、パロノセトロン類の濃度が、パロノセトロンとして０．２ｍｇ／ｍＬ以上である組成物において、パロノセトロン類の安定性を向上（又は改善）する方法であって、クエン酸類の濃度を８．５ｍｇ／ｍＬ以下、及び／又はクエン酸類の割合をパロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して３０質量部以下とする、方法。
［２０］
熱安定性及び／又は光安定性を向上（又は改善）する、［１９］記載の方法。
［２１］
さらに、経時的なｐＨ変化を抑制する、［１９］又は［２０］記載の方法。
That is, the present invention relates to the following inventions, etc.
[1]
Contains palonosetrons and citric acids,
The concentration of palonosetrons is 0.2 mg/mL or more as palonosetron,
A composition having a concentration of citric acids of 8.5 mg/mL or less.
[2]
Contains palonosetrons and citric acids,
The concentration of palonosetrons is 0.2 mg/mL or more as palonosetron,
A composition in which the proportion of citric acids is 30 parts by mass or less per 1 part by mass of palonosetron (palonosetrons based on palonosetron).
[3]
Contains palonosetrons and citric acids,
The concentration of palonosetrons is 0.2 mg/mL or more as palonosetron,
The concentration of citric acids is 8.5 mg/mL or less,
A composition in which the proportion of citric acids is 30 parts by mass or less per 1 part by mass of palonosetron (palonosetrons based on palonosetron).
[4]
The composition according to any one of [1] to [3], wherein the palonosetron is palonosetron hydrochloride, and the concentration of the palonosetron is 0.25 to 0.5 mg/mL as palonosetron.
[5]
The palonosetrons are palonosetron hydrochloride, and the proportion of citric acids is 25 parts by mass or less with respect to 1 part by mass of palonosetron (palonosetrons based on palonosetron),
The composition according to any one of [1] to [4].
[6]
The composition according to any one of [1] to [5], wherein the citric acids are citric acid and citrate salts.
[7]
The citric acids are citric acid and citrates, the concentration of citric acid is 2.9 mg/mL or less, the concentration of citrate is 6.5 mg/mL, and the proportion of citric acids is palonosetron (palonosetron based on palonosetron standards) 1 The composition according to any one of [1] to [6], which is 1 to 25 parts by weight based on parts by weight.
[8]
The citric acids are citric acid and sodium citrate, the concentration of citric acid is 0.5 to 2.2 mg/mL, the concentration of citrate is 1 to 5 mg/mL, and the proportion of citric acids is palonosetron (based on palonosetron). The composition according to any one of [1] to [7], wherein the amount is 2 to 20 parts by mass per 1 part by mass of palonosetrons.
[9]
The composition according to any one of [1] to [8], further comprising edetic acids.
[10]
The composition according to any one of [1] to [9], further comprising an edetate, the edetate is sodium edetate (disodium), and the concentration of the edetate is 0.1 mg/mL or more.
[11]
The composition according to any one of [1] to [10], further comprising edetate, wherein the edetate is sodium edetate (disodium), and the concentration of the edetate is 0.2 to 3 mg/mL. .
[12]
The composition according to any one of [1] to [11], further comprising an isotonizing agent.
[13]
The composition according to any one of [1] to [12], further comprising an isotonicity agent, and the isotonicity agent is mannitol.
[14]
The composition according to any one of [1] to [13], further comprising an isotonicity agent, and the concentration of the tonicity agent is 20 to 60 mg/mL.
[15]
The composition according to any one of [1] to [14], which has a pH of 4 to 6.
[16]
Furthermore, it contains edetic acids and isotonic agents,
The palonosetrons are palonosetron hydrochloride, the citric acids are citric acid and sodium citrate, the tonicity agent is mannitol, the edetic acids are sodium edetate (disodium),
The concentration of palonosetrons is 0.3 to 0.45 mg/mL as palonosetron,
The concentration of citric acid is 1 to 2 mg/mL,
The concentration of citrate is 2.5 to 4.5 mg/mL,
The ratio of citric acids is 1.5 to 20 parts by mass per 1 part by mass of palonosetron (palonosetron based on palonosetron),
The concentration of edetic acids is 0.8 to 2 mg/mL,
The concentration of the tonicity agent is 30 to 50 mg/mL,
The composition according to any one of [1] to [15], which has a pH of 4.5 to 5.5.
[17]
The composition according to any one of [1] to [16], which is a formulation with a total volume of less than 5 mL.
[18]
The composition according to any one of [1] to [17], which is a syringe preparation with a total volume of 3 mL or less.
[19]
A method for improving (or improving) the stability of palonosetrons in a composition containing palonosetrons and citric acids, wherein the concentration of palonosetrons is 0.2 mg/mL or more as palonosetron, the method comprising: 8.5 mg/mL or less, and/or the ratio of citric acids to 1 part by mass of palonosetron (palonosetrons based on palonosetron) is 30 parts by mass or less.
[20]
The method according to [19], which improves (or improves) thermal stability and/or photostability.
[21]
Furthermore, the method according to [19] or [20], which suppresses pH changes over time.
本発明によれば、新規なパロノセトロン組成物（パロノセトロン製剤）を提供できる。 According to the present invention, a novel palonosetron composition (palonosetron formulation) can be provided.
このような組成物は、市販品に比べて、高濃度でパロノセトロンを含んでおり、例えば、低容量ないし省スペース化［例えば、全量５ｍＬ未満（例えば、２ｍＬ等）の製剤］等が可能である。 Such compositions contain palonosetron at a higher concentration than commercially available products, and can be made, for example, in a low volume or space-saving form [e.g., a formulation with a total volume of less than 5 mL (e.g., 2 mL, etc.)]. .
しかも、このような組成物では、高濃度でパロノセトロンを含んでいても、市販品の処方（組成）に比べ、十分な安定性を担保［例えば、市販品の処方（組成）と同等の安定性ないしより高い安定性を実現］しうる。このような組成物は、高濃度でありながら、長期保存に耐えうるものであり、非常に有用である。 Moreover, even if such a composition contains palonosetron at a high concentration, it ensures sufficient stability compared to the formulation (composition) of a commercial product [e.g., the same stability as the formulation (composition) of a commercial product]. or achieve higher stability]. Although such a composition has a high concentration, it can withstand long-term storage and is very useful.
なお、安定性としては、保存安定性、光安定性、ｐＨ変化の大きさ等が挙げられる。保存安定性や光安定性は、例えば、パロノセトロンの類縁物質の生成（副生）量を測定することで、評価しうる。 Note that the stability includes storage stability, photostability, magnitude of pH change, and the like. Storage stability and photostability can be evaluated, for example, by measuring the amount of palonosetron related substances produced (by-products).
＜組成物＞
本発明の組成物（パロノセトロン組成物、パロノセトロン製剤、医薬組成物）は、パロノセトロン類及びクエン酸類を少なくとも含む。
<Composition>
The composition of the present invention (palonosetron composition, palonosetron preparation, pharmaceutical composition) contains at least palonosetrons and citric acids.
［パロノセトロン類］
パロノセトロン類としては、パロノセトロン（下記式で表される化合物）、パロノセトロンの塩（特に、薬理学的に許容可能な塩）、これらの水和物などが含まれる。
[Palonosetrons]
Palonosetrons include palonosetron (a compound represented by the following formula), salts of palonosetron (especially pharmacologically acceptable salts), hydrates thereof, and the like.
塩を形成する成分（塩）としては、特に限定されず、例えば、無機酸（例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等）、有機酸｛例えば、カルボン酸［例えば、酢酸、プロピオン酸、ヘキサン酸、シクロペンタンプロピオン酸、グリコール酸、ピルビン酸、乳酸、マロン酸、コハク酸、リンゴ酸、フマル酸、酒石酸、クエン酸、安息香酸、ｏ－（４－ヒドロキシベンゾイル）安息香酸、桂皮酸、マンデル酸、グルコヘプタン酸、３－フェニルプロピオン酸、グルコン酸、グルタミン酸、ヒドロキシナフトエ酸、サリチル酸、ステアリン酸、ムコン酸］、スルホン酸［例えば、メタンスルホン酸、エタンスルホン酸、１，２－エタンジスルホン酸、２－ヒドロキシエタンスルホン酸、ベンゼンスルホン酸、ｐ－クロロベンゼンスルホン酸、２－ナフタレンスルホン酸、ｐ－トルエンスルホン酸、カンファースルホン酸］、硫酸の部分エステル（例えば、ラウリル硫酸等）等｝等の酸（酸の塩）が挙げられる。
これらの成分は、単独で又は２種以上組み合わせて、塩を形成してもよい。
The salt-forming component (salt) is not particularly limited, and includes, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), organic acids (e.g., carboxylic acids [e.g., acetic acid, etc.) , propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid , cinnamic acid, mandelic acid, glucoheptanoic acid, 3-phenylpropionic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid], sulfonic acid [e.g. methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid], partial esters of sulfuric acid (for example, lauryl sulfate, etc.) ), etc.}, and the like (acid salts).
These components may be used alone or in combination of two or more to form a salt.
代表的なパロノセトロン類には、パロノセトロン、パロノセトロンと酸（例えば、無機酸）との塩などが挙げられ、特に、パロノセトロン塩酸塩（下記式で表される化合物）が好ましい。 Typical palonosetrons include palonosetron and a salt of palonosetron with an acid (for example, an inorganic acid), and palonosetron hydrochloride (a compound represented by the following formula) is particularly preferred.
なお、パロノセトロン塩酸塩は、前記の通り、市販品で使用のパロノセトロン類である。 As mentioned above, palonosetron hydrochloride is a commercially available palonosetron.
［クエン酸類］
クエン酸類としては、クエン酸、クエン酸塩等が挙げられる。
[Citric acids]
Examples of citric acids include citric acid and citrates.
クエン酸塩としては、例えば、クエン酸金属塩［例えば、アルカリ金属塩（例えば、クエン酸ナトリウム、クエン酸カリウム等）、アルカリ土類金属塩（例えば、クエン酸カルシウム）等］等が挙げられる。 Examples of citrates include metal citrates [eg, alkali metal salts (eg, sodium citrate, potassium citrate, etc.), alkaline earth metal salts (eg, calcium citrate), etc.].
好ましいクエン酸塩には、クエン酸ナトリウム等が含まれる。 Preferred citrate salts include sodium citrate and the like.
クエン酸類は、単独で又は２種以上組み合わせて使用してもよい。２種以上組み合わせる場合、クエン酸とクエン酸塩とを組み合わせてもよいし、２種以上のクエン酸塩を組み合わせてもよいし、クエン酸と２種以上のクエン酸塩を組み合わせてもよい。 Citric acids may be used alone or in combination of two or more. When combining two or more types, citric acid and citrates may be combined, two or more types of citrates may be combined, or citric acid and two or more types of citrates may be combined.
これらの中でも、クエン酸及びクエン酸塩（例えば、クエン酸ナトリウム）が好ましく、特にこれらを組み合わせて使用するのが好ましい。 Among these, citric acid and citrate salts (eg, sodium citrate) are preferred, and it is particularly preferred to use these in combination.
なお、クエン酸類は、抗酸化剤及び／又は緩衝剤（緩衝液）として機能してもよい。 In addition, citric acids may function as an antioxidant and/or a buffer (buffer).
クエン酸類は、水和物の形態（例えば、クエン酸水和物、クエン酸ナトリウム水和物）で組成物に含有（配合）されてもよい。 Citric acids may be contained (blended) in the composition in the form of hydrates (eg, citric acid hydrate, sodium citrate hydrate).
なお、クエン酸（クエン酸水和物）及びクエン酸ナトリウム（クエン酸ナトリウム水和物）は、前記の通り、市販品で使用のクエン酸類である。 In addition, as mentioned above, citric acid (citric acid hydrate) and sodium citrate (sodium citrate hydrate) are citric acids used as commercially available products.
［エデト酸類］
組成物は、エデト酸類を含んでいてもよい。
エデト酸類は、製剤に混入しうる金属成分を効率良くトラップできる等の観点から、好適に組成物に含有させうる。
[Edetic acids]
The composition may include edetic acids.
Edetic acids can be suitably included in the composition from the viewpoint of efficiently trapping metal components that may be mixed into the preparation.
エデト酸類としては、エデト酸、エデト酸塩等が挙げられる。
エデト酸塩としては、例えば、エデト酸金属塩［例えば、アルカリ金属塩（例えば、エデト酸ナトリウム（二ナトリウム）、エデト酸カリウム等）等］等が挙げられる。
エデト酸類は、単独で又は２種以上組み合わせて使用してもよい。
Examples of edetic acids include edetic acid and edetate salts.
Examples of edetate salts include metal salts of edetate [eg, alkali metal salts (eg, sodium (disodium) edetate, potassium edetate, etc.)], and the like.
Edetic acids may be used alone or in combination of two or more.
これらの中でも、エデト酸ナトリウムが好ましい。 Among these, sodium edetate is preferred.
エデト酸類は、水和物の形態（例えば、エデト酸ナトリウム水和物）で組成物に含有（配合）されてもよい。 Edetate acids may be contained (blended) in the composition in the form of a hydrate (for example, sodium edetate hydrate).
なお、エデト酸ナトリウム（エデト酸ナトリウム水和物）は、前記の通り、市販品で使用のエデト酸類である。 As described above, sodium edetate (sodium edetate hydrate) is a commercially available edetate.
［等張化剤］
組成物は、等張化剤を含んでいてもよい。
等張化剤は、浸透圧の調整等の観点から、好適に組成物に含有させうる。
[Tonicity agent]
The composition may also include a tonicity agent.
The tonicity agent can be suitably included in the composition from the viewpoint of adjusting osmotic pressure and the like.
等張化剤としては、例えば、有機成分［例えば、糖アルコール類（例えば、ソルビトール、マンニトール（Ｄ－マンニトール等）、キシリトール、トレハロース、グリセリンなど）、糖類（例えば、ブドウ糖、乳糖など）、グリコール類（例えば、プロピレングリコール）、アルコール類（例えば、ベンジルアルコール）、マクロゴール等］、無機成分［例えば、無機塩（例えば、塩化ナトリウム、塩化カリウム、塩化マグネシウム、塩化カルシウム、臭化ナトリウム等のハロゲン化物）等］等が挙げられる。
等張化剤は、単独で又は２種以上組み合わせて使用してもよい。
Isotonic agents include, for example, organic components [e.g., sugar alcohols (e.g., sorbitol, mannitol (D-mannitol, etc.), xylitol, trehalose, glycerin, etc.), sugars (e.g., glucose, lactose, etc.), glycols, etc. (e.g., propylene glycol), alcohols (e.g., benzyl alcohol), macrogol, etc.], inorganic components [e.g., inorganic salts (e.g., halides such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium bromide, etc.) ) etc.] etc.
The tonicity agents may be used alone or in combination of two or more.
これらの中でも、糖アルコール類、糖類、ハロゲン化物（例えば、アルカリ金属やアルカリ土類金属とハロゲン化水素との塩）等が好ましく、特に、糖アルコール類（中でもマンニトール）が好ましい。 Among these, sugar alcohols, saccharides, halides (for example, salts of alkali metals or alkaline earth metals and hydrogen halides), etc. are preferred, and sugar alcohols (among them mannitol) are particularly preferred.
なお、マンニトール（Ｄ－マンニトール）は、前記の通り、市販品で使用の成分（等張化剤）である。 As mentioned above, mannitol (D-mannitol) is a component (isotonizing agent) used in commercially available products.
［ｐＨ調整剤］
組成物は、ｐＨ調整剤を含んでいてもよい。このようなｐＨ調整剤としては、特に限定されず、例えば、無機酸（例えば、塩酸、リン酸、ホウ酸など）、有機酸［例えば、カルボン酸（クエン酸、酒石酸、フマル酸、乳酸、マレイン酸、酢酸、シュウ酸、アジピン酸、グルコン酸など）、スルホン酸（メタンスルホン酸など）など］、水酸化物（例えば、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウムなどの水酸化アルカリ又はアルカリ土類金属塩など）、アミン類［例えば、アルカノールアミン（例えば、モノエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリスヒドロキシメチルアミノメタンなど）］、アミノ酸（例えば、グリシンなど）、これらの塩などが挙げられる。
[pH adjuster]
The composition may also include a pH adjusting agent. Such pH adjusters are not particularly limited, and include, for example, inorganic acids (e.g., hydrochloric acid, phosphoric acid, boric acid, etc.), organic acids [e.g., carboxylic acids (citric acid, tartaric acid, fumaric acid, lactic acid, maleic acid, etc.)] acids, acetic acid, oxalic acid, adipic acid, gluconic acid, etc.), sulfonic acids (such as methanesulfonic acid), hydroxides (such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, etc.) oxidized alkali or alkaline earth metal salts, etc.), amines [e.g., alkanolamines (e.g., monoethanolamine, triethanolamine, diisopropanolamine, trishydroxymethylaminomethane, etc.)], amino acids (e.g., glycine, etc.), Examples include these salts.
これらの中でも、塩酸、水酸化ナトリウム等が代表的である。一方、本発明の組成物は、このようなｐＨ調整剤（例えば、塩酸、水酸化ナトリウム等）を含んでいなくてもよい。 Among these, hydrochloric acid, sodium hydroxide, etc. are representative. On the other hand, the composition of the present invention does not need to contain such a pH adjusting agent (eg, hydrochloric acid, sodium hydroxide, etc.).
ｐＨ調整剤は、単独で又は２種以上組み合わせて使用してもよい。 The pH adjusters may be used alone or in combination of two or more.
［他の成分］
組成物は、本発明の効果を害しない範囲で、さらに、必要に応じて、他の成分［パロノセトロン類、クエン酸類、エデト酸類、等張化剤、及びｐＨ調整剤以外の成分（非溶媒成分、固形分）］を含んでいてもよい。このような他の成分としては、例えば、界面活性剤、消泡剤、溶解剤、溶解補助剤、分散剤、防腐剤などが挙げられる。
[Other ingredients]
The composition may further contain other components [components other than palonosetrons, citric acids, edetate acids, isotonic agents, and pH adjusters (non-solvent components]) within a range that does not impair the effects of the present invention. , solid content)]. Examples of such other components include surfactants, antifoaming agents, solubilizers, solubilizers, dispersants, and preservatives.
他の成分は、単独で又は２種以上組み合わせてもよい。組成物は、これらの他の成分を実質的に含んでいなくてもよい。 Other components may be used alone or in combination of two or more. The composition may be substantially free of these other components.
［溶媒］
組成物は、通常、溶媒を含む組成物（液剤）であってもよい。なお、溶媒としては、通常、水性溶媒［例えば、水、水に混和する溶媒（アルコールなど）、これらの混合溶媒］が挙げられ、溶媒は、特に水（水のみ）であってもよい。
[solvent]
The composition may be a composition (liquid) containing a solvent. Note that the solvent usually includes an aqueous solvent [for example, water, a water-miscible solvent (such as alcohol), and a mixed solvent thereof], and the solvent may particularly be water (water only).
液剤において、溶媒（水性溶媒、特に水）の割合は、例えば、７０質量％以上、好ましくは８０質量％以上、さらに好ましくは９０質量％以上であってもよい。 In the liquid formulation, the proportion of the solvent (aqueous solvent, especially water) may be, for example, 70% by mass or more, preferably 80% by mass or more, and more preferably 90% by mass or more.
［各成分の割合］
組成物において、パロノセトロン類（例えば、パロノセトロン塩酸塩）の割合（濃度）は、パロノセトロンとして（パロノセトロン基準でパロノセトロン類）０．２ｍｇ／ｍＬ以上の範囲から選択でき、好ましくは０．２５ｍｇ／ｍＬ以上、さらに好ましくは０．３ｍｇ／ｍＬ以上、特に０．３３ｍｇ／ｍＬ以上、特に好ましくは０．３５ｍｇ／ｍＬ以上であってもよい。
パロノセトロン類（例えば、パロノセトロン塩酸塩）の割合（濃度）の上限値は、パロノセトロンとして、例えば、３ｍｇ／ｍＬ、２ｍｇ／ｍＬ、１ｍｇ／ｍＬ、０．８ｍｇ／ｍＬ等であってもよく、好ましくは０．７ｍｇ／ｍＬ以下（例えば、０．６ｍｇ／ｍＬ以下、０．５ｍｇ／ｍＬ以下、０．４５ｍｇ／ｍＬ以下、０．４ｍｇ／ｍＬ以下、０．３８ｍｇ／ｍＬ以下）であってもよい。
[Ratio of each component]
In the composition, the proportion (concentration) of palonosetron (for example, palonosetron hydrochloride) can be selected from a range of 0.2 mg/mL or more as palonosetron (palonosetron based on palonosetron standards), preferably 0.25 mg/mL or more, More preferably, it may be 0.3 mg/mL or more, particularly 0.33 mg/mL or more, particularly preferably 0.35 mg/mL or more.
The upper limit of the proportion (concentration) of palonosetron (for example, palonosetron hydrochloride) may be, for example, 3 mg/mL, 2 mg/mL, 1 mg/mL, 0.8 mg/mL, etc., and is preferably It may be 0.7 mg/mL or less (for example, 0.6 mg/mL or less, 0.5 mg/mL or less, 0.45 mg/mL or less, 0.4 mg/mL or less, 0.38 mg/mL or less).
本発明の組成物の第１の態様では、クエン酸類の割合（濃度、質量／体積割合）を調整する。このような組成物（第１の態様の組成物）において、クエン酸類［例えば、クエン酸及びクエン酸塩（クエン酸ナトリウム等）の総量］の割合（濃度）は、８．５ｍｇ／ｍＬ以下の範囲から選択してもよく、好ましくは８ｍｇ／ｍＬ以下、さらに好ましくは７．５ｍｇ／ｍＬ以下（例えば、７ｍｇ／ｍＬ以下）、特に６．５ｍｇ／ｍＬ以下（例えば、６ｍｇ／ｍＬ以下）、特に好ましくは５．５ｍｇ／ｍＬ以下（例えば、５．２ｍｇ／ｍＬ以下）であってもよい。
クエン酸類［例えば、クエン酸及びクエン酸塩（クエン酸ナトリウム等）の総量］の割合（濃度）の下限値は、例えば、０．１ｍｇ／ｍＬ、０．５ｍｇ／ｍＬ、１ｍｇ／ｍＬ、１．５ｍｇ／ｍＬ等であってもよく、好ましくは２ｍｇ／ｍＬ以上（例えば、２．５ｍｇ／ｍＬ以上、３ｍｇ／ｍＬ以上、３．５ｍｇ／ｍＬ以上、４ｍｇ／ｍＬ以上、４．５ｍｇ／ｍＬ以上）であってもよい。
In the first aspect of the composition of the present invention, the proportion (concentration, mass/volume ratio) of citric acids is adjusted. In such a composition (composition of the first aspect), the proportion (concentration) of citric acids [for example, the total amount of citric acid and citrate (sodium citrate, etc.)] is 8.5 mg/mL or less. It may be selected from a range, preferably 8 mg/mL or less, more preferably 7.5 mg/mL or less (e.g. 7 mg/mL or less), especially 6.5 mg/mL or less (e.g. 6 mg/mL or less), especially Preferably, it may be 5.5 mg/mL or less (for example, 5.2 mg/mL or less).
The lower limit of the ratio (concentration) of citric acids [for example, the total amount of citric acid and citrate (sodium citrate, etc.)] is, for example, 0.1 mg/mL, 0.5 mg/mL, 1 mg/mL, 1. It may be 5 mg/mL or the like, preferably 2 mg/mL or more (for example, 2.5 mg/mL or more, 3 mg/mL or more, 3.5 mg/mL or more, 4 mg/mL or more, 4.5 mg/mL or more). It may be.
クエン酸類が、クエン酸とクエン酸塩を含有する場合、クエン酸の割合（濃度）は、例えば、７ｍｇ／ｍＬ以下、好ましくは６ｍｇ／ｍＬ以下、さらに好ましくは５ｍｇ／ｍＬ以下（例えば、４ｍｇ／ｍＬ以下、３．５ｍｇ／ｍＬ以下）、特に３ｍｇ／ｍＬ以下（例えば、２．９ｍｇ／ｍＬ以下、２．５ｍｇ／ｍＬ以下、２．２ｍｇ／ｍＬ以下）、特に好ましくは２ｍｇ／ｍＬ以下（例えば、１．８ｍｇ／ｍＬ以下）であってもよい。
クエン酸の割合（濃度）の下限値は、例えば、０．０５ｍｇ／ｍＬ、０．１ｍｇ／ｍＬ、０．２ｍｇ／ｍＬ等であってもよく、好ましくは０．３ｍｇ／ｍＬ以上（例えば、０．５ｍｇ／ｍＬ以上、０．６ｍｇ／ｍＬ以上、０．７ｍｇ／ｍＬ以上、０．８ｍｇ／ｍＬ以上、１ｍｇ／ｍＬ以上、１．２ｍｇ／ｍＬ以上）であってもよい。
When the citric acids contain citric acid and citrate, the ratio (concentration) of citric acid is, for example, 7 mg/mL or less, preferably 6 mg/mL or less, more preferably 5 mg/mL or less (for example, 4 mg/mL or less). mL or less, 3.5 mg/mL or less), particularly 3 mg/mL or less (e.g., 2.9 mg/mL or less, 2.5 mg/mL or less, 2.2 mg/mL or less), particularly preferably 2 mg/mL or less (e.g. , 1.8 mg/mL or less).
The lower limit of the proportion (concentration) of citric acid may be, for example, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, etc., and preferably 0.3 mg/mL or more (for example, 0 .5 mg/mL or more, 0.6 mg/mL or more, 0.7 mg/mL or more, 0.8 mg/mL or more, 1 mg/mL or more, 1.2 mg/mL or more).
クエン酸類が、クエン酸とクエン酸塩を含有する場合、クエン酸塩（クエン酸ナトリウム等）の割合（濃度）は、例えば、８ｍｇ／ｍＬ以下、好ましくは７．５ｍｇ／ｍＬ以下、さらに好ましくは７ｍｇ／ｍＬ以下（例えば、６．５ｍｇ／ｍＬ以下）、特に６ｍｇ／ｍＬ以下（例えば、５．５ｍｇ／ｍＬ以下）、特に好ましくは５ｍｇ／ｍＬ以下（例えば、４．５ｍｇ／ｍＬ以下）であってもよい。
クエン酸塩の割合（濃度）の下限値は、例えば、０．１ｍｇ／ｍＬ、０．３ｍｇ／ｍＬ、０．５ｍｇ／ｍＬ、０．８ｍｇ／ｍＬ等であってもよく、好ましくは１ｍｇ／ｍＬ以上（例えば、１．２ｍｇ／ｍＬ以上、１．５ｍｇ／ｍＬ以上、１．８ｍｇ／ｍＬ以上、２ｍｇ／ｍＬ以上、２．２ｍｇ／ｍＬ以上、２．５ｍｇ／ｍＬ以上）であってもよい。
When the citric acids contain citric acid and citrate, the ratio (concentration) of the citrate (sodium citrate, etc.) is, for example, 8 mg/mL or less, preferably 7.5 mg/mL or less, more preferably 7 mg/mL or less (e.g., 6.5 mg/mL or less), particularly 6 mg/mL or less (e.g., 5.5 mg/mL or less), particularly preferably 5 mg/mL or less (e.g., 4.5 mg/mL or less). It's okay.
The lower limit of the proportion (concentration) of citrate may be, for example, 0.1 mg/mL, 0.3 mg/mL, 0.5 mg/mL, 0.8 mg/mL, etc., and preferably 1 mg/mL. or more (for example, 1.2 mg/mL or more, 1.5 mg/mL or more, 1.8 mg/mL or more, 2 mg/mL or more, 2.2 mg/mL or more, 2.5 mg/mL or more).
本発明の組成物の第２の態様では、パロノセトロン類（パロノセトロン）に対するクエン酸類の割合を調整する。このような組成物（第２の態様の組成物）において、クエン酸類［例えば、クエン酸及びクエン酸塩（クエン酸ナトリウム等）の総量］の割合は、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して、３０質量部以下程度の範囲から選択してもよく、好ましくは２５質量部以下、さらに好ましくは２２質量部以下、特に２０質量部以下、特に好ましくは１８質量部以下（例えば、１６質量部以下、１５質量部以下）であってもよい。
第２の態様において、クエン酸類の割合の下限値は、例えば、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して、０．１質量部、０．３質量部、０．５質量部、０．８質量部等であってもよく、好ましくは１質量部以上（例えば、１．２質量部以上、１．５質量部以上、１．８質量部以上、２質量部以上、２．２質量部以上、２．５質量部以上、２．８質量部以上、３質量部以上、３．２質量部以上、３．５質量部以上、３．８質量部以上、４質量部以上、４．２質量部以上、４．５質量部以上、４．８質量部以上、５質量部以上、６質量部以上、８質量部以上、１０質量部以上、１２質量部以上等）であってもよい。
In a second aspect of the composition of the invention, the ratio of citric acids to palonosetrons (palonosetron) is adjusted. In such a composition (composition of the second aspect), the proportion of citric acids [for example, the total amount of citric acid and citrate (sodium citrate, etc.)] is 1 mass of palonosetron (palonosetron based on palonosetron). 30 parts by weight or less, preferably 25 parts by weight or less, more preferably 22 parts by weight or less, particularly 20 parts by weight or less, particularly preferably 18 parts by weight or less (e.g. 16 parts by mass or less, 15 parts by mass or less).
In the second aspect, the lower limit of the proportion of citric acids is, for example, 0.1 parts by mass, 0.3 parts by mass, 0.5 parts by mass, with respect to 1 part by mass of palonosetron (palonosetrons based on palonosetron). It may be 0.8 parts by mass or the like, preferably 1 part by mass or more (for example, 1.2 parts by mass or more, 1.5 parts by mass or more, 1.8 parts by mass or more, 2 parts by mass or more, 2.2 parts by mass or more). At least 2.5 parts by mass, at least 2.8 parts by mass, at least 3 parts by mass, at least 3.2 parts by mass, at least 3.5 parts by mass, at least 3.8 parts by mass, at least 4 parts by mass, 4 parts by mass or more .2 parts by mass or more, 4.5 parts by mass or more, 4.8 parts by mass or more, 5 parts by mass or more, 6 parts by mass or more, 8 parts by mass or more, 10 parts by mass or more, 12 parts by mass or more) good.
クエン酸類が、クエン酸とクエン酸塩を含有する場合、クエン酸の割合は、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して、例えば、１５質量部以下程度の範囲から選択してもよく、好ましくは１０質量部以下、さらに好ましくは８質量部以下、特に７質量部以下、特に好ましくは６質量部以下（例えば、５．５質量部以下、５質量部以下、４．５質量部以下）であってもよい。
クエン酸の割合の下限値は、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して、例えば、０．０１質量部、０．０５質量部、０．１質量部、０．３質量部等であってもよく、好ましくは０．５質量部以上（例えば、０．８質量部以上、１質量部以上、１．２質量部以上、１．５質量部以上、１．８質量部以上、２質量部以上、２．２質量部以上、２．５質量部以上、２．８質量部以上、３質量部以上、３．２質量部以上、３．５質量部以上、３．８質量部以上等）であってもよい。
When the citric acids contain citric acid and citrate, the proportion of citric acid may be selected from a range of, for example, 15 parts by mass or less per 1 part by mass of palonosetron (palonosetrons based on palonosetron). Often, preferably 10 parts by weight or less, more preferably 8 parts by weight or less, particularly 7 parts by weight or less, particularly preferably 6 parts by weight or less (for example, 5.5 parts by weight or less, 5 parts by weight or less, 4.5 parts by weight or less). (below).
The lower limit of the proportion of citric acid is, for example, 0.01 parts by mass, 0.05 parts by mass, 0.1 parts by mass, 0.3 parts by mass, etc. with respect to 1 part by mass of palonosetron (palonosetrons based on palonosetron). and preferably 0.5 parts by mass or more (for example, 0.8 parts by mass or more, 1 part by mass or more, 1.2 parts by mass or more, 1.5 parts by mass or more, 1.8 parts by mass or more, 2 parts by mass or more, 2.2 parts by mass or more, 2.5 parts by mass or more, 2.8 parts by mass or more, 3 parts by mass or more, 3.2 parts by mass or more, 3.5 parts by mass or more, 3.8 parts by mass above, etc.).
クエン酸類が、クエン酸とクエン酸塩を含有する場合、クエン酸塩の割合は、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して、例えば、３０質量部以下程度の範囲から選択してもよく、好ましくは２５質量部以下、さらに好ましくは２０質量部以下、特に１８質量部以下、特に好ましくは１５質量部以下（例えば、１４質量部以下、１３質量部以下、１２質量部以下、１１質量部以下、１０質量部以下）であってもよい。
クエン酸塩の割合の下限値は、パロノセトロン（パロノセトロン基準でパロノセトロン類）１質量部に対して、例えば、０．０１質量部、０．０５質量部、０．１質量部、０．３質量部等であってもよく、好ましくは０．５質量部以上（例えば、０．８質量部以上、１質量部以上、１．２質量部以上、１．５質量部以上、１．８質量部以上、２質量部以上、２．２質量部以上、２．５質量部以上、２．８質量部以上、３質量部以上、３．２質量部以上、３．５質量部以上、３．８質量部以上、４質量部以上、４．５質量部以上、５質量部以上、５．５質量部以上、６質量部以上、６．５質量部以上、７質量部以上、７．５質量部以上、８質量部以上、８．５質量部以上、９質量部以上等）であってもよい。
When the citric acids contain citric acid and citrate, the proportion of the citrate is selected from a range of, for example, 30 parts by mass or less per 1 part by mass of palonosetron (palonosetron based on palonosetron). Preferably 25 parts by weight or less, more preferably 20 parts by weight or less, particularly 18 parts by weight or less, particularly preferably 15 parts by weight or less (for example, 14 parts by weight or less, 13 parts by weight or less, 12 parts by weight or less, 11 parts by weight or less). 10 parts by mass or less).
The lower limit of the proportion of citrate is, for example, 0.01 parts by mass, 0.05 parts by mass, 0.1 parts by mass, 0.3 parts by mass with respect to 1 part by mass of palonosetron (palonosetrons based on palonosetron). etc., preferably 0.5 parts by mass or more (for example, 0.8 parts by mass or more, 1 part by mass or more, 1.2 parts by mass or more, 1.5 parts by mass or more, 1.8 parts by mass or more) , 2 parts by mass or more, 2.2 parts by mass or more, 2.5 parts by mass or more, 2.8 parts by mass or more, 3 parts by mass or more, 3.2 parts by mass or more, 3.5 parts by mass or more, 3.8 parts by mass parts by mass or more, 4 parts by mass or more, 4.5 parts by mass or more, 5 parts by mass or more, 5.5 parts by mass or more, 6 parts by mass or more, 6.5 parts by mass or more, 7 parts by mass or more, 7.5 parts by mass or more , 8 parts by mass or more, 8.5 parts by mass or more, 9 parts by mass or more, etc.).
なお、本発明の組成物は、通常、少なくとも第１の態様又は第２の態様を充足するが、これらの態様の双方（第１の態様及び第２の態様）を充足してもよい。 Note that the composition of the present invention usually satisfies at least the first aspect or the second aspect, but may satisfy both of these aspects (the first aspect and the second aspect).
組成物が、エデト酸類（例えば、エデト酸ナトリウム）を含有する場合、エデト酸類の割合（濃度）は、例えば、０．０１ｍｇ／ｍＬ以上（例えば、０．０５ｍｇ／ｍＬ以上）、好ましくは０．１ｍｇ／ｍＬ以上、さらに好ましくは０．２ｍｇ／ｍＬ以上、特に０．３ｍｇ／ｍＬ以上、特に好ましくは０．５ｍｇ／ｍＬ以上（例えば、０．８ｍｇ／ｍＬ以上、１ｍｇ／ｍＬ以上）であってもよい。 When the composition contains edetate acids (for example, sodium edetate), the proportion (concentration) of the edetate acids is, for example, 0.01 mg/mL or more (for example, 0.05 mg/mL or more), preferably 0.01 mg/mL or more (for example, 0.05 mg/mL or more). 1 mg/mL or more, more preferably 0.2 mg/mL or more, especially 0.3 mg/mL or more, particularly preferably 0.5 mg/mL or more (for example, 0.8 mg/mL or more, 1 mg/mL or more) Good too.
エデト酸類の割合（濃度）の上限値は、例えば、１０ｍｇ／ｍＬ、８ｍｇ／ｍＬ、７ｍｇ／ｍＬ、６ｍｇ／ｍＬ等であってもよく、好ましくは５ｍｇ／ｍＬ以下（例えば、４ｍｇ／ｍＬ以下、３ｍｇ／ｍＬ以下、２ｍｇ／ｍＬ以下、１．５ｍｇ／ｍＬ以下）であってもよい。 The upper limit of the ratio (concentration) of edetic acids may be, for example, 10 mg/mL, 8 mg/mL, 7 mg/mL, 6 mg/mL, etc., and is preferably 5 mg/mL or less (for example, 4 mg/mL or less, 3 mg/mL or less, 2 mg/mL or less, 1.5 mg/mL or less).
組成物が、等張化剤（例えば、マンニトール）を含有する場合、等張化剤の割合（濃度）は、その種類に応じて選択できるが、例えば、１ｍｇ／ｍＬ以上（例えば、３ｍｇ／ｍＬ以上）、好ましくは５ｍｇ／ｍＬ以上、さらに好ましくは１０ｍｇ／ｍＬ以上、特に１５ｍｇ／ｍＬ以上、特に好ましくは２０ｍｇ／ｍＬ以上（例えば、２５ｍｇ／ｍＬ以上、３０ｍｇ／ｍＬ以上）であってもよい。 When the composition contains an isotonizing agent (e.g., mannitol), the proportion (concentration) of the isotonizing agent can be selected depending on the type, but for example, 1 mg/mL or more (e.g., 3 mg/mL). above), preferably 5 mg/mL or more, more preferably 10 mg/mL or more, particularly 15 mg/mL or more, particularly preferably 20 mg/mL or more (for example, 25 mg/mL or more, 30 mg/mL or more).
等張化剤の割合（濃度）の上限値は、例えば、５００ｍｇ／ｍＬ、４００ｍｇ／ｍＬ、３００ｍｇ／ｍＬ、２００ｍｇ／ｍＬ等であってもよく、好ましくは１５０ｍｇ／ｍＬ以下（例えば、１２０ｍｇ／ｍＬ以下、１００ｍｇ／ｍＬ以下、８０ｍｇ／ｍＬ以下、６０ｍｇ／ｍＬ以下、５０ｍｇ／ｍＬ以下）であってもよい。 The upper limit of the ratio (concentration) of the tonicity agent may be, for example, 500 mg/mL, 400 mg/mL, 300 mg/mL, 200 mg/mL, etc., and is preferably 150 mg/mL or less (for example, 120 mg/mL). (hereinafter, 100 mg/mL or less, 80 mg/mL or less, 60 mg/mL or less, 50 mg/mL or less).
なお、これらの成分以外の成分の割合は、その用途、目的等に応じて適宜選択できる。例えば、組成物がｐＨ調整剤を含む場合、ｐＨ調整剤の割合は、所望のｐＨに応じて適宜選択できる。 Note that the proportion of components other than these components can be appropriately selected depending on the use, purpose, etc. For example, when the composition contains a pH adjuster, the proportion of the pH adjuster can be appropriately selected depending on the desired pH.
［組成物の態様］
溶媒を含む組成物（液剤）のｐＨは、酸性、中性及びアルカリ性のいずれからも選択できるが、例えば、３～１０（例えば、３～８）、好ましくは３．５～７．５、さらに好ましくは４～７（例えば、４．２～６）、特に４．５～５．５程度であってもよい。
[Aspects of composition]
The pH of the composition (liquid) containing a solvent can be selected from acidic, neutral, and alkaline, for example, 3 to 10 (for example, 3 to 8), preferably 3.5 to 7.5, and It is preferably about 4 to 7 (for example, 4.2 to 6), particularly about 4.5 to 5.5.
組成物の浸透圧は、例えば、生理食塩水に対する浸透圧比で、０．１～１０（例えば、０．２～５）、好ましくは０．３～３（例えば、０．５～２）、さらに好ましくは０．６～１．４（例えば、０．７～１．３）、特に０．８～１．２（例えば、０．９～１．１）であってもよく、１（約１）であってもよい。
浸透圧（浸透圧比）は、常温（例えば、２０～３０℃、２３℃等）における値であってもよい。浸透圧比は、例えば、日本薬局方に従って測定できる。
なお、市販品の浸透圧比は、約１である。
The osmotic pressure of the composition is, for example, an osmotic pressure ratio to physiological saline of 0.1 to 10 (eg, 0.2 to 5), preferably 0.3 to 3 (eg, 0.5 to 2), and It may preferably be between 0.6 and 1.4 (eg 0.7-1.3), especially between 0.8 and 1.2 (eg 0.9-1.1), and may be between 1 (about 1 ).
The osmotic pressure (osmotic pressure ratio) may be a value at room temperature (eg, 20 to 30°C, 23°C, etc.). The osmotic pressure ratio can be measured, for example, according to the Japanese Pharmacopoeia.
Note that the osmotic pressure ratio of commercially available products is approximately 1.
本発明では、市販品と同様の浸透圧比としても、パロノセトロン類の高濃度化と優れた安定性とを両立しうる。 In the present invention, high concentration and excellent stability of palonosetrons can be achieved at the same osmotic pressure ratio as a commercially available product.
組成物（液剤）における酸素濃度は、比較的低濃度（例えば、１０体積％以下）であってもよく、例えば、５体積％以下（例えば、３体積％以下）、好ましくは２．５体積％以下、さらに好ましくは２．０体積％以下であってもよく、１．０体積％以下（例えば、０．８体積％以下、好ましくは０．７体積％以下、さらに好ましくは０．６体積％以下、特に０．５体積％以下）であってもよい。
なお、組成物における酸素濃度（溶存酸素濃度）は、慣用の方法（不活性ガスによるバブリングなど）などにより調整（低減）できる。
The oxygen concentration in the composition (liquid) may be relatively low (for example, 10% by volume or less), for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5% by volume. Below, more preferably 2.0 volume% or less, 1.0 volume% or less (for example, 0.8 volume% or less, preferably 0.7 volume% or less, more preferably 0.6 volume% (in particular, 0.5% by volume or less).
Note that the oxygen concentration (dissolved oxygen concentration) in the composition can be adjusted (reduced) by a conventional method (such as bubbling with an inert gas).
組成物は、通常、無色であってもよく、特に無色澄明であってもよい。 The composition may generally be colorless, particularly colorless and clear.
本発明の組成物（製剤、パロノセトロン製剤）は、容器に封入（密閉）されていてもよい。換言すれば、本発明には、組成物（パロノセトロン製剤）を含む容器（内部に含む容器）も含まれる。 The composition (preparation, palonosetron preparation) of the present invention may be enclosed (sealed) in a container. In other words, the present invention also includes a container containing the composition (palonosetron formulation).
このような容器には、通常、前記組成物が封入又は密閉されていてもよい。本発明の組成物は、このような容器に封入（保存）されても、効率良く優れた安定性を実現しうる。 The composition may be normally enclosed or sealed in such a container. Even when the composition of the present invention is sealed (stored) in such a container, it can efficiently achieve excellent stability.
容器としては、投与態様等に応じて適宜選択でき、例えば、バイアル、アンプル、注射器（又はシリンジ、例えば、プレフィルドシリンジ等）、バッグなどが挙げられる。 The container can be appropriately selected depending on the mode of administration, and includes, for example, a vial, an ampoule, a syringe (or a syringe, such as a prefilled syringe), and a bag.
特に、本発明の組成物は、パロノセトロン製剤を高濃度化できるため、バイアル、アンプル、シリンジ（特に、シリンジ）等に封入してもよい（例えば、シリンジ製剤であってもよい）。例えば、シリンジは、使用時の手間が少ない、採取ミスが無い、等の点で好適に使用できる。 In particular, since the composition of the present invention can increase the concentration of the palonosetron preparation, it may be enclosed in a vial, an ampoule, a syringe (particularly a syringe), etc. (for example, it may be a syringe preparation). For example, a syringe can be suitably used because it requires less effort during use and there is no possibility of sampling errors.
容器の材質は、特に限定されず、例えば、ガラス、金属、樹脂（プラスチック）等が挙げられる。容器は、２種以上の材質を組み合わせて形成してもよい。 The material of the container is not particularly limited, and examples thereof include glass, metal, resin (plastic), and the like. The container may be formed by combining two or more types of materials.
なお、容器（例えば、容器のうち、少なくとも組成物と接触する部分）は、適宜、表面処理（例えば、ブラスト処理、表面処理剤によるコート処理など）されていてもよい。 Note that the container (for example, at least the portion of the container that comes into contact with the composition) may be appropriately surface-treated (for example, blasting treatment, coating treatment with a surface treatment agent, etc.).
容器において、組成物の量は、容器の種類・サイズ、パロノセトロン濃度（所望のパロノセトロン量）等に応じて適宜選択できるが、特に、５ｍＬ（市販品）未満、例えば、４．５ｍＬ以下（例えば、０．１～４．２ｍＬ）、好ましくは４ｍＬ以下（例えば、０．３～３．５ｍＬ）、さらに好ましくは３ｍＬ（例えば、０．５～２．５ｍＬ）、特に２．２ｍＬ以下であってもよい。具体的な組成物の量には、１ｍＬ、１．５ｍＬ、２ｍＬ、２．５ｍＬ、３ｍＬ、３．５ｍＬ、４ｍＬ等が挙げられ、代表的には２ｍＬであってもよい。 The amount of the composition in the container can be appropriately selected depending on the type and size of the container, the palonosetron concentration (desired amount of palonosetron), etc., but in particular less than 5 mL (commercially available), for example, 4.5 mL or less (for example, 0.1 to 4.2 mL), preferably 4 mL or less (for example, 0.3 to 3.5 mL), more preferably 3 mL (for example, 0.5 to 2.5 mL), especially 2.2 mL or less. good. Specific amounts of the composition include 1 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, etc., and typically may be 2 mL.
容器の内部は、前記組成物（液剤）のみで構成してもよく、空隙（空間）を有していてもよい。このような空隙（空隙部、ヘッドスペース）は、特に、不活性ガス（窒素ガスなど）で充填されている（又は置換されている）のが好ましい。 The inside of the container may be composed only of the composition (liquid), or may have voids (spaces). It is particularly preferable that such voids (voids, headspaces) are filled (or substituted) with an inert gas (nitrogen gas, etc.).
さらに、このような空隙に含まれる酸素も、比較的少なくしてもよい。例えば、容器内の空隙中の酸素濃度は、例えば、１０体積％以下であってもよく、例えば、５体積％以下（例えば、３体積％以下）、好ましくは２．５体積％以下、さらに好ましくは２．０体積％以下（例えば、１．５体積％以下）であってもよく、１．０体積％以下（例えば、０．８体積％以下、好ましくは０．７体積％以下、さらに好ましくは０．６体積％以下、特に０．５体積％以下）であってもよい。 Furthermore, the amount of oxygen contained in such voids may also be relatively small. For example, the oxygen concentration in the void inside the container may be, for example, 10% by volume or less, for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5% by volume or less, and more preferably may be 2.0 volume% or less (for example, 1.5 volume% or less), 1.0 volume% or less (for example, 0.8 volume% or less, preferably 0.7 volume% or less, more preferably may be 0.6 volume % or less, particularly 0.5 volume % or less).
酸素濃度は、慣用の方法、例えば、前記組成物及び／又は容器内部に不活性ガスをバブリングする方法、前記組成物及び／又は容器内部を脱気する方法、容器内の空隙を不活性ガスで置換する方法、これらを組み合わせた方法などにより調整できる。 The oxygen concentration can be determined by a conventional method, for example, by bubbling an inert gas into the composition and/or the container, by deaerating the composition and/or the container, or by filling a void in the container with an inert gas. It can be adjusted by a method of substitution, a method of combining these methods, etc.
本発明の組成物は、投与方法に応じて選択できるが、特に、注射剤（又は点滴静注）の形態であってもよい。
本発明には、組成物を投与する方法（投与方法）も含まれる、具体的な投与方法としては、例えば、静注（静脈注射）、筋肉注射、または皮下注射等が挙げられる。さらに具体的には、注射で動脈内、腹膜内、髄膜下、心室内、尿道内、胸骨内、頭蓋内等に投与してもよく、点滴静注により投与してもよい。
The composition of the present invention can be selected depending on the method of administration, and in particular, it may be in the form of an injection (or intravenous drip).
The present invention also includes a method of administering the composition (administration method). Specific administration methods include, for example, intravenous injection (intravenous injection), intramuscular injection, or subcutaneous injection. More specifically, the drug may be administered by injection into an artery, intraperitoneum, submeningeal, intraventricular, urethral, intrasternal, intracranial, etc., or may be administered by intravenous drip.
なお、点滴静注等で投与する場合、前記組成物を輸液に混合し溶解させることで点滴静注液を調製してもよい。本態様において、前記組成物を輸液に混合させるときの比率は、該静注液を投与される患者等の対象の体表面積、年齢、性別、適用箇所、病状の程度等に応じて適宜選択してよく、特に限定されない。 In addition, when administering by intravenous drip injection etc., the intravenous drip solution may be prepared by mixing and dissolving the composition in an infusion solution. In this embodiment, the ratio at which the composition is mixed with the infusion solution is appropriately selected depending on the body surface area, age, sex, application site, degree of disease, etc. of the subject such as the patient to whom the intravenous solution is administered. may be used, and is not particularly limited.
輸液としては、特に限定されないが、例えば、生理食塩液、糖水溶液（ブドウ糖水溶液、果糖水溶液など）、糖アルコール水溶液（Ｄ－ソルビトール水溶液、キシリトール水溶液など）、アミノ酸水溶液、リンゲル液などが挙げられる。 Examples of infusion solutions include, but are not limited to, physiological saline, aqueous sugar solutions (glucose aqueous solution, fructose aqueous solution, etc.), sugar alcohol aqueous solutions (D-sorbitol aqueous solution, xylitol aqueous solution, etc.), amino acid aqueous solution, Ringer's solution, and the like.
次に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではなく、多くの変形が本発明の技術的思想内で当分野において通常の知識を有する者により可能である。 Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples in any way, and many modifications can be made within the technical idea of the present invention in the art. It is possible for a person with ordinary knowledge to do so.
各種評価は以下のように行った。 Various evaluations were performed as follows.
［総類縁物質］
サンプルを２０ｍｍｏｌ／Ｌリン酸カリウム緩衝液（ｐＨ２．５）／アセトニトリル／メタノール混液（８：１：１）にて希釈し，７５μｇ／ｍＬ（パロノセトロンとして）とした液１００μＬにつき、次の条件で液体クロマトグラフィーにより試験を行い、各類縁物質の量をパロノセトンに由来する全ピーク面積中の各類縁物質のピーク面積の比率（％）から算出した。
[Total related substances]
The sample was diluted with 20 mmol/L potassium phosphate buffer (pH 2.5)/acetonitrile/methanol mixture (8:1:1) to give 75 μg/mL (as palonosetron), and the liquid was diluted under the following conditions. A test was conducted by chromatography, and the amount of each related substance was calculated from the ratio (%) of the peak area of each related substance to the total peak area derived from palonosetone.
（試験条件）
検出器：紫外吸光光度計（測定波長：２４２ｎｍ）
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に３μｍの液体クロマトグラフィー用フェニルシリル化シリカゲルを充填する。
カラム温度：４５℃付近の一定温度
移動相Ａ：２０ｍｍｏｌ／Ｌリン酸カリウム緩衝液（ｐＨ２．５）／アセトニトリル／メタノール混液（１８：１：１）
移動相Ｂ：２０ｍｍｏｌ／Ｌリン酸カリウム緩衝液（ｐＨ２．５）／アセトニトリル／メタノール混液（２：１：１）
移動相の送液：移動相Ａ及び移動相Ｂの混合比を次のように変えて濃度勾配制御する。
(Test condition)
Detector: Ultraviolet absorption photometer (measurement wavelength: 242 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is filled with 3 μm phenylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 45°C Mobile phase A: 20 mmol/L potassium phosphate buffer (pH 2.5)/acetonitrile/methanol mixture (18:1:1)
Mobile phase B: 20 mmol/L potassium phosphate buffer (pH 2.5)/acetonitrile/methanol mixture (2:1:1)
Transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.
［ｐＨ］
日本薬局方ｐＨ測定法に従い、２３℃において測定した。
[pH]
It was measured at 23°C according to the Japanese Pharmacopoeia pH measurement method.
下記表（表１）に示す組成物を調製し、各種評価を行った。結果（評価）を下記表（表１）に合わせて示した。
なお、組成物は、次のように調製した。
Compositions shown in the table below (Table 1) were prepared and various evaluations were performed. The results (evaluation) are shown in the table below (Table 1).
In addition, the composition was prepared as follows.
適量の注射用水に秤量したクエン酸ナトリウム水和物、クエン酸水和物、エデト酸ナトリウム水和物、Ｄ－マンニトール及びパロノセトロン塩酸塩を投入し、攪拌して溶解した。塩酸溶液又は水酸化ナトリウム水溶液を用いて必要に応じてｐＨ調整を行った。注射用水を用いて全量を合わせ、フィルターにてろ過を行った。ろ過液をガラスバイアルに充填し、ゴム栓打栓を行い、アルミキャップにて密封した。このバイアルをオートクレーブで高圧蒸気滅菌した。 Weighed amounts of sodium citrate hydrate, citric acid hydrate, sodium edetate hydrate, D-mannitol, and palonosetron hydrochloride were added to an appropriate amount of water for injection, and dissolved by stirring. The pH was adjusted as necessary using a hydrochloric acid solution or an aqueous sodium hydroxide solution. The total amount was combined using water for injection, and filtered using a filter. The filtrate was filled into a glass vial, sealed with a rubber stopper, and sealed with an aluminum cap. This vial was sterilized with high pressure steam in an autoclave.
下記表において、「８０℃・１０日」「６０℃・１ヶ月」における湿度はなりゆき湿度で行い、「２５℃・６０万ｌｘ・ｈｒ」では６０％ＲＨとした。 In the table below, the humidity at "80° C., 10 days" and "60° C., 1 month" was determined at normal humidity, and at "25° C., 600,000 lx/hr", it was set at 60% RH.
また、試験例Ｅの組成物では、調製段階で析出が生じたため、ｐＨ変化の測定については断念した。一方、試験例Ｅ以外の試験例の組成物は、調製段階において、析出が生じず、無色澄明であった。 Furthermore, in the composition of Test Example E, precipitation occurred during the preparation stage, so measurement of pH changes was abandoned. On the other hand, the compositions of Test Examples other than Test Example E did not cause precipitation during the preparation stage and were clear and colorless.
上記表の結果から明らかなように、市販品（試験例Ａ）の配合量を維持したまま、パロノセトロンを高濃度化すると、不安定化した（試験例Ｂ～Ｅ）。 As is clear from the results in the table above, when the concentration of palonosetron was increased while maintaining the blended amount of the commercial product (Test Example A), it became unstable (Test Examples B to E).
このような不安定化は、マンニトールの配合量を変更しても抑えることができず、光安定性はむしろ低下した（試験例ＤとＦとの対比）。 Such destabilization could not be suppressed even by changing the amount of mannitol blended, and the photostability was rather reduced (comparison between Test Examples D and F).
一方、クエン酸類（クエン酸、クエン酸ナトリウム）の配合量を変更することで、不安定化の程度を抑えることができた（試験例Ｇ～Ｉ）。 On the other hand, by changing the blending amount of citric acids (citric acid, sodium citrate), the degree of destabilization could be suppressed (Test Examples G to I).
また、これらの不安定化の程度を抑えられた処方間（試験例Ｇ～Ｉ）で対比すると、クエン酸類の濃度ないしパロノセトロンに対する配合量が低いもの（試験例Ｇ，Ｈ）は、総類縁物質の量が少なくなったものの、一方でｐＨ変化は大きかった。 Furthermore, when comparing the formulations that suppressed the degree of destabilization (Test Examples G to I), the formulations with low concentrations of citric acids or low amounts of palonosetron (Test Examples G and H) showed that all related substances Although the amount of was decreased, on the other hand, the pH change was large.
さらに、このような処方（試験例Ｇ～Ｉ）では、エデト酸類及びマンニトールの配合量を変動させても、特段、安定性に差異が見られなかった。そうすると、マンニトールは、浸透圧調整の観点から、市販品と同程度の濃度に、エデト酸類は、市販品と同程度の配合量とすることが好ましいことが示唆された。 Furthermore, in such formulations (Test Examples G to I), no particular difference in stability was observed even when the amounts of edetate acids and mannitol were varied. This suggests that, from the viewpoint of osmotic pressure adjustment, it is preferable to use mannitol in a concentration similar to that of a commercially available product, and edetate acids in an amount comparable to that of a commercially available product.
そのため、これらを総合的に考慮すると、試験例Ｉが最も好ましい処方と考えられる。 Therefore, considering these comprehensively, Test Example I is considered to be the most preferable formulation.
本発明により、新規なパロノセトロン組成物を提供できる。 The present invention can provide a novel palonosetron composition.
Claims (27)
パロノセトロン類が、パロノセトロン及びパロノセトロンの塩から選択された少なくとも１種であり、
クエン酸類が、クエン酸及びクエン酸塩から選択された少なくとも１種であり、
パロノセトロン類の濃度が、パロノセトロンとして０．２～３ｍｇ／ｍＬ、
クエン酸類の濃度が８．５ｍｇ／ｍＬ以下である、組成物（ただし、下記（１）又は（２）を充足する
（１）組成物が、パロノセトロン類をパロノセトロンとして０．３０ｍｇ／ｍＬの濃度、マンニトールを４１．５２ｍｇ／ｍＬの濃度で含有する、ｐＨ５．０の組成物でない
（２）組成物が、さらに、エデト酸及びエデト酸塩から選択された少なくとも１種のエデト酸類を含む）。 Contains palonosetrons and citric acids,
The palonosetrons are at least one selected from palonosetron and salts of palonosetron,
the citric acids are at least one selected from citric acid and citrates,
The concentration of palonosetrons is 0.2 to 3 mg/ mL as palonosetron,
A composition in which the concentration of citric acids is 8.5 mg/mL or less (provided that the following (1) or (2) is satisfied)
(1) The composition is not a pH 5.0 composition containing palonosetrons at a concentration of 0.30 mg/mL as palonosetron and mannitol at a concentration of 41.52 mg/mL.
(2) The composition further contains at least one edetate selected from edetate and edetate salts .
パロノセトロン類が、パロノセトロン及びパロノセトロンの塩から選択された少なくとも１種であり、
クエン酸類が、クエン酸及びクエン酸塩から選択された少なくとも１種であり、
パロノセトロン類の濃度が、パロノセトロンとして０．２～３ｍｇ／ｍＬ、
クエン酸類の割合が、パロノセトロン１質量部に対して３０質量部以下である、組成物（ただし、下記（１）又は（２）を充足する
（１）組成物が、パロノセトロン類をパロノセトロンとして０．３０ｍｇ／ｍＬの濃度、マンニトールを４１．５２ｍｇ／ｍＬの濃度で含有する、ｐＨ５．０の組成物でない
（２）組成物が、さらに、エデト酸及びエデト酸塩から選択された少なくとも１種のエデト酸類を含む）。 Contains palonosetrons and citric acids,
The palonosetrons are at least one selected from palonosetron and salts of palonosetron,
the citric acids are at least one selected from citric acid and citrates,
The concentration of palonosetrons is 0.2 to 3 mg/ mL as palonosetron,
A composition in which the proportion of citric acids is 30 parts by mass or less per 1 part by mass of palonosetron (provided that the following (1) or (2) is satisfied)
(1) The composition is not a pH 5.0 composition containing palonosetrons at a concentration of 0.30 mg/mL as palonosetron and mannitol at a concentration of 41.52 mg/mL.
(2) The composition further contains at least one edetate selected from edetate and edetate salts .
パロノセトロン類が、パロノセトロン及びパロノセトロンの塩から選択された少なくとも１種であり、
クエン酸類が、クエン酸及びクエン酸塩から選択された少なくとも１種であり、
パロノセトロン類の濃度が、パロノセトロンとして０．２～３ｍｇ／ｍＬ、
クエン酸類の濃度が８．５ｍｇ／ｍＬ以下、
クエン酸類の割合が、パロノセトロン１質量部に対して３０質量部以下である、組成物（ただし、下記（１）又は（２）を充足する
（１）組成物が、パロノセトロン類をパロノセトロンとして０．３０ｍｇ／ｍＬの濃度、マンニトールを４１．５２ｍｇ／ｍＬの濃度で含有する、ｐＨ５．０の組成物でない
（２）組成物が、さらに、エデト酸及びエデト酸塩から選択された少なくとも１種のエデト酸類を含む）。 Contains palonosetrons and citric acids,
The palonosetrons are at least one selected from palonosetron and salts of palonosetron,
the citric acids are at least one selected from citric acid and citrates,
The concentration of palonosetrons is 0.2 to 3 mg/ mL as palonosetron,
The concentration of citric acids is 8.5 mg/mL or less,
A composition in which the proportion of citric acids is 30 parts by mass or less per 1 part by mass of palonosetron (provided that the following (1) or (2) is satisfied)
(1) The composition is not a pH 5.0 composition containing palonosetrons at a concentration of 0.30 mg/mL as palonosetron and mannitol at a concentration of 41.52 mg/mL.
(2) The composition further contains at least one edetate selected from edetate and edetate salts .
パロノセトロン類がパロノセトロン塩酸塩、クエン酸類がクエン酸及びクエン酸ナトリウム、等張化剤がマンニトール、エデト酸類がエデト酸ナトリウムであり、
パロノセトロン類の濃度が、パロノセトロンとして０．３～０．４５ｍｇ／ｍＬ、
クエン酸の濃度が１～２ｍｇ／ｍＬ、
クエン酸塩の濃度が２．５～４．５ｍｇ／ｍＬ、
クエン酸類の割合がパロノセトロン１質量部に対して１．５～２０質量部、
エデト酸類の濃度が０．８～２ｍｇ／ｍＬ、
等張化剤の濃度が、３０～５０ｍｇ／ｍＬ、
ｐＨが、４．５～５．５である、請求項１～１５のいずれかに記載の組成物。 Furthermore, it contains edetic acids and isotonic agents,
The palonosetrons are palonosetron hydrochloride, the citric acids are citric acid and sodium citrate, the tonicity agent is mannitol, and the edetic acids are sodium edetate,
The concentration of palonosetrons is 0.3 to 0.45 mg/mL as palonosetron,
The concentration of citric acid is 1 to 2 mg/mL,
The concentration of citrate is 2.5 to 4.5 mg/mL,
The proportion of citric acids is 1.5 to 20 parts by mass per 1 part by mass of palonosetron,
The concentration of edetic acids is 0.8 to 2 mg/mL,
The concentration of the tonicity agent is 30 to 50 mg/mL,
The composition according to any one of claims 1 to 15, having a pH of 4.5 to 5.5.
パロノセトロン類がパロノセトロン塩酸塩、クエン酸類がクエン酸及びクエン酸ナトリウム、エデト酸類がエデト酸ナトリウム、等張化剤がマンニトールであり、The palonosetrons are palonosetron hydrochloride, the citric acids are citric acid and sodium citrate, the edetic acids are sodium edetate, and the tonicity agent is mannitol.
パロノセトロン類の濃度が、パロノセトロンとして０．３７５ｍｇ／ｍＬであり、The concentration of palonosetron is 0.375 mg/mL as palonosetron,
クエン酸の濃度が１～２ｍｇ／ｍＬであり、The concentration of citric acid is 1 to 2 mg/mL,
クエン酸ナトリウムの濃度が２．５～４．５ｍｇ／ｍＬであり、The concentration of sodium citrate is 2.5 to 4.5 mg/mL,
エデト酸類の濃度が０．８～２ｍｇ／ｍＬであり、The concentration of edetic acids is 0.8 to 2 mg/mL,
等張化剤の濃度が、３０～５０ｍｇ／ｍＬであり、The concentration of the tonicity agent is 30 to 50 mg/mL,
酒石酸、酒石酸の塩及びグルコースのいずれも含有せず、Contains neither tartaric acid, tartaric acid salts nor glucose,
ｐＨが、４．５～５．５である、組成物。A composition having a pH of 4.5 to 5.5.
パロノセトロン類が、パロノセトロン及びパロノセトロンの塩から選択された少なくとも１種であり、
クエン酸類が、クエン酸及びクエン酸塩から選択された少なくとも１種であり、
パロノセトロン類の濃度が、パロノセトロンとして０．２～３ｍｇ／ｍＬである組成物において、パロノセトロン類の安定性を向上する方法であって、クエン酸類の濃度を８．５ｍｇ／ｍＬ以下、及び／又はクエン酸類の割合をパロノセトロン１質量部に対して３０質量部以下とする、方法（ただし、下記（１）又は（２）を充足する
（１）組成物が、パロノセトロン類をパロノセトロンとして０．３０ｍｇ／ｍＬの濃度、マンニトールを４１．５２ｍｇ／ｍＬの濃度で含有する、ｐＨ５．０の組成物でない
（２）組成物が、さらに、エデト酸及びエデト酸塩から選択された少なくとも１種のエデト酸類を含む）。 Contains palonosetrons and citric acids,
The palonosetrons are at least one selected from palonosetron and salts of palonosetron,
the citric acids are at least one selected from citric acid and citrates,
A method for improving the stability of palonosetrons in a composition in which the concentration of palonosetrons is 0.2 to 3 mg/ mL as palonosetron, the method comprising: reducing the concentration of citric acids to 8.5 mg/mL or less; and/or Or a method in which the ratio of citric acids is 30 parts by mass or less per 1 part by mass of palonosetron (provided that (1) or (2) below is satisfied)
(1) The composition is not a pH 5.0 composition containing palonosetrons at a concentration of 0.30 mg/mL as palonosetron and mannitol at a concentration of 41.52 mg/mL.
(2) The composition further contains at least one edetate selected from edetate and edetate salts .
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| JP2020051745A JP7438802B2 (en) | 2020-03-23 | 2020-03-23 | Palonosetron-containing composition |
| TW110109154A TW202202142A (en) | 2020-03-23 | 2021-03-15 | Composition containing palonosetron capable of being prepared in high concentration and for long-term preservation |
| KR1020210037336A KR20210118767A (en) | 2020-03-23 | 2021-03-23 | A composition comprising palonosetron |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1682728A (en) | 2005-02-23 | 2005-10-19 | 重庆医药工业研究院有限责任公司 | Stable palonosetron injection |
| JP2006516583A (en) | 2003-01-30 | 2006-07-06 | ヘルシン ヘルスケア ソシエテ アノニム | Palonosetron liquid pharmaceutical formulation |
| JP2019137658A (en) | 2018-02-15 | 2019-08-22 | 日本化薬株式会社 | Liquid formulation of palonosetron for injection |
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- 2020-03-23 JP JP2020051745A patent/JP7438802B2/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006516583A (en) | 2003-01-30 | 2006-07-06 | ヘルシン ヘルスケア ソシエテ アノニム | Palonosetron liquid pharmaceutical formulation |
| CN1682728A (en) | 2005-02-23 | 2005-10-19 | 重庆医药工业研究院有限责任公司 | Stable palonosetron injection |
| JP2019137658A (en) | 2018-02-15 | 2019-08-22 | 日本化薬株式会社 | Liquid formulation of palonosetron for injection |
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| KR20210118767A (en) | 2021-10-01 |
| TW202202142A (en) | 2022-01-16 |
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