JP2023169446A - Fosaprepitant injection aqueous solution - Google Patents
Fosaprepitant injection aqueous solution Download PDFInfo
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- JP2023169446A JP2023169446A JP2020170581A JP2020170581A JP2023169446A JP 2023169446 A JP2023169446 A JP 2023169446A JP 2020170581 A JP2020170581 A JP 2020170581A JP 2020170581 A JP2020170581 A JP 2020170581A JP 2023169446 A JP2023169446 A JP 2023169446A
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- JP
- Japan
- Prior art keywords
- fosaprepitant
- aqueous solution
- injection
- related substances
- acid
- 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.)
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- 239000007864 aqueous solution Substances 0.000 title claims abstract description 82
- 229940032329 fosaprepitant injection Drugs 0.000 title claims abstract description 9
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical class O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 claims abstract description 151
- 229960002891 fosaprepitant Drugs 0.000 claims abstract description 150
- 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 claims abstract description 38
- 229960003330 pentetic acid Drugs 0.000 claims abstract description 36
- 239000000126 substance Substances 0.000 claims description 60
- 239000007924 injection Substances 0.000 claims description 52
- 238000002347 injection Methods 0.000 claims description 52
- 229940090044 injection Drugs 0.000 claims description 49
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 30
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 28
- 239000000243 solution Substances 0.000 abstract description 5
- -1 inorganic acid salts Chemical class 0.000 description 40
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
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- 230000000052 comparative effect Effects 0.000 description 8
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- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 7
- 229960001372 aprepitant Drugs 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
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- 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 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- 239000003633 blood substitute Substances 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
- 229920005549 butyl rubber Polymers 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
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- 238000000354 decomposition reaction Methods 0.000 description 1
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- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000013013 elastic material Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 229940021013 electrolyte solution Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000007999 glycylglycine buffer Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
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- 239000007972 injectable composition Substances 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
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- 229920003049 isoprene rubber Polymers 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000000594 mannitol Substances 0.000 description 1
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- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000004447 silicone coating Substances 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 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
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229920002725 thermoplastic elastomer Polymers 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Images
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K47/02—Inorganic compounds
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- 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
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Description
本発明は、ホスアプレピタント注射用水溶液剤に関する。 The present invention relates to an aqueous solution of fosaprepitant for injection.
ホスアプレピタントは、選択的ニューロキニン１（ＮＫ１）受容体拮抗型制吐薬であるアプレピタントのプロドラッグである。現在、ホスアプレピタントのジメグルミン塩を有効成分として含有する医薬製剤が凍結乾燥品として本邦において販売されており、ホスアプレピタントとして１５０ｍｇを５ｍＬの生理食塩液に溶解後、最終容量が１００～２５０ｍＬ（最終濃度として０．６～１．５ｍｇ／ｍＬ）となるように生理食塩液で希釈したものを点滴静注し、抗悪性腫瘍剤の投与に伴う悪心・嘔吐の予防及び症状の軽減に用いられている。 Fosaprepitant is a prodrug of aprepitant, a selective neurokinin 1 (NK1) receptor antagonist antiemetic. Currently, a pharmaceutical preparation containing the dimeglumine salt of fosaprepitant as an active ingredient is sold in Japan as a lyophilized product, and after dissolving 150 mg of fosaprepitant in 5 mL of physiological saline, the final volume is 100 to 250 mL (final concentration It is diluted with physiological saline to a concentration of 0.6 to 1.5 mg/mL and injected intravenously, and is used to prevent nausea and vomiting associated with the administration of anti-cancer drugs and to alleviate symptoms. .
しかしながら、ホスアプレピタントは、水性環境下では速やかにアプレピタントやその他類縁物質へ加水分解され、とりわけｐＨ７以下になると、より一層アプレピタントへの加水分解が進行することが報告されている（非特許文献１）。そのため、市販の医薬製剤は、安定性を考慮して剤形を凍結乾燥品とし、冷所（２～８℃）保存とされている（非特許文献２）。 However, it has been reported that fosaprepitant is rapidly hydrolyzed to aprepitant and other related substances in an aqueous environment, and that hydrolysis to aprepitant progresses even further when the pH drops below 7 (Non-Patent Document 1). . Therefore, in consideration of stability, commercially available pharmaceutical preparations are made into lyophilized products and stored in a cool place (2 to 8°C) (Non-Patent Document 2).
そこで、ホスアプレピタント製剤の安定性を向上させ、ホスアプレピタントの分解や類縁物質の生成を抑制した医薬製剤が種々検討されてきた。例えば、ホスアプレピタントにポリエチレングリコール等の非水性溶媒を含有させた注射用組成物が、設定された時間、温度及びｐＨの範囲内において保存時に劣化を示さず、不純物の生成が許容範囲となることが報告されている（特許文献１）。また、ホスアプレピタントに、マルトース又はトレハロース、あるいはピリジン誘導体を含有させた医薬製剤が、ホスアプレピタントの加水分解や類縁物質の生成を抑制できるとの報告もある（特許文献２、３）。 Therefore, various pharmaceutical preparations have been investigated that improve the stability of fosaprepitant preparations and suppress the decomposition of fosaprepitant and the production of related substances. For example, an injectable composition containing fosaprepitant and a non-aqueous solvent such as polyethylene glycol does not show any deterioration during storage within a set time, temperature, and pH range, and the formation of impurities is within an acceptable range. has been reported (Patent Document 1). There are also reports that a pharmaceutical preparation containing maltose, trehalose, or a pyridine derivative in fosaprepitant can suppress the hydrolysis of fosaprepitant and the production of related substances (Patent Documents 2 and 3).
しかしながら、これら先行技術文献は、いずれも非水系環境下におけるホスアプレピタントの安定化技術を開示するに過ぎず、水性環境下におけるホスアプレピタントの安定化については一切検討されていない。
本発明の課題は、ホスアプレピタント類縁物質の生成が抑制されたホスアプレピタント注射用水溶液剤を提供することにある。
However, all of these prior art documents only disclose techniques for stabilizing fosaprepitant in a non-aqueous environment, and do not consider stabilization of fosaprepitant in an aqueous environment at all.
An object of the present invention is to provide an aqueous solution of fosaprepitant for injection in which the production of fosaprepitant related substances is suppressed.
本発明者らは、上記課題に鑑み詳細に検討したところ、ホスアプレピタントを特定化合物と共存させることで、水性環境下におけるホスアプレピタントの安定性が高められ、ホスアプレピタント類縁物質の生成が抑制されたホスアプレピタント注射用水溶液剤が得られることを見出した。 The present inventors conducted a detailed study in view of the above issues and found that by allowing fosaprepitant to coexist with a specific compound, the stability of fosaprepitant in an aqueous environment was increased and the formation of fosaprepitant related substances was suppressed. It has been found that an aqueous solution of fosaprepitant for injection can be obtained.
即ち、本発明は、次の〔１〕～〔９〕を提供するものである。
〔１〕ホスアプレピタント及びジエチレントリアミン五酢酸を含有する、ホスアプレピタント注射用水溶液剤。
〔２〕ジエチレントリアミン五酢酸の含有量がホスアプレピタント１質量部に対して０．００５～０．０８質量部である、前記〔１〕記載のホスアプレピタント注射用水溶液剤。
〔３〕更に、炭酸水素ナトリウムを含有する、前記〔１〕又〔２〕記載のホスアプレピタント注射用水溶液剤。
〔４〕炭酸水素ナトリウムの含有量がホスアプレピタント１質量部に対して０．０５～１．５質量部である、前記〔３〕記載のホスアプレピタント注射用水溶液剤。
〔５〕ｐＨが８．０～１０．０である、前記〔１〕～〔４〕のいずれか一に記載のホスアプレピタント注射用水溶液剤。
〔６〕ジエチレントリアミン五酢酸を有効成分として含有する、ホスアプレピタント注射用水溶液剤におけるホスアプレピタント類縁物質の生成抑制剤。
〔７〕ホスアプレピタントをジエチレントリアミン五酢酸と共存させる、ホスアプレピタント注射用水溶液剤におけるホスアプレピタント類縁物質の生成抑制方法。
〔８〕ホスアプレピタント注射用水溶液剤におけるホスアプレピタント類縁物質の生成を抑制するための、ジエチレントリアミン五酢酸の使用。
〔９〕ジエチレントリアミン五酢酸と混合する工程を含む、ホスアプレピタント注射用水溶液剤の製造方法。
That is, the present invention provides the following [1] to [9].
[1] An aqueous solution of fosaprepitant for injection containing fosaprepitant and diethylenetriaminepentaacetic acid.
[2] The aqueous solution for fosaprepitant injection according to [1] above, wherein the content of diethylenetriaminepentaacetic acid is 0.005 to 0.08 parts by mass per 1 part by mass of fosaprepitant.
[3] The aqueous solution for injection of fosaprepitant according to [1] or [2] above, which further contains sodium hydrogen carbonate.
[4] The aqueous solution for injection of fosaprepitant according to [3] above, wherein the content of sodium hydrogen carbonate is 0.05 to 1.5 parts by mass per 1 part by mass of fosaprepitant.
[5] The aqueous solution of fosaprepitant for injection according to any one of [1] to [4] above, which has a pH of 8.0 to 10.0.
[6] An inhibitor for the formation of fosaprepitant related substances in an aqueous solution of fosaprepitant for injection, which contains diethylenetriaminepentaacetic acid as an active ingredient.
[7] A method for inhibiting the formation of fosaprepitant related substances in an aqueous solution of fosaprepitant for injection, which comprises coexisting fosaprepitant with diethylenetriaminepentaacetic acid.
[8] Use of diethylenetriaminepentaacetic acid to suppress the formation of fosaprepitant related substances in an aqueous solution of fosaprepitant injection.
[9] A method for producing an aqueous solution of fosaprepitant for injection, including the step of mixing with diethylenetriaminepentaacetic acid.
本発明のホスアプレピタント注射用水溶液剤は、水性環境下におけるホスアプレピタントの安定性が十分に高められているため、ホスアプレピタント類縁物質の生成を抑制することができる。したがって、本発明のホスアプレピタント注射用水溶液剤は、ホスアプレピタントの効能を安全かつ十分に享受できるから、抗悪性腫瘍剤の投与に伴う悪心・嘔吐の予防及び症状の軽減に有用である。 The fosaprepitant injectable aqueous solution of the present invention has sufficiently enhanced stability of fosaprepitant in an aqueous environment, and therefore can suppress the production of fosaprepitant related substances. Therefore, the fosaprepitant injectable aqueous solution of the present invention can safely and fully enjoy the efficacy of fosaprepitant, and is therefore useful for preventing nausea and vomiting and alleviating symptoms associated with administration of anti-cancer agents.
以下、本発明について詳細に説明する。
〔ホスアプレピタント注射用水溶液剤〕
本発明のホスアプレピタント注射用水溶液剤（以下、単に「水溶液剤」とも称する）は、その剤形がそのまま投与可能な水溶液剤でも、使用直前に希釈して投与される、濃縮された水溶液剤でもよい。
The present invention will be explained in detail below.
[Fosaprepitant aqueous solution for injection]
The fosaprepitant injectable aqueous solution of the present invention (hereinafter also simply referred to as "aqueous solution") may be an aqueous solution that can be administered as is or a concentrated aqueous solution that is diluted and administered immediately before use. good.
本発明の水溶液剤は、ホスアプレピタントを含有する。ここで、本明細書において「ホスアプレピタント」とは、ホスアプレピタント及びその薬理学的に許容される塩を包含する概念である。薬理学的に許容される塩は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば特に限定されないが、例えば、酸付加塩、塩基塩を挙げることができる。 The aqueous solution of the present invention contains fosaprepitant. Here, in this specification, "fosaprepitant" is a concept that includes fosaprepitant and its pharmacologically acceptable salts. The pharmacologically acceptable salt is not particularly limited as long as it is medicinally, pharmacologically (pharmacologically) or physiologically acceptable, and examples thereof include acid addition salts and base salts. .
酸付加塩は、無機酸の塩でも、有機酸の塩でもよい。具体的には、例えば、塩酸塩、リン酸塩、重硫酸塩、臭化水素酸塩、ヨウ化水素酸塩、過硫酸塩等の無機酸塩、酢酸塩、アジピン酸塩、安息香酸塩、ベンゼンスルホン酸塩、酪酸塩、クエン酸塩、樟脳酸塩、樟脳スルホン酸塩、エタンスルホン酸塩、フマル酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、メタンスルホン酸塩、乳酸塩、マレイン酸塩、メタンスルホン酸塩、２－ナフタレンスルホン酸塩、蓚酸塩、パモ酸塩、ピクリン酸塩、ピバリン酸塩、プロピオン酸塩、コハク酸塩、酒石酸塩、トシレート塩、ウンデカン酸塩等の有機酸塩が挙げられる。
塩基塩としては、例えば、アンモニウム塩；ナトリウム塩、リチウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；Ｎ－メチル－Ｄ－グルカミン（メグルミン）、ジシクロヘキシルアミン塩等の有機アミンとの塩、アルギニン、リシン，オルニチン等のアミノ酸との塩を挙げることができる。
中でも、ホスアプレピタントとしては、ホスアプレピタントのジメグルミン塩（ホスアプレピタントメグルミン）が好ましい。
The acid addition salt may be a salt of an inorganic acid or a salt of an organic acid. Specifically, for example, inorganic acid salts such as hydrochloride, phosphate, bisulfate, hydrobromide, hydroiodide, persulfate, acetate, adipate, benzoate, Benzene sulfonate, butyrate, citrate, camphorate, camphor sulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, picrate, pivalate, propionate, succinate, tartrate, tosylate, undecanoate, etc. Examples include organic acid salts.
Examples of base salts include ammonium salts; alkali metal salts such as sodium salts, lithium salts, and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; N-methyl-D-glucamine (meglumine), and dicyclohexylamine. Examples include salts with organic amines such as salts, and salts with amino acids such as arginine, lysine, ornithine.
Among these, the dimeglumine salt of fosaprepitant (fosaprepitant meglumine) is preferred as fosaprepitant.
本発明の水溶液剤中のホスアプレピタントの含有量は、治療上有効な量であれば特に限定されないが、最終投与形態としての水溶液剤中に、好ましくは０．１５～２０ｍｇ／ｍＬ、より好ましくは０．３～５ｍｇ／ｍＬ、更に好ましくは０．５～２ｍｇ／ｍＬである。なお、ホスアプレピタントが塩の形態である場合、ホスアプレピタントの含有量は、ホスアプレピタント量に換算した値とする。以下の量比の説明においても、ホスアプレピタントが塩の形態である場合には同様に換算するものとする。 The content of fosaprepitant in the aqueous solution of the present invention is not particularly limited as long as it is a therapeutically effective amount, but the content of fosaprepitant in the aqueous solution as the final dosage form is preferably 0.15 to 20 mg/mL, more preferably It is 0.3 to 5 mg/mL, more preferably 0.5 to 2 mg/mL. Note that when fosaprepitant is in the form of a salt, the content of fosaprepitant is a value converted to the amount of fosaprepitant. In the explanation of quantitative ratios below, when fosaprepitant is in the form of a salt, the same conversion will be made.
本発明の水溶液剤は、キレート剤としてジエチレントリアミン五酢酸を含有する。ジエチレントリアミン五酢酸は、水性環境下におけるホスアプレピタントの安定性を高め、ホスアプレピタント類縁物質生成抑制剤として機能するものである。ここで、本明細書において「ホスアプレピタント類縁物質」とは、ホスアプレピタント注射用水溶液剤を、下記に示した分析条件にしたがって高速液体クロマトグラフ（以下、「ＨＰＬＣ」とも称する）分析をしたときに、ホスアプレピタントの保持時間（ＲＴ）を指標とした相対保持時間（ＲＲＴ）０．９５±０．１に検出されるホスアプレピタント由来の物質をいう。なお、ホスアプレピタント注射用水溶液剤は、ＨＰＬＣ分析に適するホスアプレピタント濃度に調整して分析するものとする。具体的には、希釈が必要な場合には適切な溶媒で希釈し、濃縮が必要な場合は適切な方法で濃縮し、ホスアプレピタント濃度をＨＰＬＣ分析に適する濃度範囲内となるように調整し、それをＨＰＬＣ分析に供する。なお、析出などにより前処理が必要な場合は、適切な前処理を行った後、濃度調整を行う。また、この分析条件と同等の結果が得られる場合には、他の分析条件によりＨＰＬＣ分析を行っても構わない。 The aqueous solution of the present invention contains diethylenetriaminepentaacetic acid as a chelating agent. Diethylenetriaminepentaacetic acid increases the stability of fosaprepitant in an aqueous environment and functions as a fosaprepitant related substance production inhibitor. Here, in this specification, "fosaprepitant related substances" means that when an aqueous solution of fosaprepitant for injection is analyzed by high performance liquid chromatography (hereinafter also referred to as "HPLC") according to the analysis conditions shown below. , refers to a fosaprepitant-derived substance detected at a relative retention time (RRT) of 0.95±0.1 using the retention time (RT) of fosaprepitant as an index. The fosaprepitant aqueous solution for injection shall be analyzed after adjusting the fosaprepitant concentration to a level suitable for HPLC analysis. Specifically, if dilution is necessary, dilute with an appropriate solvent, if concentration is necessary, concentrate by an appropriate method, adjust the fosaprepitant concentration to be within a concentration range suitable for HPLC analysis, It is subjected to HPLC analysis. In addition, if pretreatment is required due to precipitation, etc., the concentration is adjusted after performing the appropriate pretreatment. In addition, HPLC analysis may be performed under other analysis conditions if results equivalent to those obtained under these analysis conditions can be obtained.
ホスアプレピタント類縁物質量は、クロマトグラムのピーク面積より下記式に基づいて計算する。即ち、ＨＰＬＣ分析により得られたクロマトグラムにおける、相対保持時間（ＲＲＴ）０．９５±０．１に検出されるホスアプレピタントの類縁物質、ホスアプレピタント、及び相対保持時間（ＲＲＴ）１．４１±１．４に検出されるアプレピタントの各ピーク面積を用いて、ホスアプレピタント類縁物質量を算出する。 The amount of fosaprepitant related substances is calculated based on the following formula from the peak area of the chromatogram. That is, in the chromatogram obtained by HPLC analysis, a related substance of fosaprepitant, fosaprepitant, detected at a relative retention time (RRT) of 0.95±0.1, and a relative retention time (RRT) of 1.41±1. Using each peak area of aprepitant detected in .4, calculate the amount of fosaprepitant related substances.
ホスアプレピタント類縁物質量（％）＝ｘ／（ｘ＋ｙ＋ｚ）×１００ Fosaprepitant related substance amount (%) = x/(x+y+z)×100
〔式中、ｘはホスアプレピタントの類縁物質のピーク面積を示し、ｙはホスアプレピタントのピーク面積を示し、ｚはアプレピタントのピーク面積を示す。〕 [In the formula, x represents the peak area of a related substance of fosaprepitant, y represents the peak area of fosaprepitant, and z represents the peak area of aprepitant. ]
分析条件
・分析装置 ：高速液体クロマトグラフ（Ｗａｔｅｒｓ Ａｌｌｉｎａｃｅ ２９９６）
・カラム ：カラムサイズ ４．６×２５０ｍｍ、粒子径 ５μｍのオクタデシルシリル
化シリカゲル（Ｌ－ｃｏｌｕｍｎ２ ＯＤＳ、（一財）化学物質評価研究
機構）
・カラム温度：３０℃付近の一定温度
・移動相Ａ ：０．１％リン酸（Ｖ／Ｖ％）
・移動相Ｂ ：アセトニトリル
・分析条件 ：グラジエント分析
時間（分） 移動相Ａ（体積％） 移動相Ｂ（体積％）
０．０１ ６５ ３５
５ ６５ ３５
２０ ３０ ７０
４０ ５ ９５
４２ ６５ ３５
５０ ６５ ３５
・試料注入量：２０μＬ
・送液量 ：１．０ｍＬ／ｍｉｎ
・検出器波長：２６３ｎｍ
Analysis conditions/analyzer: High performance liquid chromatograph (Waters Allinace 2996)
・Column: Column size 4.6 x 250 mm, particle size 5 μm octadecylsilyl
Chemical silica gel (L-column2 ODS, Chemical Substance Evaluation Research)
mechanism)
・Column temperature: constant temperature around 30°C ・Mobile phase A: 0.1% phosphoric acid (V/V%)
・Mobile phase B: Acetonitrile ・Analysis conditions: Gradient analysis Time (minutes) Mobile phase A (volume %) Mobile phase B (volume %)
0.01 65 35
5 65 35
20 30 70
40 5 95
42 65 35
50 65 35
・Sample injection volume: 20μL
・Liquid feeding amount: 1.0mL/min
・Detector wavelength: 263nm
本発明の水溶液剤は、５０℃にて７日間保存した後、上記と同一条件にてＨＰＬＣ分析したときに、ホスアプレピタントの保持時間（ＲＴ）を指標とした相対保持時間（ＲＲＴ）０．９５±０．１の類縁物質の含有量を、通常０．２％以下、好ましくは０．１％以下とすることができる。 When the aqueous solution of the present invention was stored at 50°C for 7 days and then analyzed by HPLC under the same conditions as above, the relative retention time (RRT) using the retention time (RT) of fosaprepitant as an index was 0.95. The content of analogous substances of ±0.1 can be generally 0.2% or less, preferably 0.1% or less.
本発明の水溶液剤中のジエチレントリアミン五酢酸の含有量は、ホスアプレピタント類縁物質の生成抑制の観点から、ホスアプレピタント１質量部に対して、０．００５～０．０８質量部が好ましく、０．００５～０．０７５質量部がより好ましく、０．００５～０．０７質量部が更に好ましい。 The content of diethylenetriaminepentaacetic acid in the aqueous solution of the present invention is preferably 0.005 to 0.08 parts by mass, and 0.005 to 1 part by mass of fosaprepitant, from the viewpoint of suppressing the formation of fosaprepitant related substances. The amount is more preferably 0.075 parts by mass, and even more preferably 0.005 to 0.07 parts by mass.
本発明の水溶液剤は、更に炭酸水素ナトリウムを含有することが好ましい。炭酸水素ナトリウムをジエチレントリアミン五酢酸と組み合わせて含有させることで、ホスアプレピタント類縁物質の生成抑制効果をより高いレベルで発現することができる。 It is preferable that the aqueous solution of the present invention further contains sodium hydrogen carbonate. By containing sodium bicarbonate in combination with diethylenetriaminepentaacetic acid, the effect of inhibiting the production of fosaprepitant related substances can be expressed at a higher level.
本発明の水溶液剤中の炭酸水素ナトリウムの含有量は、ホスアプレピタント類縁物質の生成抑制の観点から、ホスアプレピタント１質量部に対して、０．０５～１．５質量部が好ましく、０．０５～１．３質量部がより好ましく、０．０５～１．２質量部が更に好ましい。 The content of sodium hydrogen carbonate in the aqueous solution of the present invention is preferably 0.05 to 1.5 parts by mass, and 0.05 to 1.5 parts by mass, based on 1 part by mass of fosaprepitant, from the viewpoint of suppressing the formation of fosaprepitant related substances. The amount is more preferably 1.3 parts by mass, and even more preferably 0.05 to 1.2 parts by mass.
また、（Ａ）ジエチレントリアミン五酢酸と（Ｂ）炭酸水素ナトリウムとの質量比[（Ｂ）／（Ａ）]は、ホスアプレピタント類縁物質の生成抑制の観点から、０．４～３００が好ましく、０．５～２５０がより好ましく、０．６２５～２００が更に好ましい。 In addition, the mass ratio [(B)/(A)] of (A) diethylenetriaminepentaacetic acid and (B) sodium hydrogen carbonate is preferably 0.4 to 300, from the viewpoint of suppressing the production of fosaprepitant related substances, and 0. .5 to 250 is more preferable, and 0.625 to 200 is even more preferable.
本発明の水溶液剤は、ホスアプレピタント類縁物質の生成抑制の観点から、ｐＨ調整剤を含有することが好ましい。ｐＨ調整剤は、１又は２以上含有することができる。
ｐＨ調整剤としては、例えば、酸剤、アルカリ剤が挙げられる。酸剤としては、例えば、塩酸、リン酸、ホウ酸、炭酸等の無機酸；アスコルビン酸、酢酸、クエン酸、コハク酸、酒石酸等の有機酸が挙げられ、１又は２以上含有することができる。また、アルカリ剤としては、例えば、アンモニア、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、トリエチルアミン、トリスヒドロキシメチルアミノメタン（トロメタモール）等の無機又は有機塩基；水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属又はアルカリ土類金属の水酸化物；リン酸二水素ナトリウム、リン酸一水素二ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム等の無機酸のアルカリ土類金属塩が挙げられる。また、酸剤とアルカリ剤を併用しても構わない。
The aqueous solution of the present invention preferably contains a pH adjuster from the viewpoint of suppressing the production of fosaprepitant related substances. One or more pH adjusters may be contained.
Examples of the pH adjuster include acid agents and alkaline agents. Examples of the acid agent include inorganic acids such as hydrochloric acid, phosphoric acid, boric acid, and carbonic acid; and organic acids such as ascorbic acid, acetic acid, citric acid, succinic acid, and tartaric acid, and may contain one or more of them. . Examples of alkaline agents include inorganic or organic bases such as ammonia, monoethanolamine, diethanolamine, triethanolamine, triethylamine, trishydroxymethylaminomethane (trometamol); sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. hydroxides of alkali metals or alkaline earth metals; examples include alkaline earth metal salts of inorganic acids such as sodium dihydrogen phosphate, disodium monohydrogen phosphate, sodium carbonate, and sodium hydrogen carbonate. Further, an acid agent and an alkaline agent may be used in combination.
ｐＨ調整剤の含有量は、ｐＨ調整剤の種類に応じて所望のｐＨとなるように適宜設定することができる。なお、ｐＨは、最終投与形態としての水溶液剤において、８．０～１０が好ましく、８．０～９．５がより好ましく、８．５～９．５が更に好ましく、８．８～９．２が殊更に好ましい。なお、ｐＨは、ｐＨメーターを用いて測定するものとする。 The content of the pH adjuster can be appropriately set depending on the type of pH adjuster so as to achieve a desired pH. In addition, the pH is preferably 8.0 to 10, more preferably 8.0 to 9.5, even more preferably 8.5 to 9.5, and even more preferably 8.8 to 9.5 in the aqueous solution as the final dosage form. 2 is particularly preferred. In addition, pH shall be measured using a pH meter.
本発明の水溶液剤は、界面活性剤を含有することができる。界面活性剤は、１又は２以上含有しても構わない。
界面活性剤としては、非イオン界面活性剤が好ましく、例えば、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンヒドロキシ脂肪酸エステルを挙げることができる。
The aqueous solution of the present invention can contain a surfactant. One or more surfactants may be contained.
As the surfactant, nonionic surfactants are preferred, and examples thereof include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyethylene hydroxy fatty acid ester.
ポリオキシエチレンソルビタン脂肪酸エステルとしては、ポリオキシエチレンソルビタンＣ10-20脂肪酸エステルが好ましい。具体的には、例えば、ポリオキシエチレン（２０）ソルビタンモノラウリン酸エステル、ポリオキシエチレン（２０）ソルビタンモノパルミチン酸エステル、ポリオキシエチレン（２０）ソルビタンモノステアリン酸エステル、ポリオキシエチレン（２０）ソルビタントリステアリン酸エステル、ポリオキシエチレン（２０）ソルビタンモノオレイン酸エステルを挙げることができる。なお、カッコ内の数値は、エチレンオキサイドの平均付加モル数であり、以下においても同様である。 As the polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan C 10-20 fatty acid ester is preferred. Specifically, for example, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan triester, etc. Examples include stearic acid ester and polyoxyethylene (20) sorbitan monooleic acid ester. Note that the numerical value in parentheses is the average number of added moles of ethylene oxide, and the same applies to the following.
ポリオキシエチレン硬化ヒマシ油としては、エチレンオキサイドが５～２００モル付加したものが好ましく、より好ましくは１０～１５０モル、更に好ましくは２０～１２０モル付加したものである。具体的には、例えば、ポリオキシエチレン（２５）硬化ヒマシ油、ポリオキシエチレン（４０）硬化ヒマシ油、ポリオキシエチレン（５０）硬化ヒマシ油、ポリオキシエチレン（６０）硬化ヒマシ油、ポリオキシエチレン（１００）硬化ヒマシ油が挙げられる。
ポリオキシエチレンヒマシ油としては、例えば、ポリオキシエチレン（３５）ヒマシ油を挙げることができる。
ポリオキシエチレンヒドロキシ脂肪酸エステルとしては、ポリオキシエチレンヒドロキシＣ10-20脂肪酸エステルが好ましく、ポリオキシエチレン（１５）ヒドロキシステアリン酸エステルが更に好ましい。
The polyoxyethylene hydrogenated castor oil preferably contains 5 to 200 moles of ethylene oxide, more preferably 10 to 150 moles, and even more preferably 20 to 120 moles. Specifically, for example, polyoxyethylene (25) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (100) hydrogenated castor oil.
Examples of polyoxyethylene castor oil include polyoxyethylene (35) castor oil.
As the polyoxyethylene hydroxy fatty acid ester, polyoxyethylene hydroxy C 10-20 fatty acid ester is preferred, and polyoxyethylene (15) hydroxystearate is more preferred.
中でも、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油及びポリオキシエチレンヒドロキシ脂肪酸エステルから選択される１又は２以上が好ましい。 Among these, one or more selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyethylene hydroxy fatty acid ester are preferred.
界面活性剤の含有量は、ホスアプレピタント１質量部に対して０．１～７０質量部が好ましく、０．２～５０質量部がより好ましく、０．３～２７質量部が更に好ましく、０．４～１８質量部が殊更に好ましい。 The content of the surfactant is preferably 0.1 to 70 parts by weight, more preferably 0.2 to 50 parts by weight, even more preferably 0.3 to 27 parts by weight, and 0.1 to 70 parts by weight, even more preferably 0.3 to 27 parts by weight, per 1 part by weight of fosaprepitant. Particularly preferred is 4 to 18 parts by weight.
本発明の水溶液剤は、所望により、更に他の成分を含有してもよい。他の成分としては、例えば、安定化剤、緩衝剤、保存剤、等張化剤を挙げることができるが、乳糖等の賦形剤やシクロデキストリンは含有することを必ずしも要しない。
安定化剤としては、例えば、亜硫酸ナトリウム、メタ亜硫酸ナトリウムが挙げられる。
緩衝剤としては、例えば、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、グリシン緩衝剤、グリシルグリシン緩衝剤、トリス緩衝剤、アスパラギン酸、アスパラギン酸塩、イプシロン－アミノカプロン酸が挙げられる。
保存剤としては、例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ソルビン酸、フェノール、クレゾール、クロロクレゾールなどが挙げられる。
等張化剤としては、たとえば、塩化ナトリウム、グルコース、ソルビトール、マンニト－ル、キシリトールなどが挙げられる。中でも、塩化ナトリウム、グルコースが好ましい。
これらの添加剤の含有量は、本発明の目的を損なわない範囲内で適宜設定することができる。
The aqueous solution of the present invention may further contain other components if desired. Other components include, for example, stabilizers, buffers, preservatives, and tonicity agents, but it is not necessary to include excipients such as lactose and cyclodextrin.
Examples of the stabilizer include sodium sulfite and sodium metasulfite.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, glycine buffer, glycylglycine buffer, Tris buffer, aspartic acid, and aspartate. , epsilon-aminocaproic acid.
Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
Examples of tonicity agents include sodium chloride, glucose, sorbitol, mannitol, xylitol, and the like. Among them, sodium chloride and glucose are preferred.
The content of these additives can be appropriately set within a range that does not impair the purpose of the present invention.
本発明の水溶液剤は、容器に充填することができる。容器は、使用目的に応じて適宜選択することができるが、例えば、バイアル、アンプル、バッグ、注射器のような規定容量の形状のもの、瓶のような大容量の形状のものが挙げられる。容器の材質については、例えば、ガラス、プラスチックが挙げられる。また、容器内の表面には、シリカコート処理、シリコーンコート処理、サルファー処理、各種低アルカリ処理等が施されてもよい。また、プレフィルドシリンジのガスケット又はプレフィルドシリンジ若しくはバイアルの栓部の材質は特に限定されず、例えば、天然ゴム、ブチルゴム、クロロブチルゴム、イソプレンゴム、ブタジエンゴム、スチレン－ブタジエンゴム、シリコーンゴムのような各種ゴム材料；ポリウレタン系、ポリエステル系、ポリアミド系、オレフィン系、スチレン系等の各種熱可塑性エラストマー；又はそれらの混合物等の弾性材料等が挙げられる。 The aqueous solution of the present invention can be filled into a container. The container can be appropriately selected depending on the purpose of use, and includes, for example, a container with a specified capacity such as a vial, an ampoule, a bag, or a syringe, and a container with a large capacity such as a bottle. Examples of the material of the container include glass and plastic. Further, the surface inside the container may be subjected to silica coating treatment, silicone coating treatment, sulfur treatment, various low alkali treatments, etc. The material of the gasket of the prefilled syringe or the stopper of the prefilled syringe or vial is not particularly limited, and examples thereof include various rubbers such as natural rubber, butyl rubber, chlorobutyl rubber, isoprene rubber, butadiene rubber, styrene-butadiene rubber, and silicone rubber. Materials include various thermoplastic elastomers such as polyurethane, polyester, polyamide, olefin, and styrene; or elastic materials such as mixtures thereof.
本発明の水溶液剤は、適宜の方法で調製することができる。例えば、剤形がそのまま投与可能な水溶液剤である場合、ホスアプレピタント及びジエチレントリアミン五酢酸、必要により他の成分を水性媒体に溶解することにより製造することができる。また、剤形が濃縮された水溶液剤である場合には、水性媒体の使用量を調整し、これを所定の倍率で希釈したときに有効量のホスアプレピタントを含む水溶液剤となり得るように調製すればよい。更に、そのまま投与可能な水溶液剤を公知の方法により濃縮することで、濃縮された水溶液剤としてもよい。水性媒体としては、例えば、生理食塩液、５％グルコース、注射用蒸留水、キシリトール液及び輸液から選択される１又は２以上を使用することができる。輸液としては、例えば、電解質液（リンゲル液等）、栄養輸液、蛋白アミノ酸注射液、ビタミン注射液等、電解液や栄養輸液（糖液等）を組み合わせた代用血液、脂肪を乳化した脂肪乳剤が挙げられるが、２価イオンを含まない水性媒体を用いることが好ましい。 The aqueous solution of the present invention can be prepared by any appropriate method. For example, when the dosage form is an aqueous solution that can be administered as is, it can be prepared by dissolving fosaprepitant, diethylenetriaminepentaacetic acid, and, if necessary, other ingredients in an aqueous medium. In addition, if the dosage form is a concentrated aqueous solution, the amount of aqueous medium used should be adjusted so that when diluted at a predetermined ratio, an aqueous solution containing an effective amount of fosaprepitant can be obtained. Bye. Furthermore, a concentrated aqueous solution may be obtained by concentrating an aqueous solution that can be administered as is by a known method. As the aqueous medium, one or more selected from, for example, physiological saline, 5% glucose, distilled water for injection, xylitol solution, and infusion can be used. Examples of infusions include electrolyte solutions (Ringer's solution, etc.), nutrient infusions, protein and amino acid injections, vitamin injections, blood substitutes that combine electrolytes and nutrient infusions (sugar solutions, etc.), and fat emulsions that emulsify fat. However, it is preferable to use an aqueous medium that does not contain divalent ions.
濃縮された水溶液剤は、用時に、例えば、上記において説明した水性媒体の１又は２以上を用いて、最終投与形態としての水溶液剤中のホスアプレピタント濃度が上記範囲内となるように希釈すればよい。 The concentrated aqueous solution can be diluted, for example, with one or more of the aqueous media described above, so that the concentration of fosaprepitant in the aqueous solution as the final dosage form is within the above range before use. good.
本発明の水溶液剤は、最終投与形態としての水溶液剤において、生理食塩液に対する浸透圧比が、好ましくは０．５～３．０であり、より好ましくは０．７～２．５であり、更に好ましくは０．９～２．０である。なお、浸透圧は、自動浸透圧分析装置を用いて測定することができる In the aqueous solution of the present invention as a final dosage form, the osmotic pressure ratio to physiological saline is preferably 0.5 to 3.0, more preferably 0.7 to 2.5, and Preferably it is 0.9 to 2.0. Note that osmotic pressure can be measured using an automatic osmotic pressure analyzer.
水溶液剤の投与経路としては、例えば、皮下投与、筋肉内投与、静脈内投与が挙げられる。中でも、静脈内投与が好ましい。静脈内投与としては、例えば、静脈内注射、静脈内点滴を挙げることができる。静脈内注射は、単回注射でも、複数回注射でもよい。静脈内点滴は、重力滴下点滴、点滴チューブポンプを介するポンプ注入、点滴シリンジドライバーの形態での投与が可能である。 Administration routes for aqueous solutions include, for example, subcutaneous administration, intramuscular administration, and intravenous administration. Among these, intravenous administration is preferred. Examples of intravenous administration include intravenous injection and intravenous infusion. Intravenous injection may be a single injection or multiple injections. Intravenous infusions can be administered in the form of gravity drip infusions, pump infusions through IV tubing pumps, or IV syringe drivers.
〔類縁物質生成抑制剤、類縁物質生成抑制方法及び製造方法〕
本発明の類縁物質生成抑制剤及び類縁物質生成抑制方法は、水性環境下におけるホスアプレピタント類縁物質の生成を抑制するものである。
具体的には、本発明の生成抑制剤は、ホスアプレピタント注射用水溶液剤におけるホスアプレピタント類縁物質の生成抑制剤であって、ジエチレントリアミン五酢酸を有効成分として含有するものである。
また、本発明の生成抑制方法は、ホスアプレピタント注射用水溶液剤におけるホスアプレピタント類縁物質の生成抑制方法であって、ホスアプレピタントをジエチレントリアミン五酢酸と共存させるものである。ホスアプレピタント及びジエチレントリアミン五酢酸は、最終的にホスアプレピタント注射用水溶液剤中に共存した状態にあればよく、共存させるタイミングや配合順序は特に限定されない。
更に、本発明のホスアプレピタント注射用水溶液剤の製造方法は、ジエチレントリアミン五酢酸と混合する工程を含むものである。当該製造方法においても、ジエチレントリアミン五酢酸は、ホスアプレピタント注射用水溶液剤の製造工程のいずれかにおいてホスアプレピタントと共存した状態になればよく、混合するタイミングや混合順序は特に限定されない。
なお、ホスアプレピタント注射用水溶液剤、ホスアプレピタント及びジエチレントリアミン五酢酸の具体的構成は、上記において説明したとおりである。
ホスアプレピタント類縁物質の生成をより高いレベルで抑制するために、有効成分として炭酸水素ナトリウムを更に含有してもよい。ホスアプレピタントに対するジエチレントリアミン五酢酸及び炭酸水素ナトリウムの配合量、ジエチレントリアミン五酢酸と炭酸水素ナトリウムの質量比は、上記において説明したとおりである。
[Related substance production inhibitor, related substance production suppression method, and manufacturing method]
The related substance production inhibitor and related substance production suppression method of the present invention suppress the production of fosaprepitant related substances in an aqueous environment.
Specifically, the production inhibitor of the present invention is a production inhibitor of fosaprepitant related substances in an aqueous solution of fosaprepitant for injection, and contains diethylenetriaminepentaacetic acid as an active ingredient.
Furthermore, the method for inhibiting the production of fosaprepitant related substances in an aqueous solution for injection of fosaprepitant of the present invention is a method for inhibiting the production of fosaprepitant analogues, in which fosaprepitant is allowed to coexist with diethylenetriaminepentaacetic acid. Fosaprepitant and diethylenetriaminepentaacetic acid only need to coexist in the final aqueous solution of fosaprepitant for injection, and the timing of their coexistence and the order of blending are not particularly limited.
Further, the method for producing an aqueous solution of fosaprepitant for injection of the present invention includes a step of mixing with diethylenetriaminepentaacetic acid. Also in this manufacturing method, diethylenetriaminepentaacetic acid only needs to coexist with fosaprepitant in any of the manufacturing steps of the aqueous solution for injection of fosaprepitant, and the timing and order of mixing are not particularly limited.
The specific compositions of the fosaprepitant aqueous solution for injection, fosaprepitant, and diethylenetriaminepentaacetic acid are as described above.
In order to suppress the production of fosaprepitant related substances at a higher level, sodium hydrogen carbonate may be further contained as an active ingredient. The blending amounts of diethylenetriaminepentaacetic acid and sodium hydrogencarbonate and the mass ratio of diethylenetriaminepentaacetic acid and sodium hydrogencarbonate relative to fosaprepitant are as explained above.
以下、実施例を挙げて、本発明の実施の形態を更に具体的に説明する。但し、本発明は、下記の実施例に限定されるものではない。 Hereinafter, embodiments of the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the following examples.
ホスアプレピタント類縁物質の分析
ホスアプレピタント注射用水溶液剤を０．４５μｍのメンブランフィルターでろ過したろ液をホスアプレピタント濃度がＨＰＬＣ分析に適する濃度となるように水で希釈し、試料を調製した。次いで、この試料を、カラム（オクタデシルシリル化シリカゲル、Ｌ－ｃｏｌｕｍｎ２ ＯＤＳ、（一財）化学物質評価研究機構）を装着した、高速液体クロマトグラフ（型式Ａｌｌｉａｎｃｅ ２９９６、Ｗａｔｅｒｓ製）を用い、カラム温度３０℃でグラジエント法により分析した。移動相として０．１％リン酸及びアセトニトリルを用い、送液量１．０ｍＬ／ｍｉｎ、試料注入量は２０μＬ、ＵＶ検出器波長は２６３ｎｍの条件で行った。そして、ＨＰＬＣ分析により得られたクロマトグラムにおける、相対保持時間（ＲＲＴ）０．９５±０．１に検出されるホスアプレピタントの類縁物質、ホスアプレピタント、及び相対保持時間（ＲＲＴ）１．４１±１．４に検出されるアプレピタントの各ピーク面積を用いて、下記式によりホスアプレピタント類縁物質量を算出した。
Analysis of Fosaprepitant Related Substances A sample was prepared by diluting the filtrate of an aqueous solution of fosaprepitant for injection through a 0.45 μm membrane filter with water so that the fosaprepitant concentration was suitable for HPLC analysis. Next, this sample was applied to a high-performance liquid chromatograph (model Alliance 2996, manufactured by Waters) equipped with a column (octadecylsilylated silica gel, L-column2 ODS, Chemical Substances Evaluation and Research Institute) at a column temperature of 30. It was analyzed by the gradient method at ℃. The experiment was carried out using 0.1% phosphoric acid and acetonitrile as the mobile phase, with a liquid feeding rate of 1.0 mL/min, a sample injection rate of 20 μL, and a UV detector wavelength of 263 nm. In the chromatogram obtained by HPLC analysis, fosaprepitant analogs and fosaprepitant were detected at a relative retention time (RRT) of 0.95 ± 0.1, and a relative retention time (RRT) of 1.41 ± 1. Using each peak area of aprepitant detected in .4, the amount of fosaprepitant related substances was calculated by the following formula.
ホスアプレピタント類縁物質量（％）＝ｘ／（ｘ＋ｙ＋ｚ）×１００ Fosaprepitant related substance amount (%) = x/(x+y+z)×100
〔式中、ｘはホスアプレピタントの類縁物質のピーク面積を示し、ｙはホスアプレピタントのピーク面積を示し、ｚはアプレピタントのピーク面積を示す。〕 [In the formula, x represents the peak area of a related substance of fosaprepitant, y represents the peak area of fosaprepitant, and z represents the peak area of aprepitant. ]
実施例１
調製濃度が表１の実施例１に示す濃度となるように、ジエチレントリアミン五酢酸及びポリソルベート８０を生理食塩液で溶解し、水酸化ナトリウムでｐＨを８．５に調整した後、生理食塩液でメスアップして、製剤調製用の溶媒とした。次いで、調製濃度が表１に示す濃度となるように、ホスアプレピタントメグルミンを製剤調製用の溶媒で溶解し、水酸化ナトリウムでｐＨを８．５に調整した後、製剤調製用の溶媒でメスアップして、表１に示すホスアプレピタント注射用水溶液剤を製造した。次いで、このホスアプレピタント注射用水溶液剤を、５０℃で７日間保存した。保存後のホスアプレピタント注射用水溶液剤について、水で２０倍希釈した後、ＨＰＬＣによりホスアプレピタントの保持時間（ＲＴ）を１．０としたときに、相対保持時間（ＲＲＴ）０．９５±０．１に検出される類縁物質について分析した。その結果を図１に示す。また、ＨＰＬＣ分析して得られたクロマトグラムのピーク面積より上記式に基づいて類縁物質量を算出した。その結果、当該類縁物質は検出されなかった（表２）。
Example 1
Diethylenetriaminepentaacetic acid and polysorbate 80 were dissolved in physiological saline so that the prepared concentration was as shown in Example 1 in Table 1, and the pH was adjusted to 8.5 with sodium hydroxide. It was used as a solvent for preparing formulations. Next, fosaprepitant meglumine was dissolved in a solvent for formulation preparation so that the prepared concentration was as shown in Table 1, the pH was adjusted to 8.5 with sodium hydroxide, and then diluted with a solvent for formulation preparation. In this way, an aqueous solution of fosaprepitant for injection shown in Table 1 was produced. This aqueous fosaprepitant injection solution was then stored at 50°C for 7 days. After storage, the aqueous solution of fosaprepitant for injection was diluted 20 times with water and determined by HPLC to have a relative retention time (RRT) of 0.95±0.0 when the retention time (RT) of fosaprepitant was 1.0. We analyzed related substances detected in 1. The results are shown in Figure 1. Further, the amount of related substances was calculated based on the above formula from the peak area of the chromatogram obtained by HPLC analysis. As a result, the related substance was not detected (Table 2).
比較例１
ジエチレントリアミン五酢酸を、等モルのエデト酸ナトリウム水和物に変更したこと以外は、実施例１と同様の操作によりホスアプレピタント注射用水溶液剤を製造した（表１、比較例１）。次いで、ホスアプレピタント注射用水溶液剤を、５０℃で７日間保存した。保存後のホスアプレピタント注射用水溶液剤について、実施例１と同様に水で２０倍希釈した後、ＨＰＬＣによりホスアプレピタント類縁物質について分析した。その結果を図２に示す。また、ＨＰＬＣ分析して得られたクロマトグラムのピーク面積より上記式に基づいて類縁物質量を算出した。その結果を表２に示す。
Comparative example 1
An aqueous solution of fosaprepitant for injection was produced in the same manner as in Example 1, except that diethylenetriaminepentaacetic acid was replaced with equimolar sodium edetate hydrate (Table 1, Comparative Example 1). The aqueous solution of fosaprepitant for injection was then stored at 50°C for 7 days. The aqueous solution of fosaprepitant for injection after storage was diluted 20 times with water in the same manner as in Example 1, and then analyzed for fosaprepitant related substances by HPLC. The results are shown in FIG. Further, the amount of related substances was calculated based on the above formula from the peak area of the chromatogram obtained by HPLC analysis. The results are shown in Table 2.
ジエチレントリアミン五酢酸を含有するホスアプレピタント注射用水溶液剤は、ホスアプレピタント類縁物質が検出されなかったのに対し（表２、実施例１）、ジエチレントリアミン五酢酸に代えてエデト酸ナトリウム水和物を含有させたホスアプレピタント注射用水溶液剤は、ホスアプレピタント類縁物質が検出されたことから（表２、比較例１）、ホスアプレピタントとジエチレントリアミン五酢酸との共存下において、ホスアプレピタント類縁物質の生成が抑制され、同じキレート剤であるエデト酸ナトリウム水和物ではそのような効果は認められないことがわかる。 In the aqueous solution of fosaprepitant for injection containing diethylenetriaminepentaacetic acid, no fosaprepitant related substances were detected (Table 2, Example 1); Since fosaprepitant related substances were detected in the fosaprepitant injection aqueous solution (Table 2, Comparative Example 1), the production of fosaprepitant related substances was suppressed in the coexistence of fosaprepitant and diethylenetriaminepentaacetic acid. It can be seen that the same chelating agent, sodium edetate hydrate, has no such effect.
実施例２
調製濃度が表３の実施例２に示す濃度となるように、ジエチレントリアミン五酢酸、ポリソルベート８０及び炭酸水素ナトリウムを生理食塩液で溶解し、水酸化ナトリウムでｐＨを９．０に調整した後、生理食塩液でメスアップして、製剤調製用の溶媒とした。次いで、調製濃度が表３の実施例２に示す濃度となるようにホスアプレピタントメグルミンを、製剤調製用の溶媒で溶解し、水酸化ナトリウムでｐＨを９．０に調整した後、製剤調製用の溶媒でメスアップして、ホスアプレピタント注射用水溶液剤を製造した。次いで、ホスアプレピタント注射用水溶液剤を、５０℃で７日間保存した。保存後のホスアプレピタント注射用水溶液剤について、実施例１と同様に水で２０倍希釈した後、ＨＰＬＣによりホスアプレピタント類縁物質について分析した。その結果、当該類縁物質は検出されなかった。
Example 2
Diethylenetriaminepentaacetic acid, polysorbate 80, and sodium hydrogen carbonate were dissolved in physiological saline so that the prepared concentration was as shown in Example 2 in Table 3, and the pH was adjusted to 9.0 with sodium hydroxide. It was diluted with a saline solution and used as a solvent for preparation of formulations. Next, fosaprepitant meglumine was dissolved in a solvent for formulation preparation so that the prepared concentration was as shown in Example 2 in Table 3, and the pH was adjusted to 9.0 with sodium hydroxide. The mixture was diluted with a solvent to produce an aqueous solution of fosaprepitant for injection. The aqueous solution of fosaprepitant for injection was then stored at 50°C for 7 days. The aqueous solution of fosaprepitant for injection after storage was diluted 20 times with water in the same manner as in Example 1, and then analyzed for fosaprepitant related substances by HPLC. As a result, the related substance was not detected.
比較例２
ジエチレントリアミン五酢酸を、等モルのエデト酸ナトリウムに変更したこと以外は、実施例２と同様の操作によりホスアプレピタント注射用水溶液剤を製造した。次いで、ホスアプレピタント注射用水溶液剤を、５０℃で７日間保存した。保存後のホスアプレピタント注射用水溶液剤について、実施例１と同様に水で２０倍希釈した後、ＨＰＬＣによりホスアプレピタント類縁物質について分析し、比較例１と同様にピーク面積より上記式に基づいて類縁物質量を算出した。その結果を表４に示す。
Comparative example 2
An aqueous solution of fosaprepitant for injection was produced in the same manner as in Example 2, except that diethylenetriaminepentaacetic acid was replaced with equimolar sodium edetate. The aqueous solution of fosaprepitant for injection was then stored at 50°C for 7 days. After storage, the aqueous solution of fosaprepitant for injection was diluted 20 times with water in the same manner as in Example 1, and then analyzed for fosaprepitant related substances by HPLC, and similar substances were determined based on the above formula based on the peak area in the same manner as in Comparative Example 1. The amount of substance was calculated. The results are shown in Table 4.
実施例３
炭酸水素ナトリウムを添加しなかったこと以外は、実施例２と同様の操作によりホスアプレピタント注射用水溶液剤を製造した（表３、実施例３）。次いで、ホスアプレピタント注射用水溶液剤を、５０℃で７日間保存した。保存後のホスアプレピタント注射用水溶液剤について、実施例１と同様にＨＰＬＣにより水で２０倍希釈した後、ホスアプレピタント類縁物質について分析し、比較例１と同様にピーク面積より上記式に基づいて類縁物質量を算出した。その結果を表４に示す。
Example 3
An aqueous solution of fosaprepitant for injection was produced in the same manner as in Example 2, except that sodium hydrogen carbonate was not added (Table 3, Example 3). The aqueous solution of fosaprepitant for injection was then stored at 50°C for 7 days. After storage, the aqueous solution of fosaprepitant for injection was diluted 20 times with water by HPLC in the same manner as in Example 1, and then analyzed for fosaprepitant related substances, and similar substances were determined based on the peak area based on the above formula in the same manner as in Comparative Example 1. The amount of substance was calculated. The results are shown in Table 4.
ジエチレントリアミン五酢酸を含有するホスアプレピタント注射用水溶液剤は、ホスアプレピタント類縁物質の生成量がジエチレントリアミン五酢酸に代えてエデト酸ナトリウム水和物を含有させたホスアプレピタント注射用水溶液剤に比べて低減されていることから（表４、実施例２～３ｖｓ比較例２）、ホスアプレピタントとジエチレントリアミン五酢酸との共存下において、ホスアプレピタント類縁物質の生成が抑制され、同じキレート剤であるエデト酸ナトリウム水和物ではそのような効果は認められないことがわかる。また、ジエチレントリアミン五酢酸とともに炭酸水素ナトリウムを共存させることで、ホスアプレピタント類縁物質の生成抑制効果がより一層高められることがわかる（表４、実施例２ｖｓ実施例３）。 The aqueous solution of fosaprepitant for injection containing diethylenetriaminepentaacetic acid has a reduced production amount of fosaprepitant related substances compared to the aqueous solution of fosaprepitant for injection containing sodium edetate hydrate instead of diethylenetriaminepentaacetic acid. (Table 4, Examples 2 to 3 vs Comparative Example 2), in the coexistence of fosaprepitant and diethylenetriaminepentaacetic acid, the production of fosaprepitant related substances was suppressed, and the same chelating agent, sodium edetate hydrate, was suppressed. It can be seen that no such effect is observed. Furthermore, it can be seen that by coexisting sodium hydrogen carbonate with diethylenetriaminepentaacetic acid, the effect of suppressing the production of fosaprepitant related substances is further enhanced (Table 4, Example 2 vs. Example 3).
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