JP6516831B2 - シクロホスファミド液状濃縮物の製剤 - Google Patents
シクロホスファミド液状濃縮物の製剤 Download PDFInfo
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- JP6516831B2 JP6516831B2 JP2017511153A JP2017511153A JP6516831B2 JP 6516831 B2 JP6516831 B2 JP 6516831B2 JP 2017511153 A JP2017511153 A JP 2017511153A JP 2017511153 A JP2017511153 A JP 2017511153A JP 6516831 B2 JP6516831 B2 JP 6516831B2
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- Prior art keywords
- cyclophosphamide
- containing composition
- aqueous liquid
- substantially non
- ethanol
- Prior art date
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- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 title claims description 109
- 229960004397 cyclophosphamide Drugs 0.000 title claims description 105
- 239000000203 mixture Substances 0.000 title claims description 72
- 238000009472 formulation Methods 0.000 title description 19
- 235000014666 liquid concentrate Nutrition 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 102
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 49
- 239000007788 liquid Substances 0.000 claims description 23
- 239000002535 acidifier Substances 0.000 claims description 20
- 229960004106 citric acid Drugs 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 11
- PWOQRKCAHTVFLB-UHFFFAOYSA-N cyclophosphamide hydrate Chemical group O.ClCCN(CCCl)P1(=O)NCCCO1 PWOQRKCAHTVFLB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000007774 longterm Effects 0.000 claims description 6
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 5
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical group 0.000 claims description 3
- WQNHWIYLCRZRLR-UHFFFAOYSA-N 2-(3-hydroxy-2,5-dioxooxolan-3-yl)acetic acid Chemical compound OC(=O)CC1(O)CC(=O)OC1=O WQNHWIYLCRZRLR-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- 229960004543 anhydrous citric acid Drugs 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 235000006109 methionine Nutrition 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 2
- SDKQRNRRDYRQKY-UHFFFAOYSA-N Dioxacarb Chemical compound CNC(=O)OC1=CC=CC=C1C1OCCO1 SDKQRNRRDYRQKY-UHFFFAOYSA-N 0.000 claims 1
- UDEJEOLNSNYQSX-UHFFFAOYSA-J tetrasodium;2,4,6,8-tetraoxido-1,3,5,7,2$l^{5},4$l^{5},6$l^{5},8$l^{5}-tetraoxatetraphosphocane 2,4,6,8-tetraoxide Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P1(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1 UDEJEOLNSNYQSX-UHFFFAOYSA-J 0.000 claims 1
- 239000000243 solution Substances 0.000 description 31
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
- 229940079593 drug Drugs 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 238000003860 storage Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 6
- 150000004682 monohydrates Chemical class 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 3
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- -1 cyclic phosphonic acid ester amides Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 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
- 229960002713 calcium chloride Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 1
- 229960003178 choline chloride Drugs 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
-
- 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
- A61K31/66—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
- A61K47/06—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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
Alamらは、米国特許第4,879,286号で、非経口又は経口投与用のシクロホスファミドの溶液を開示した。シクロホスファミドを含む製剤は、ポリオール、好ましくはプロピレングリコール、ポリエチレングリコール又はグリセリン、もしくはこれらの組み合わせ等の有機溶媒を含有する溶液中に溶解される。これらの安定性データは、ポリオール系の非水性製剤が、FDA承認を得るために適切な安定性を有さないことを示唆した。
シクロホスファミドは、本質的に高水溶性薬剤であり、Alamらは、米国特許第4,879,286号において、低い薬剤濃度を試験したために、有機溶媒が、許容される非経口溶媒で得られる溶解度を制限するという予想であった。
エタノールの何らかの蒸発損失を観察するために、異なる濃度及びバイアルの異なるサイズにおける安定性試験を実行した。安定性データを表8に示す。
Claims (19)
- a)100〜600mg/mlのシクロホスファミドと、
b)エタノールのみからなる溶媒系と、
c)エタノール可溶性酸性化剤と
を含み、
前記シクロホスファミド及び前記エタノール可溶性酸性化剤がエタノールに溶解しており、前記シクロホスファミドが唯一の医薬活性成分である、長期にわたる安定性を有する、実質的に非水性の液状シクロホスファミド含有組成物。 - 前記エタノール可溶性酸性化剤が、有機又は無機酸である、請求項1に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記エタノール可溶性酸性化剤が、クエン酸又は無水クエン酸である、請求項2に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記シクロホスファミドの濃度が、200〜550mg/mlである、請求項1に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記シクロホスファミドの濃度が、200又は400mg/mlである、請求項4に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記シクロホスファミドが、シクロホスファミド一水和物である、請求項1に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記クエン酸が、0.2〜2.0%W/Vの量で存在する、請求項3に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記クエン酸が、0.4〜0.8%W/Vの量で存在する、請求項7に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記クエン酸が、0.4〜0.6%W/Vの量で存在する、請求項8に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 塩化物イオンの供給源をさらに含む、請求項1に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 抗酸化剤をさらに含む、請求項1に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記抗酸化剤が、チオグリセリン、没食子酸プロピル、メチオニン、システイン及びこれらの組み合わせからなる群から選択される、請求項11に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記抗酸化剤が、チオグリセリンである、請求項12に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記溶液が、5℃の温度で18か月後に、少なくとも95%のシクロホスファミド含有量を維持する、請求項1に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記溶液が、5℃の温度で18か月後に、少なくとも97%のシクロホスファミド含有量を維持する、請求項14に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- a)シクロホスファミドと、
b)エタノールからなる溶媒と、
c)クエン酸と
から本質的に構成され、
前記シクロホスファミド及び前記クエン酸がエタノールに溶解しており、前記シクロホスファミドが唯一の医薬活性成分である、実質的に非水性の液状シクロホスファミド含有組成物。 - 前記クエン酸が、無水クエン酸であり、前記シクロホスファミドが、シクロホスファミド一水和物である、請求項16に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- シクロホスファミドのクエン酸に対する比が、50:1である、請求項16に記載の実質的に非水性の液状シクロホスファミド含有組成物。
- 前記組成物におけるシクロホスファミドの濃度が、200又は400mg/mlである、請求項18に記載の実質的に非水性の液状シクロホスファミド含有組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461991247P | 2014-05-09 | 2014-05-09 | |
US61/991,247 | 2014-05-09 | ||
PCT/US2015/028862 WO2015171460A2 (en) | 2014-05-09 | 2015-05-01 | Formulations of cyclophosphamide liquid concentrate |
Publications (3)
Publication Number | Publication Date |
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JP2017514924A JP2017514924A (ja) | 2017-06-08 |
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JP6516831B2 true JP6516831B2 (ja) | 2019-05-22 |
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US (3) | US9662342B2 (ja) |
EP (1) | EP3139929A4 (ja) |
JP (1) | JP6516831B2 (ja) |
KR (1) | KR20170008252A (ja) |
CN (1) | CN106456654A (ja) |
AU (1) | AU2015256331B2 (ja) |
BR (1) | BR112016026140A2 (ja) |
CA (1) | CA2948148C (ja) |
RU (1) | RU2016147362A (ja) |
WO (1) | WO2015171460A2 (ja) |
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WO2016005962A2 (en) * | 2014-07-11 | 2016-01-14 | Dr. Reddy’S Laboratories Limited | Stable liquid formulations of cyclophosphamide and processes |
WO2016132270A1 (en) * | 2015-02-16 | 2016-08-25 | Leiutis Pharmaceuticals Pvt Ltd | Stable ready to use cyclophosphamide liquid formulations |
WO2020178725A1 (en) * | 2019-03-04 | 2020-09-10 | Alembic Pharmaceuticals Limited | Stable liquid composition of cyclophosphamide |
WO2021005544A1 (en) | 2019-07-10 | 2021-01-14 | Intas Pharmaceuticals Ltd. | Stable oral composition of cyclophosphamide |
WO2021009595A1 (en) * | 2019-07-15 | 2021-01-21 | Hetero Healthcare Limited | Cyclophosphamide injectable composition and methods for producing same |
US20230310468A1 (en) | 2020-08-17 | 2023-10-05 | Sandoz Ag | Parenteral pharmaceutical composition comprising cyclophosphamide and a mixture of liquids |
US11931370B2 (en) | 2021-10-08 | 2024-03-19 | Slayback Pharma Llc | Stable pharmaceutical compositions of cyclophosphamide |
US11642358B1 (en) | 2022-02-14 | 2023-05-09 | Extrovis Ag | Stable pharmaceutical formulation |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
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NL99649C (ja) | 1956-12-20 | |||
DE3772482D1 (de) * | 1986-07-11 | 1991-10-02 | Asta Pharma Ag | Loesungen von oxazaphosphorinen mit verbesserter stabilitaet und verfahren zu deren herstellung. |
US4879286A (en) | 1987-01-28 | 1989-11-07 | Lyphomed, Inc. | Cyclophosphamide |
US5036060A (en) * | 1988-07-25 | 1991-07-30 | Fujisawa Usa, Inc. | Cyclophosphamide |
CA2039742A1 (en) * | 1990-04-23 | 1991-10-24 | Andrew B. Dennis | Tablet composition and method for problem pharmaceutical materials |
EP1023075B1 (de) * | 1997-10-13 | 2006-12-20 | Stada Arzneimittel Ag | Flüssige darreichungsformen oxazaphosphorinhaltiger pharmazeutischer produkte |
US6811788B2 (en) * | 2000-01-19 | 2004-11-02 | Baofa Yu | Combinations and methods for treating neoplasms |
AUPQ849900A0 (en) * | 2000-06-30 | 2000-07-27 | Dbl Australia Pty Ltd. | Injectable composition |
DE602005027727D1 (de) * | 2004-10-15 | 2011-06-09 | Seo Hong Yoo | Zusammensetzungen zur verringerung der toxizität von cisplatin, carboplatin und oxaliplatin |
US8436190B2 (en) | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
US7872050B2 (en) | 2005-03-14 | 2011-01-18 | Yaupon Therapeutics Inc. | Stabilized compositions of volatile alkylating agents and methods of using thereof |
CN1923280A (zh) * | 2005-08-30 | 2007-03-07 | 孔庆忠 | 一种含双氯乙胺类药物的抗癌缓释注射剂 |
JP5318403B2 (ja) * | 2007-11-30 | 2013-10-16 | 株式会社Sokudo | 基板処理装置 |
US8278220B2 (en) * | 2008-08-08 | 2012-10-02 | Fei Company | Method to direct pattern metals on a substrate |
CN104398471A (zh) * | 2008-11-28 | 2015-03-11 | Abbvie公司 | 稳定的抗体组合物和用于稳定其的方法 |
KR20120052937A (ko) * | 2009-06-18 | 2012-05-24 | 아보트 러보러터리즈 | 안정한 나노입자형 약물 현탁액 |
US20140005148A1 (en) * | 2012-06-29 | 2014-01-02 | Coldstream Laboratories Inc. | Stable liquid formulations of nitrogen mustards |
WO2014068585A1 (en) * | 2012-10-29 | 2014-05-08 | Leiutis Pharmaceuticals Pvt. Ltd. | Novel lyophilized compositions of cyclophosphamide |
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- 2015-05-01 AU AU2015256331A patent/AU2015256331B2/en not_active Ceased
- 2015-05-01 JP JP2017511153A patent/JP6516831B2/ja not_active Expired - Fee Related
- 2015-05-01 CA CA2948148A patent/CA2948148C/en active Active
- 2015-05-01 BR BR112016026140A patent/BR112016026140A2/pt active Search and Examination
- 2015-05-01 EP EP15789798.4A patent/EP3139929A4/en not_active Withdrawn
- 2015-05-01 WO PCT/US2015/028862 patent/WO2015171460A2/en active Application Filing
- 2015-05-01 RU RU2016147362A patent/RU2016147362A/ru unknown
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AU2015256331B2 (en) | 2020-03-12 |
EP3139929A2 (en) | 2017-03-15 |
JP2017514924A (ja) | 2017-06-08 |
AU2015256331A1 (en) | 2016-11-17 |
RU2016147362A (ru) | 2018-06-13 |
US20150320774A1 (en) | 2015-11-12 |
WO2015171460A2 (en) | 2015-11-12 |
CN106456654A (zh) | 2017-02-22 |
EP3139929A4 (en) | 2018-01-03 |
US20170232015A1 (en) | 2017-08-17 |
KR20170008252A (ko) | 2017-01-23 |
US20150320775A1 (en) | 2015-11-12 |
US9662342B2 (en) | 2017-05-30 |
CA2948148C (en) | 2022-12-06 |
RU2016147362A3 (ja) | 2018-10-01 |
CA2948148A1 (en) | 2015-11-12 |
BR112016026140A2 (pt) | 2018-08-07 |
WO2015171460A3 (en) | 2016-04-21 |
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