JP2022519343A - ベンゾアゼピン化合物含有医薬組成物 - Google Patents
ベンゾアゼピン化合物含有医薬組成物 Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- -1 Benzodiazepine compound Chemical class 0.000 title description 5
- 229940049706 benzodiazepine Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 229910052751 metal Inorganic materials 0.000 claims abstract description 40
- 239000002184 metal Substances 0.000 claims abstract description 40
- 230000000694 effects Effects 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims description 63
- 239000007864 aqueous solution Substances 0.000 claims description 25
- 206010033675 panniculitis Diseases 0.000 claims description 12
- 210000004304 subcutaneous tissue Anatomy 0.000 claims description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 9
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical group [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 8
- 206010015150 Erythema Diseases 0.000 claims description 6
- 208000008454 Hyperhidrosis Diseases 0.000 claims description 6
- 208000003251 Pruritus Diseases 0.000 claims description 6
- 231100000321 erythema Toxicity 0.000 claims description 6
- 230000037315 hyperhidrosis Effects 0.000 claims description 6
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 229960001256 tolvaptan Drugs 0.000 abstract description 19
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 abstract description 19
- 239000000243 solution Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 229940126062 Compound A Drugs 0.000 description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 150000002016 disaccharides Chemical class 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000001802 infusion Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 206010016807 Fluid retention Diseases 0.000 description 6
- 229940090044 injection Drugs 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 206010019280 Heart failures Diseases 0.000 description 5
- 239000003002 pH adjusting agent Substances 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000010061 Autosomal Dominant Polycystic Kidney Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 102000004136 Vasopressin Receptors Human genes 0.000 description 3
- 108090000643 Vasopressin Receptors Proteins 0.000 description 3
- 208000022185 autosomal dominant polycystic kidney disease Diseases 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 229940093181 glucose injection Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 150000003751 zinc Chemical class 0.000 description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- 208000026292 Cystic Kidney disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010021036 Hyponatraemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 201000008284 inappropriate ADH syndrome Diseases 0.000 description 2
- 239000002171 loop diuretic Substances 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229940097271 other diuretics in atc Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 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
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000008101 lactose Substances 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
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate 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
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
項1.
式(1):
項2.
式(1)で表される化合物又はその金属塩が、平均2/3(mg/分)以下の速さで投与されるように用いられる、項1に記載の医薬組成物。
項3.
式(1)で表される化合物又はその金属塩4~20mgが、10分~4時間かけて経血管投与されるように用いられる、項1又は2に記載の医薬組成物。
項4.
式(1)で表される化合物又はその金属塩の投与により皮膚又は皮下組織に生じる副作用を低減するための、項1~3のいずれかに記載の医薬組成物。
項5.
式(1)で表される化合物又はその金属塩の投与により皮膚又は皮下組織に生じる副作用が、紅斑、多汗、及び掻痒からなる群より選択される少なくとも1種である、項4に記載の医薬組成物。
項6.
心不全(好ましくはうっ血性心不全)における体液貯留、肝硬変における体液貯留、又は抗利尿ホルモン不適合分泌症候群(SIADH)による低ナトリウム血症、あるいは常染色体優性多発性嚢胞腎の治療用である、項1~5のいずれかに記載の医薬組成物。
項7.
治療のため、一回の投与で、式(1)で表される化合物又はその金属塩4~20mgを投与することが必要な患者用である、項1~6のいずれかに記載の医薬組成物。
項8.
凍結乾燥組成物又は水溶液組成物である、項1~7のいずれかに記載の医薬組成物。
項9.
前記金属塩が、2ナトリウム塩である、項1~8のいずれかに記載の医薬組成物。
項10.
項1~9のいずれかに記載の医薬組成物が、当該医薬組成物に含有される式(1)で表される化合物又はその金属塩量が4~20mgとなるよう容器(好ましくはバイアル)に備えられた、医薬製剤。
は本明細書に開示され当業者が認識できる全てを包含する。
が好ましい。なお、当該化合物(1)又はその金属塩4~20mgとの範囲において、上限または下限は例えば4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、又は19.5mgであってもよい。例えば、当該範囲は、5~19mg、6~18mg、6.5~17.5mg、7~17mg、7.5~16.5mg、又は8~16mg程度であってもよい。
く含有する。緩衝剤としては、リン酸緩衝剤、炭酸緩衝剤が好ましく、特に、リン酸緩衝
剤が好ましく、より具体的には、例えばリン酸水素2ナトリウム(リン酸水素ナトリウム水和物)及び/又はリン酸2水素ナトリウムが好ましく挙げられる。
特許文献1(国際公開第2007/074915号)の実施例(特に実施例1、3、及び9)に記載の方法に従って、化合物(1)及びその2ナトリウム塩を調製した。当該2ナトリウム塩を化合物Aとして、以下の検討に用いた。当該調製は、具体的には、次のようにして行った。なお、以下の具体的な調製方法の記載においては、当該化合物(1b)が化合物(1)にあたり、化合物(1b)の2ナトリウム塩が化合物Aにあたる。
結晶化した。結晶を濾取し、減圧下乾燥(五酸化二リン)することにより、化合物(1b)の白色粉末3.5g(収量88.5%)を得た。
下記表1に記載の組成に従って、化合物A、スクロース、リン酸水素ナトリウム水和物、及びリン酸二水素ナトリウムを注射用水に溶解し、水酸化ナトリウムでpHを8.5に調整し、表1の組成の水溶液を調製した。組成の水溶液を無菌ろ過後、滅菌されたガラスバイアルに5.21mL充填した。さらに、-40℃以下に凍結後、真空に減圧し、棚温を-10℃にして水分を除去した後、棚温を30℃にして残存水分を除去することで、表2の組成の無菌の凍結乾燥組成物(バイアル入り)を得た。
Lを加えて溶解すると、5mg/mLの有効成分(化合物A)が含まれる表1の水溶液組
成物(25mg製剤注射用水溶液)が5.21mL再構成される。そして、下記表3の組成
に従って、25mg製剤注射用水溶液及び0mg製剤注射用水溶液並びに生理食塩液(生理食塩水)を混合し、各投与液を調製した。
多汗、又は掻痒)を発症した人数を記録した。結果を表4に示す。7.5mg又は15mgの化合物Aを含む投与液を1分間又は5分間で静脈内投与すると紅斑、多汗、又は掻痒が高頻度に発現した(表4:投与液3~6の投与結果)。一方、7.5mg又は15mgの化合物Aを含む投与液を2時間かけて緩徐に投与すると、紅斑、多汗、又は掻痒等皮膚または皮下組織に現れ得る副作用は全く認められなかった(表4:投与液1~2の投与結果)。また、表4には、それぞれの投与液を投与した被験者におけるトルバプタンの最高血中濃度(Cmax)も併せて示す。
Claims (10)
- 式(1)で表される化合物又はその金属塩が、平均2/3(mg/分)以下の速さで投与されるように用いられる、請求項1に記載の医薬組成物。
- 式(1)で表される化合物又はその金属塩4~20mgが、10分~4時間かけて経血管投与されるように用いられる、請求項1又は2に記載の医薬組成物。
- 式(1)で表される化合物又はその金属塩の投与により皮膚又は皮下組織に生じる副作用を低減するための、請求項1~3のいずれかに記載の医薬組成物。
- 式(1)で表される化合物又はその金属塩の投与により皮膚又は皮下組織に生じる副作用が、紅斑、多汗、及び掻痒からなる群より選択される少なくとも1種である、請求項4に記載の医薬組成物。
- 心不全における体液貯留、肝硬変における体液貯留、又は抗利尿ホルモン不適合分泌症候群(SIADH)による低ナトリウム血症、あるいは常染色体優性多発性嚢胞腎の治療用である、請求項1~5のいずれかに記載の医薬組成物。
- 治療のため、一回の投与で、式(1)で表される化合物又はその金属塩4~20mgを投与することが必要な患者用である、請求項1~6のいずれかに記載の医薬組成物。
- 凍結乾燥組成物又は水溶液組成物である、請求項1~7のいずれかに記載の医薬組成物。
- 前記金属塩が、2ナトリウム塩である、請求項1~8のいずれかに記載の医薬組成物。
- 請求項1~9のいずれかに記載の医薬組成物が、当該医薬組成物に含有される式(1)で表される化合物又はその金属塩量が4~20mgとなるよう容器に備えられた、医薬製剤。
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JP2015134837A (ja) * | 2007-06-26 | 2015-07-27 | 大塚製薬株式会社 | 医薬 |
JP2016533317A (ja) * | 2013-10-15 | 2016-10-27 | 大塚製薬株式会社 | 多発性嚢胞腎の予防及び/又は治療薬 |
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JP2015134837A (ja) * | 2007-06-26 | 2015-07-27 | 大塚製薬株式会社 | 医薬 |
JP2016533317A (ja) * | 2013-10-15 | 2016-10-27 | 大塚製薬株式会社 | 多発性嚢胞腎の予防及び/又は治療薬 |
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