JP2004269363A - Stable aqueous medicinal composition comprising acetaminophen - Google Patents
Stable aqueous medicinal composition comprising acetaminophen Download PDFInfo
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- JP2004269363A JP2004269363A JP2003057963A JP2003057963A JP2004269363A JP 2004269363 A JP2004269363 A JP 2004269363A JP 2003057963 A JP2003057963 A JP 2003057963A JP 2003057963 A JP2003057963 A JP 2003057963A JP 2004269363 A JP2004269363 A JP 2004269363A
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- acetaminophen
- pharmaceutical composition
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- pyrosulfite
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 title abstract description 13
- 238000002347 injection Methods 0.000 claims abstract description 25
- 239000007924 injection Substances 0.000 claims abstract description 25
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 21
- 235000010262 sodium metabisulphite Nutrition 0.000 claims abstract description 21
- 239000006188 syrup Substances 0.000 claims abstract description 18
- 235000020357 syrup Nutrition 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 230000000087 stabilizing effect Effects 0.000 claims description 12
- 239000003381 stabilizer Substances 0.000 claims description 9
- HOMROMWVNDUGRI-RVZXSAGBSA-N (2s)-2-aminopentanedioic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O HOMROMWVNDUGRI-RVZXSAGBSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007788 liquid Substances 0.000 description 13
- 239000012153 distilled water Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 238000004040 coloring Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229920003081 Povidone K 30 Polymers 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 description 4
- 229940024898 povidone k30 Drugs 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229960002920 sorbitol Drugs 0.000 description 4
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229960005042 mequitazine Drugs 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- -1 glycerin and ethanol Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明はアセトアミノフェンを含有する安定な水性医薬組成物に関する。
【０００２】
【従来の技術】
アセトアミノフェン（パラセタモールと呼ばれる場合もある）は成人はもちろん小児に対しても安全に使用できる有用なパラアミノフェノール系の解熱鎮痛剤であり、頭痛、筋肉痛、月経痛、歯痛、歯科治療後の疼痛などの鎮痛及び急性上気道炎における解熱や鎮痛に汎用されている。アセトアミノフェンは通常は経口投与で用いられ、錠剤のほか、液剤としてシロップ剤が用いられている（例えば小児用解熱剤として「カロナールシロップ」（昭和薬品化工株式会社製造販売）が提供されており、マレイン酸クロルフェニラミン、無水カフェインなどの薬剤も含む総合感冒剤としては「ＬＬシロップ」（和光堂株式会社販売）、「レパロンシロップ」（大洋薬品工業株式会社製造販売）などが用いられている）。また、ヨーロッパ諸国、特にフランス国では軽度から中等度の急性疼痛と発熱の治療に静脈注射剤として使用されている。
【０００３】
しかしながら、アセトアミノフェンは水溶液中で不安定であり、加水分解して橙色から褐色に着色してしまうという問題がある（例えば、薬局， Ｖｏｌ．２９， １１６１， １９７８； Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ， Ｖｏｌ．５０， １１３， １９６１）。水溶液におけるアセトアミノフェンの安定性を改善すべく鋭意研究が行われているが（例えば、Ｊｏｕｒｎａｌ ｏｆ Ｃｌｉｎｉｃａｌ Ｐｈａｒｍａｃｙ ａｎｄ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｖｏｌ．１７， １０７， １９９２）、着色などの問題を十分に解決できる安定化剤は提供されていない。例えば、アセトアミノフェンと安定剤として遊離ラジカル捕集剤とを含む液体組成物が提案されているが（特表平１１−５１４０１３号公報）、この液体組成物の安定性も満足すべきものとは言えない。
【０００４】
一方、ピロ亜硫酸ナトリウムはメタ重亜硫酸ナトリウムとも呼ばれ、医薬品添加物事典（薬事日報社発行、２０００年）には安定（化）剤、抗酸化剤としての記載がある。しかしながら、ピロ亜硫酸ナトリウムなどのピロ亜硫酸塩類がアセトアミノフェンの水溶液での不安定性を改善できることは従来知られていない。特開２００２−３００５４号公報には、アセトアミノフェンの製造工程においてＮ−メチル−ｐ−ヒドロキシベンズアルデヒドの生成を抑制するためにピロ亜硫酸ナトリウムが用いられているが、この刊行物にはピロ亜硫酸ナトリウムがアセトアミノフェン自体を安定化することは示唆ないし教示されていない。特開平１１−２０９２８８号公報にはメキタジン水溶液の安定性を高めるためにアセトアミノフェン及びピロ亜硫酸塩などから選ばれる物質をメキタジン液製剤に配合することが開示されているが、この刊行物にもピロ亜硫酸塩類がアセトアミノフェンを安定化することは示唆ないし教示されていない。
【特許文献１】特開２００２−３００５４号公報
【特許文献２】特開平１１−２０９２８８号公報
【０００５】
【発明が解決しようとする課題及び課題を解決するための手段】
本発明は、アセトアミノフェンを有効成分として含む水溶液を安定化する手段を提供することを課題としている。本発明者らは上記の課題を解決すべく鋭意研究を行ない、種々の安定化剤や抗酸化剤をアセトアミノフェンの水溶液に添加して安定化作用を検討していたが、種々の亜硫酸塩類のなかでも特にピロ亜硫酸塩類がアセトアミノフェンに対して極めて優れた安定化作用を有していることを発見した。亜硫酸塩類は抗酸化剤あるいは安定化剤として医薬の製造に汎用されているが、例えば亜硫酸ナトリウムはアセトアミノフェンに対してほとんど安定化作用を有していない。従って、亜硫酸塩類のうちピロ亜硫酸塩類が特異的にアセトアミノフェンを安定化できることは極めて驚くべきことである。本発明は上記の知見を基にして完成された。
【０００６】
すなわち、本発明は、アセトアミノフェン及びピロ亜硫酸塩類を含む水性の医薬組成物を提供するものである。この水溶液は長期保存においても安定であり、着色などの品質劣化が生じないという優れた効果を有している。
本発明の好ましい態様によれば、注射剤の形態である上記の医薬組成物；シロップ剤の形態である上記の医薬組成物；ピロ亜硫酸塩がピロ亜硫酸ナトリウムである上記の医薬組成物；及び、さらにＬ−グルタミン酸Ｌ−リジンを含む上記の医薬組成物が提供される。
【０００７】
別の観点からは、本発明により、アセトアミノフェンを含む水溶液の安定化剤であって、ピロ亜硫酸塩類を含む安定化剤が提供される。この発明の好ましい態様によれば、上記水溶液が注射剤又はシロップ剤の形態である上記の安定化剤；及びピロ亜硫酸塩がピロ亜硫酸ナトリウムである上記の安定化剤が提供される。さらに別の観点からは、アセトアミノフェンを含む水溶液の安定化方法であって、上記水溶液にピロ亜硫酸塩類を添加する工程を含む方法が本発明により提供される。この発明の好ましい態様によれば、上記水溶液が注射剤又はシロップ剤の形態である上記の方法；及びピロ亜硫酸塩がピロ亜硫酸ナトリウムである上記の方法が提供される。
【０００８】
【発明の実施の形態】
本発明の医薬組成物は水性の医薬組成物であり、有効成分であるアセトアミノフェンとアセトアミノフェンの安定化剤であるピロ亜硫酸塩類とを含むことを特徴としている。アセトアミノフェン〔Ｎ−（４−ヒドロキシフェニル）アセトアミド〕は第１４改正日本薬局方に収載された医薬品であり、容易に入手可能な医薬品である。ピロ亜硫酸塩類としてはピロ亜硫酸ナトリウム又はピロ亜硫酸カリウムなどを用いることができるが、医薬品添加物としての安全性の観点から、第１４改正日本薬局方に収載されたピロ亜硫酸ナトリウム（ｓｏｄｉｕｍ ｐｙｒｏｓｕｌｆｉｔｅ）を用いることが好ましい。ピロ亜硫酸ナトリウムは医薬品添加物や食品添加物として汎用されており、市販品を容易に入手できる（例えば医薬品添加物事典、日本医薬品添加剤協会編集、薬事日報社発行２０００年の２１７〜２１８頁に医薬品添加物としての規格や商品名が記載されている）。
【０００９】
アセトアミノフェンを有効成分として含む水溶液の有効成分濃度は特に限定されないが、例えば、０．１〜５重量％程度であり、例えば注射剤として調製する場合には０．１〜２重量％程度であり、経口投与用のシロップ剤として調製する場合には０．１〜４重量％程度である。アセトアミノフェンに対するピロ亜硫酸塩類の添加量は、例えば、アセトアミノフェン１重量部に対して０．０１〜０．１重量部程度であり、好ましくは０．０３〜０．１重量部程度である。もっとも、有効成分濃度やアセトアミノフェンに対するピロ亜硫酸塩類の添加量は医薬組成物の形態や使用目的などの種々の条件に応じて当業者が適宜選択可能であることは言うまでもない。また、本発明の医薬組成物には、アセトアミノフェンの安定化をさらに高めるために、ピロ亜硫酸塩と組み合わせてＬ−グルタミン酸Ｌ−リジンを添加することが好ましい。Ｌ−グルタミン酸Ｌ−リジンの使用量は特に限定されないが、例えば、アセトアミノフェン１重量部に対して０．０１〜０．１重量部程度であり、好ましくは０．０３〜０．１重量部程度である。
【００１０】
本発明の医薬組成物は、皮下投与、筋肉内投与、又は静脈内投与用の注射剤あるいは静脈内投与用の点滴剤として調製することができる。また、経口投与用のシロップ剤として調製することも好ましい。また、本発明の医薬組成物は、水性の組成物を封入したソフトカプセルなどの形態であってもよい。本発明の医薬組成物には、他の医薬の有効成分を１種又は２種以上配合することも可能である。例えば、マレイン酸クロルフェニラミンなどの抗ヒスタミン剤やカフェインなどの解熱剤などを注射剤又はシロップ剤の形態の医薬組成物に配合することもでき、このような他の医薬の種類と配合量は当業者に適宜選択可能である。本発明の医薬の投与量は、有効成分であるアセトアミノフェンの通常の投与量に従って決定することが可能である。
【００１１】
本発明の医薬組成物の調製にあたっては、医薬組成物の製造に通常用いられる製剤添加物の１種又は２種以上を用いることができる。本明細書において「水性」という用語は医薬組成物を構成する液状媒体が水を含んでいることを意味しており、通常は液状媒体の大部分又は全体が水からなる。水以外の液状媒体としては、エチレングリコール、プロピレングリコール、又はポリエチレングリコールなどのグリコール類、グリセリン、エタノールなどのアルコール類などを用いることができるが、これらに限定されることはない。液状媒体としては、蒸留水や注射用蒸留水のほか、生理食塩水又は緩衝液などを用いることもできる。本発明の医薬組成物に用いられる製剤用添加物としては、例えば、ｐＨ調節剤（無機又は有機の酸又は塩基など），等張化剤（塩化ナトリウム、ブドウ糖、グリセリンなど）、甘味剤などの矯味剤などを用いることができるが、これらに限定されることはなく、医薬組成物の形態に応じて当業者が適宜選択可能である。
【００１２】
【実施例】
以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されることはない。
実施例１
アセトアミノフェン１ｇ、ピロ亜硫酸ナトリウム４０ｍｇ、塩化ナトリウム７００ｍｇを注射用蒸留水８０ｍＬに溶解し、水酸化ナトリウムを適量加えてｐＨ６に調整した後、全量を１００ｍＬになるように注射用蒸留水を加えて静脈内投与用注射剤を製造した。
実施例２
アセトアミノフェン０．５ｇ、ピロ亜硫酸ナトリウム４０ｍｇ、塩化ナトリウム７００ｍｇを注射用蒸留水８０ｍＬに溶解し、水酸化ナトリウムを適量加えてｐＨ６に調整した後、全量を１００ｍＬになるように注射用蒸留水を加えて静脈内投与用注射剤を製造した。
【００１３】
実施例３
アセトアミノフェン１ｇ、ピロ亜硫酸ナトリウム４０ｍｇ、Ｌ−グルタミン酸Ｌ−リジン６００ｍｇ、塩化ナトリウム４００ｍｇを注射用蒸留水８０ｍＬに溶解し、水酸化ナトリウムを適量加えてｐＨ６に調整した後、全量を１００ｍＬになるように注射用蒸留水を加えて静脈内投与用注射剤を製造した。
実施例４
マクロゴール４００ ８ｇにアセトアミノフェン２ｇを加え、プロピレングリコール３ｇを加えて混合溶解してＩ液とした。別にＤ−ソルビト−ル２０ｇにポビドンｋ３０ １ｇ、ピロ亜硫酸ナトリウム０．０５ｇを加えて混合溶解しＩＩ液とした。Ｉ液とＩＩ液を混合して全量を１００ｍＬになるように精製水を加えてシロップ剤を製造した。
実施例５
マクロゴール４００ ８ｇにアセトアミノフェン２ｇを加え、プロピレングリコール３ｇを加えて混合溶解しＩ液とした。別にＤ−ソルビト−ル２０ｇにポビドンｋ３０ １ｇ、ピロ亜硫酸ナトリウム０．０７５ｇを加えて混合溶解しＩＩ液とした。Ｉ液とＩＩ液を混合して全量を１００ｍＬになるように精製水を加えてシロップ剤を製造した。
【００１４】
比較例１
アセトアミノフェン１ｇを注射用蒸留水８０ｍＬに溶解し、水酸化ナトリウムを適量加えてｐＨ６に調整した後、全量を１００ｍＬになるように注射用蒸留水を加えて静脈内投与用注射剤を製造した。
比較例２
アセトアミノフェン１ｇ、亜硫酸ナトリウム６０ｍｇを注射用蒸留水８０ｍＬに溶解し、水酸化ナトリウムを適量加えてｐＨ６に調整した後、全量を１００ｍＬになるように注射用蒸留水を加えて静脈内投与用注射剤を製造した。
【００１５】
比較例３
マクロゴール４００ ８ｇにアセトアミノフェン２ｇを加え、プロピレングリコール３ｇを加えて混合溶解しＩ液とした。別にＤ−ソルビト−ル２０ｇにポビドンｋ３０ １ｇを加えて混合溶解しＩＩ液とした。Ｉ液とＩＩ液を混合して全量を１００ｍＬになるように精製水を加えてシロップ剤を製造した。
比較例４
マクロゴール４００ ８ｇにアセトアミノフェン２ｇを加え、プロピレングリコール３ｇを加えて混合溶解しＩ液とした。別にＤ−ソルビト−ル２０ｇにポビドンｋ３０ １ｇ、亜硫酸ナトリウム０．７５ｇを加えて混合溶解しＩＩ液とした。Ｉ液とＩＩ液を混合して全量を１００ｍＬになるように精製水を加えてシロップ剤を製造した。
【００１６】
試験例１
実施例及び比較例で調製した各静脈内投与用注射剤２０ｍＬをそれぞれバイアル瓶に充填し、４０℃で７５％ ＲＨの保存条件下に１２日間または４２日間保存して外観の観察を行った。シロップ剤については各１００ｍＬをそれぞれバイアル瓶に充填し、４０℃で７５％ ＲＨの保存条件下６箇月間保存した際の外観観察を行った。結果を表１（注射剤）及び表２（シロップ剤）に示す。これらの結果から、ピロ亜硫酸ナトリウムを含む本発明の組成物では安定性が極めて優れており、着色が全く認められないこと、及び安定化剤として汎用されている亜硫酸ナトリウムを含む組成物では安定性が悪く、着色が認められることが分かる。亜硫酸ナトリウムで十分な安定化作用が得られないアセトアミノフェンに対してピロ亜硫酸ナトリウムが顕著な安定化効果を奏することは極めて驚くべきことである。また、ピロ亜硫酸ナトリウムとともにＬ−グルタミン酸Ｌ−リジンを含む実施例３の組成物を同様の条件下で８９日保存しても組成物は無色澄明であったが、同様の保存条件では実施例１及び２の組成物にかすかに着色が認めらた。この結果から、ピロ亜硫酸ナトリウムとＬ−グルタミン酸Ｌ−リジンとを組み合わせた場合に極めて高い安定化効果が達成されることが分かった。
【００１７】
【表１】
【表２】
【発明の効果】
アセトアミノフェンを有効成分として含む本発明の水性組成物は長期間保存しても着色が認められず極めて安定である。また、本発明の組成物に含まれるピロ亜硫酸塩は医薬品や食品の添加物として汎用されている物質であり、安全性が高いことが確認されていることから、本発明の医薬組成物は安全な医薬として利用できる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to stable aqueous pharmaceutical compositions containing acetaminophen.
[0002]
[Prior art]
Acetaminophen (sometimes called paracetamol) is a useful para-aminophenol-based antipyretic analgesic that can be used safely in adults as well as children, and is useful for treating headache, muscle pain, menstrual pain, toothache, and dental treatment. It is widely used for analgesia such as pain and antipyretic and analgesic in acute upper respiratory inflammation. Acetaminophen is usually used for oral administration, and in addition to tablets, syrups are used as liquids (for example, "Caronal Syrup" (manufactured and sold by Showa Yakuhin Kako Co., Ltd.) is provided as a pediatric antipyretic, "LL Syrup" (manufactured and sold by Wakodo Co., Ltd.) and "Repalon Syrup" (manufactured and sold by Taiyo Pharmaceutical Co., Ltd.) are used as general cold remedies including drugs such as chlorpheniramine maleate and anhydrous caffeine. ). In Europe, especially France, it is used as an intravenous injection for the treatment of mild to moderate acute pain and fever.
[0003]
However, acetaminophen is unstable in an aqueous solution, and has a problem that it is hydrolyzed and colored from orange to brown (for example, Pharmacy, Vol. 29, 1161, 1978; Journal of Pharmaceutical Sciences, Vol. 50, 113, 1961). Efforts have been made to improve the stability of acetaminophen in an aqueous solution (for example, Journal of Clinical Pharmacy and Therapeutics, Vol. 17, 107, 1992), but stabilization capable of sufficiently solving problems such as coloring. No agent was provided. For example, a liquid composition containing acetaminophen and a free radical scavenger as a stabilizer has been proposed (Japanese Unexamined Patent Application Publication No. 11-514013). However, the stability of the liquid composition is not satisfactory. I can not say.
[0004]
On the other hand, sodium metabisulfite is also called sodium metabisulfite, and is described as a stabilizing (stabilizing) agent and an antioxidant in the Pharmaceutical Excipients Dictionary (published by Yakuji Nippo, 2000). However, it has not been known that pyrosulfites such as sodium pyrosulfite can improve the instability of acetaminophen in an aqueous solution. Japanese Patent Application Laid-Open No. 2002-30054 uses sodium pyrosulfite to suppress the production of N-methyl-p-hydroxybenzaldehyde in the process of producing acetaminophen. Does not suggest or teach stabilizing acetaminophen itself. JP-A-11-209288 discloses that a substance selected from acetaminophen and pyrosulfite is added to a mequitazine liquid preparation in order to enhance the stability of an aqueous solution of mequitazine. It is not suggested or taught that pyrosulfites stabilize acetaminophen.
[Patent Document 1] JP-A-2002-30054 [Patent Document 2] JP-A-11-209288 [0005]
Problems to be Solved by the Invention and Means for Solving the Problems
An object of the present invention is to provide a means for stabilizing an aqueous solution containing acetaminophen as an active ingredient. The present inventors have conducted intensive studies to solve the above-mentioned problems, and studied the stabilizing action by adding various stabilizers and antioxidants to an aqueous solution of acetaminophen. Among them, it has been discovered that pyrosulfites have an extremely excellent stabilizing effect on acetaminophen. Sulfites are widely used in the manufacture of pharmaceuticals as antioxidants or stabilizers. For example, sodium sulfite has almost no stabilizing effect on acetaminophen. Accordingly, it is extremely surprising that pyrosulfites among sulfites can specifically stabilize acetaminophen. The present invention has been completed based on the above findings.
[0006]
That is, the present invention provides an aqueous pharmaceutical composition containing acetaminophen and pyrosulfites. This aqueous solution is stable even during long-term storage, and has an excellent effect that quality deterioration such as coloring does not occur.
According to a preferred embodiment of the present invention, the above-mentioned pharmaceutical composition in the form of an injection; the above-mentioned pharmaceutical composition in the form of a syrup; the above-mentioned pharmaceutical composition, wherein the pyrosulfite is sodium pyrosulfite; Further provided is the above pharmaceutical composition comprising L-glutamic acid L-lysine.
[0007]
In another aspect, the present invention provides a stabilizer for an aqueous solution containing acetaminophen, which contains pyrosulfites. According to a preferred embodiment of the present invention, there is provided the above stabilizer, wherein the aqueous solution is in the form of an injection or syrup; and the above stabilizer, wherein the pyrosulfite is sodium pyrosulfite. From yet another aspect, the present invention provides a method for stabilizing an aqueous solution containing acetaminophen, the method including a step of adding pyrosulfites to the aqueous solution. According to a preferred aspect of the present invention, there is provided the above method, wherein the aqueous solution is in the form of an injection or syrup; and the above method, wherein the pyrosulfite is sodium pyrosulfite.
[0008]
BEST MODE FOR CARRYING OUT THE INVENTION
The pharmaceutical composition of the present invention is an aqueous pharmaceutical composition, and is characterized by containing acetaminophen as an active ingredient and pyrosulfites as a stabilizer for acetaminophen. Acetaminophen [N- (4-hydroxyphenyl) acetamide] is a drug listed in the 14th revised Japanese Pharmacopoeia and is a drug that can be easily obtained. As the pyrosulfite, sodium pyrosulfite or potassium pyrosulfite can be used, but from the viewpoint of safety as a pharmaceutical additive, sodium pyrosulfite listed in the 14th revised Japanese Pharmacopoeia is used. Is preferred. Sodium pyrosulfite is widely used as a pharmaceutical additive or a food additive, and a commercially available product can be easily obtained (for example, Pharmaceutical Excipients Dictionary, edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo pp. 217-218 in 2000) Standards and trade names for pharmaceutical excipients are listed).
[0009]
The concentration of the active ingredient in the aqueous solution containing acetaminophen as an active ingredient is not particularly limited, but is, for example, about 0.1 to 5% by weight, and for example, when prepared as an injection, about 0.1 to 2% by weight. When prepared as a syrup for oral administration, the content is about 0.1 to 4% by weight. The amount of the pyrosulfite added to acetaminophen is, for example, about 0.01 to 0.1 part by weight, preferably about 0.03 to 0.1 part by weight, based on 1 part by weight of acetaminophen. . Needless to say, those skilled in the art can appropriately select the concentration of the active ingredient and the amount of the pyrosulfite added to acetaminophen according to various conditions such as the form of the pharmaceutical composition and the purpose of use. In addition, in order to further enhance the stabilization of acetaminophen, it is preferable to add L-glutamic acid L-lysine to the pharmaceutical composition of the present invention in combination with pyrosulfite. The amount of L-glutamic acid L-lysine used is not particularly limited, but is, for example, about 0.01 to 0.1 part by weight, preferably 0.03 to 0.1 part by weight, based on 1 part by weight of acetaminophen. It is about.
[0010]
The pharmaceutical composition of the present invention can be prepared as an injection for subcutaneous administration, intramuscular administration, or intravenous administration, or a drip for intravenous administration. It is also preferable to prepare a syrup for oral administration. Further, the pharmaceutical composition of the present invention may be in the form of a soft capsule or the like enclosing an aqueous composition. The pharmaceutical composition of the present invention may contain one or more other active ingredients of other drugs. For example, an antihistamine such as chlorpheniramine maleate or an antipyretic such as caffeine can be blended into a pharmaceutical composition in the form of an injection or syrup.The types and amounts of such other pharmaceuticals can be determined by those skilled in the art. Can be appropriately selected. The dose of the medicament of the present invention can be determined according to the usual dose of acetaminophen as an active ingredient.
[0011]
In preparing the pharmaceutical composition of the present invention, one or more pharmaceutical additives commonly used for the production of a pharmaceutical composition can be used. As used herein, the term "aqueous" means that the liquid medium constituting the pharmaceutical composition contains water, and usually most or all of the liquid medium is composed of water. Examples of the liquid medium other than water include glycols such as ethylene glycol, propylene glycol, and polyethylene glycol, and alcohols such as glycerin and ethanol, but are not limited thereto. As the liquid medium, in addition to distilled water and distilled water for injection, physiological saline or buffer can also be used. Pharmaceutical additives used in the pharmaceutical composition of the present invention include, for example, pH adjusters (such as inorganic or organic acids or bases), tonicity agents (such as sodium chloride, glucose, glycerin) and sweeteners. Flavoring agents and the like can be used, but are not limited thereto, and can be appropriately selected by those skilled in the art according to the form of the pharmaceutical composition.
[0012]
【Example】
Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.
Example 1
1 g of acetaminophen, 40 mg of sodium pyrosulfite, and 700 mg of sodium chloride were dissolved in 80 mL of distilled water for injection, adjusted to pH 6 by adding an appropriate amount of sodium hydroxide, and then added with distilled water for injection so that the total amount became 100 mL. An injection for intravenous administration was produced.
Example 2
0.5 g of acetaminophen, 40 mg of sodium pyrosulfite and 700 mg of sodium chloride were dissolved in 80 mL of distilled water for injection, adjusted to pH 6 by adding an appropriate amount of sodium hydroxide, and then distilled water for injection was added so that the total amount became 100 mL. In addition, injections for intravenous administration were manufactured.
[0013]
Example 3
Dissolve 1 g of acetaminophen, 40 mg of sodium pyrosulfite, 600 mg of L-glutamic acid L-lysine and 400 mg of sodium chloride in 80 mL of distilled water for injection, adjust the pH to 6 by adding an appropriate amount of sodium hydroxide, and adjust the total volume to 100 mL. Was added to distilled water for injection to prepare an injection for intravenous administration.
Example 4
2 g of acetaminophen was added to 8 g of Macrogol 400, and 3 g of propylene glycol was added and mixed and dissolved to obtain a liquid I. Separately, 1 g of povidone k30 and 0.05 g of sodium pyrosulfite were added to 20 g of D-sorbitol and mixed and dissolved to obtain a solution II. Solution I and solution II were mixed and purified water was added to make a total volume of 100 mL to produce a syrup.
Example 5
Acetaminophen (2 g) was added to Macrogol 400 (8 g), and propylene glycol (3 g) was added and mixed and dissolved to obtain a liquid I. Separately, 1 g of povidone k30 and 0.075 g of sodium pyrosulfite were added to 20 g of D-sorbitol and mixed and dissolved to obtain a liquid II. Solution I and solution II were mixed and purified water was added to make a total volume of 100 mL to produce a syrup.
[0014]
Comparative Example 1
1 g of acetaminophen was dissolved in 80 mL of distilled water for injection, adjusted to pH 6 by adding an appropriate amount of sodium hydroxide, and then distilled water for injection was added so that the total amount became 100 mL, thereby preparing an injection for intravenous administration. .
Comparative Example 2
Dissolve 1 g of acetaminophen and 60 mg of sodium sulfite in 80 mL of distilled water for injection, adjust the pH to 6 by adding an appropriate amount of sodium hydroxide, and then add distilled water for injection so that the total amount becomes 100 mL, and inject for intravenous administration. An agent was manufactured.
[0015]
Comparative Example 3
Acetaminophen (2 g) was added to Macrogol 400 (8 g), and propylene glycol (3 g) was added and mixed and dissolved to obtain a liquid I. Separately, 1 g of povidone k30 was added to 20 g of D-sorbitol and mixed and dissolved to obtain a solution II. Solution I and solution II were mixed and purified water was added to make a total volume of 100 mL to produce a syrup.
Comparative Example 4
Acetaminophen (2 g) was added to Macrogol 400 (8 g), and propylene glycol (3 g) was added and mixed and dissolved to obtain a liquid I. Separately, 1 g of povidone k30 and 0.75 g of sodium sulfite were added to 20 g of D-sorbitol and mixed and dissolved to obtain a solution II. Solution I and solution II were mixed and purified water was added to make a total volume of 100 mL to produce a syrup.
[0016]
Test example 1
20 mL of each injection for intravenous administration prepared in Examples and Comparative Examples were filled in vials, respectively, and preserved at 40 ° C under 75% RH storage conditions for 12 days or 42 days, and the appearance was observed. The syrup was filled in vials with 100 mL each, and the appearance was observed when stored for 6 months at 40 ° C. and 75% RH. The results are shown in Table 1 (injection) and Table 2 (syrup). From these results, the composition of the present invention containing sodium pyrosulfite is extremely excellent in stability, no coloring is observed, and the composition containing sodium sulfite, which is widely used as a stabilizer, has stability. It was found that the color was poor and coloring was observed. It is extremely surprising that sodium pyrosulfite exhibits a remarkable stabilizing effect on acetaminophen, for which a sufficient stabilizing effect cannot be obtained with sodium sulfite. The composition of Example 3 containing L-glutamic acid L-lysine together with sodium pyrosulfite was stored under the same conditions for 89 days, but the composition was colorless and clear. Slight coloring was observed in the compositions of Nos. 2 and 3. From these results, it was found that an extremely high stabilizing effect was achieved when sodium pyrosulfite and L-glutamic acid L-lysine were combined.
[0017]
[Table 1]
[Table 2]
【The invention's effect】
The aqueous composition of the present invention containing acetaminophen as an active ingredient shows no coloring even after long-term storage, and is extremely stable. In addition, the pyrosulfite contained in the composition of the present invention is a substance widely used as an additive for pharmaceuticals and foods, and has been confirmed to be highly safe, so that the pharmaceutical composition of the present invention is safe. It can be used as a new medicine.
Claims (7)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008001605A (en) * | 2006-06-20 | 2008-01-10 | Mitsubishi Pharma Corp | Aqueous solution containing pyrazolone compound |
| JP2011503198A (en) * | 2007-11-13 | 2011-01-27 | ケイデンス ファーマシューティカルズ，インク． | Low dose intravenous acetaminophen |
| WO2012077696A1 (en) | 2010-12-09 | 2012-06-14 | 丸石製薬株式会社 | Stabilizer of acetaminophen |
| JP2012524738A (en) * | 2009-04-22 | 2012-10-18 | フレゼニウス カービ ドイチュラント ゲーエムベーハー | Paracetamol for parenteral administration |
-
2003
- 2003-03-05 JP JP2003057963A patent/JP4358535B2/en not_active Expired - Lifetime
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008001605A (en) * | 2006-06-20 | 2008-01-10 | Mitsubishi Pharma Corp | Aqueous solution containing pyrazolone compound |
| JP2011503198A (en) * | 2007-11-13 | 2011-01-27 | ケイデンス ファーマシューティカルズ，インク． | Low dose intravenous acetaminophen |
| US9399012B2 (en) | 2007-11-13 | 2016-07-26 | Mallinckrodt Ip | Reduced dose intravenous acetaminophen |
| US9610265B2 (en) | 2007-11-13 | 2017-04-04 | Mallinckrodt Ip | Reduced dose intravenous acetaminophen |
| US9987238B2 (en) | 2007-11-13 | 2018-06-05 | Mallinckrodt Ip | Reduced dose intravenous acetaminophen |
| JP2012524738A (en) * | 2009-04-22 | 2012-10-18 | フレゼニウス カービ ドイチュラント ゲーエムベーハー | Paracetamol for parenteral administration |
| WO2012077696A1 (en) | 2010-12-09 | 2012-06-14 | 丸石製薬株式会社 | Stabilizer of acetaminophen |
| JPWO2012077696A1 (en) * | 2010-12-09 | 2014-05-19 | 丸石製薬株式会社 | Acetaminophen stabilizer |
| EP2649993A4 (en) * | 2010-12-09 | 2014-07-30 | Maruishi Pharma | Stabilizer of acetaminophen |
| US9452216B2 (en) | 2010-12-09 | 2016-09-27 | Maruishi Pharmaceutical Co., Ltd. | Agent for stabilizing acetaminophen |
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| JP4358535B2 (en) | 2009-11-04 |
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