TWI453020B - 嗎啡喃衍生物或其藥理容許酸加成鹽之用以製造防止皮膚乾燥、改善肌膚粗糙、改善伴隨角質肥厚之發暗之改善治療藥之用途 - Google Patents
嗎啡喃衍生物或其藥理容許酸加成鹽之用以製造防止皮膚乾燥、改善肌膚粗糙、改善伴隨角質肥厚之發暗之改善治療藥之用途 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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- A61Q19/007—Preparations for dry skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
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Description
本發明為提供有關仲介肌膚之保濕效果來改善皮膚性狀之治療有用之嗎啡喃衍生物或其藥理容許酸加成鹽之新穎藥劑。
已知肌膚粗糙、皮膚之乾燥、發暗等為皮膚障壁之機能降低而來，以往以改善皮膚性狀為目的作為化粧水、粉底、乳液、馬油、軟膏等使用。作為改善皮膚性狀之醫藥品、外用劑有喜療妥(Hirudoid)、艾莉得、苦拉德意得、西列羅以施(SELELOIZ)、必索府天(BESOFTEN)等肝素類似物質或尿素、玻尿酸及膠原等，以皮脂缺乏症、進行性指掌角皮症等為適應症用這些來處方。又有令含有剛竹、淡竹、孟宗竹之根、地下莖或葉以親水性有機溶劑來萃取而得之萃取物之化粧料(專利文獻1)，以竹類之幹或枝之萃取物為主成分之化粧料(專利文獻2)對改善伴隨皮脂缺乏性變化之乾燥肌膚有效之報告。也有部分植物萃取精促進由角化細胞之β-腦內嗎啡(endorphin)游離，促使皮膚保濕之報告(非專利文獻1)。
一般於健常皮膚角層、角質細胞間脂質形成脂質雙層而保持水分，角質細胞內之低分子水溶性物質保持柔軟性，而皮脂抑制由經皮之水分蒸散來保持皮膚表面之潤滑性。神經醯胺(ceramide)雖演皮膚之水分保持和角層障壁機能之維持重要角色，但可能於鹼領域，神經醯胺酶活性上昇，而促進由神經醯胺(ceramide)至脂肪酸及神經鞘胺醇(Sphingosine)之水解反應，以致成乾燥性皮膚(非專利文獻2)。於維持血液透析患者有約6成呈現搔癢(非專利文獻3，非專利文獻4)，有約9成伴隨乾燥性皮膚，於這些患者呈現角層水分量和經皮水分喪失量之顯著減少及皮膚pH值之顯著上昇(非專利文獻5)。又除這些之外，也有於腎透析患者最多見之乾皮症也呈現皮膚表面脂質量之減少(非專利文獻6)，且皮膚之pH平均值比健常人高，由於塗布令乳酸緩衝液作成水相之酸性霜劑而減輕搔癢之報告(非專利文獻7)。基於皮膚乾燥之場合，多伴隨於老化或異位性皮膚炎或冬季易發之乾皮症，期待開發兼具水分保持機能和障壁機能之保濕劑。
於本發明作為有效成分之嗎啡喃化合物，除了鴉片樣物質κ激動性，並就其鎮痛活性、利尿活性、鎮咳活性已揭示其用途(專利文獻3)。又已揭示作為腦細胞保護藥(專利文獻4)、止癢藥(專利文獻5)、低鈉血症治療藥(專利文獻6)、ORL-1受體拮抗藥(專利文獻7)、神經因性疼痛治療藥(專利文獻8)、精神神經疾病治療藥(專利文獻9)、藥物依存治療藥(專利文獻10)、敗血症治療藥(專利文獻11)、及多發性硬化症所由來之搔癢治療藥(專利文獻12)等之用途，於專利文獻5已揭示由κ激動劑之仲介中樞機能之止癢效果。
除上述以外，就皮膚改善效果揭示之嗎啡等鴉片樣物質系其他藥物，作為外用劑，對面皰等皮脂腺障礙、火傷有效之報告(專利文獻13)或以β-腦內嗎啡於皮膚之水分量增加、障壁機能改善、轉換促進、初期老化預防效果之報告(非專利文獻8)。β-腦內嗎啡為於1999年得知存在於皮膚，於活體外呈示1)天然保濕因子(胺基酸、聚角蛋白微絲蛋白)之增加、2)轉換調節因子(細胞角蛋白1)之增加、3)細胞接著因子(desmosome)之增加、4)角層包(因波苦林，羅利苦林)之增加、5)錨複合體(層粘素5)之增加等報告。鴉片樣物質予以皮膚細胞影響，有激動劑β-腦內嗎啡使表皮角化細胞之分化標幟細胞角蛋白16之產性亢進之報告(非專利文獻9)、或由β-腦內嗎啡刺激角化細胞之游走等報告(非專利文獻10)。
以往已知，鴉片樣物質具有鎮痛作用，同時也作為搔癢之化學傳遞物質發揮機能，如β-腦內嗎啡或腦啡(enkephalin)等內因性鴉片樣物質胜肽引起搔癢之報告(非專利文獻11)。詳細雖未明，但一般而言，μ受體和δ受體抑制疼痛．誘發搔癢，κ受體與疼痛‧搔癢之抑制有關(非專利文獻12)。作為鴉片樣物質系藥物有止癢效果之報告者有烯丙羥嗎啡酮(Naloxone)、環丙甲羥二氫嗎啡酮(Naltrexone)(非專利文獻13、非專利文獻14)及由本發明之有效成分特定之嗎啡喃化合物之止癢效果等報告(非專利文獻15、非專利文獻16、非專利文獻17)。又於具有μ受體拮抗活性之藥物中也有慢性搔癢症之預防等治療(專利文獻14)、或有關由麩胺酸受體之選擇性阻礙仲介皮膚末梢感覺神經之抑制作用之搔癢治療之先行技術(專利文獻15)報告。
皮膚之搔癢乃定義為「引起想欲搔破皮膚之感覺」。皮膚之乾燥狀態與搔癢之程度一般為正相關，熟知皮膚乾燥狀態之改善與搔癢之低減連結。他方面，不伴隨皮膚性狀異常之皮膚搔癢也有存在(非專利文獻18)，尤其中樞性搔癢與皮膚性狀之關係不明，由於腦內鴉片樣物質胜肽之平衡崩潰而對搔癢信號過敏地反應之中樞性搔癢不伴隨皮膚之性狀異常。
故對具有本發明特定之嗎啡喃骨架之有效成分之皮膚性狀改善效果無任何揭示。
【專利文獻1】特開平5-124930號公報
【專利文獻2】特開平7-187990號公報
【專利文獻3】國際公開 第93/015081號小冊
【專利文獻4】國際公開 第95/003307號小冊
【專利文獻5】國際公開 第98/023290號小冊
【專利文獻6】國際公開 第99/005146號小冊
【專利文獻7】特開2000-53572號公報
【專利文獻8】國際公開 第01/014383號小冊
【專利文獻9】國際公開 第02/078744號小冊
【專利文獻10】國際公開 第99/011289號小冊
【專利文獻11】國際公開 第02/089845號小冊
【專利文獻12】國際公開 第06/095836號小冊
【專利文獻13】美國專利第5834480號明細書
【專利文獻14】特開2004-352714號公報
【專利文獻15】特開2004-107209號公報
【非專利文獻1】芋川玄爾，「對濕疹．皮膚炎群之外用劑之基礎和臨床於皮膚科領域使用之保濕劑」，日本臨床皮膚科醫學會雜誌，日本臨床皮膚科醫學會，1998年4月，第56卷，p.87-96
【非專利文獻2】Yukihiro Yada，外2名，「Purification and biochemical characterization of membrane-bound epidermal ceramidases from guinea pig skin」,The Journal of Biological Chemistry，(美國)，American Society for Biochemistry and Molecular Biology，1995年5月26日，第270卷，第21號，p.12677-12684
【非專利文獻3】熊谷裕生，外3名，「搔癢up date透析患者對搔癢之κ-鴉片樣物質．激動劑之有效性」，MB Derma，全日本病院出版會,2005年8月25日，第104卷，p.59-64
【非專利文獻4】Idit F.Schwartz，外1名，「Uraemic pruritus」,Nephrology,Dialysis,Transplantation:official publication of the European Dialysis and Transplant Association-European Renal Association，(英國)，Oxford University Press,1999年，第14卷，第4號，p.834-839
【非專利文獻5】服部瑛，「透析患者之皮膚病變I)總論」，臨床透析，日本醫學中心，1995年10月，第11卷，第13號，p.1877-1881
【非專利文獻6】服部瑛，「與尿毒症．慢性透析所見合併症關連諸物質X)皮膚障礙」，臨床透析，日本醫學中心，2005年8月10日，第21卷，第9號，p.1237-1242
【非專利文獻7】服部瑛外，5名，「透析患者與皮膚病變」，臨床皮膚科，醫學書院，1990年1月，第44卷，第1號，p.21-24
【非專利文獻8】安達美香，外1名，「β-腦內嗎啡於皮膚之新角色」，Fragrance Journal公司，2005年6月15日，第33卷，第6號，p.35-38
【非專利文獻9】Mei Bigliardi-Qi，外4名，「β-endorphin stimulates cytokeratin 16 expression and downregulates μ-opiate receptor expression in human epidermis」,The Journal of Investigative Dermatology，(美國)，Nature Publishing Group，2000年3月，第114卷，第3號，p.527-532
【非專利文獻10】Mei Bigliardi-Qi，外4名，「μ-opiate receptor and Beta-endorphin expression in nerve endings and keratinocytes in human skin」,Dermatology，(瑞士)，Karger,2004年，第209卷，第3號，p.183-189
【非專利文獻11】Fjellner B.,「Experimental and clinical pruritus.Studies on some putative peripheral mediators. The influence of ultraviolet light and transcutaneous nerve stimulation」,Acta Dermato-venereologica. Supplementum，(挪威)，Scandinavian University Press，1981年，第97卷，p.1-34
【非專利文獻12】高森健二，「以鴉片樣物質胜肽為標的之搔癢之治療」，臨床皮膚科，醫學書院，2002年4月10日，第56卷，第5號，p.145-147
【非專利文獻13】Tatsuya Maekawa，外3名，「Effects of naltrexone on spontaneous itch-associated responses in NC mice with chronic dermatitis」,Japanese Journal of Pharmacology，日本藥理學會，2002年10月1日，第90卷，第2號，p.193-196
【非專利文獻14】Takayuki Miyamoto，外4名，「Itch-associated response induced by experimental dry skin in mice」,Japanese Journal of Pharmacology,日本藥理學會，2002年3月1日，第88卷，第3號，p.285-292
【非專利文獻15】熊谷裕生，外5名，「作為搔癢-愁訴之單位-搔癢之診斷．治療 全身疾病 腎疾病-搔癢之機序，κ-激動劑TRK-820之有效性-」，綜合臨床，永井書店，2004年5月1日，第53卷，第5號，p.1678-1684
【非專利文獻16】Hideo Umeuchi，外6名，「Involvement of central μ-opioid system in the scratching behavior in mice,and the suppression of it by the activation of κ-opioid system」,European Journal of Pharmacology,(荷蘭)，Elsevier Science，2003年，第447卷，第1號，p.29-35
【非專利文獻17】Hideo Umeuchi，外6名，「鴉片樣物質κ受體激動藥TRK-820之抗搔癢效果」，Journal of pharmacological sciences，日本藥理學會，2003年3月1日，第91卷，Supplement第1號，p.198
【非專利文獻18】河內繁雄，「外科醫必須之皮膚科一般疾病之知識6，皮膚搔癢症和搔癢之機制」，臨床外科，醫學書院，2001年11月20日，第56卷，第12號，p.1522-1524
本發明之目的為提供對種種原因引起之皮膚機能降低，防止皮膚乾燥、改善肌膚粗糙、改善伴隨角質肥厚之發暗等皮膚性狀之改善有效之新穎藥劑。
本發明者等為解決上述課題反複檢討之結果，發現具有特定之嗎啡喃骨架之化合物或其藥理容許酸加成鹽作為皮膚性狀改善治療藥有用，終於完成本發明。
即本發明為有關以下之[1]至[3]。又本發明為有關以下之[1]至[3]所示化合物之有效量投與具有皮膚性狀之患者之改善皮膚性狀之方法。
[1]一種皮膚性狀改善治療藥，係以如下式(I)化合物或其藥理容許酸加成鹽為有效成分
[式中點線和實線之二重線為雙鍵或單鍵，R1
為碳數4～7之環烷基烷基，R2
為碳數1~5之直鏈或分岐烷基，B為-CH=CH-]。
[2]式(I)中，R1
為環丙基甲基、環丁基甲基、環戊基甲基或環己基甲基，R2
為甲基、乙基或丙基之[1]記載之皮膚性狀改善治療藥。
[3]式(I)化合物為(-)-17-(環丙基甲基)-3,14β
-二羥基-4,5α
-環氧基-6β
-[N-甲基-反-3-(3-呋喃基)丙烯醯胺基]嗎啡喃之[1]記載之皮膚性狀改善治療藥。
本發明提供以嗎啡喃衍生物或其藥理容許酸加成鹽為有效成分之皮膚性狀改善治療藥。投與如此皮膚性狀改善治療藥，則可防止皮膚之乾燥、改善肌膚粗糙、改善伴隨角質肥厚之發暗等皮膚性狀。
本發明之皮膚性狀改善治療藥含有以式(1)化合物或其藥理容許酸加成鹽為有效成分。
R1
為碳數1~5之烷基、碳數4~7之環烷基烷基、碳數5～7之環烯基烷基、碳數6～12之芳基、碳數7～13之芳烷基、碳數4～7之烯基、烯丙基、呋喃-2-基烷基(烷基部之碳數為1～5)、或噻吩-2-基烷基(烷基部之碳數為1～5)。
R14
為氫、羥基、硝基、碳數1～5之烷醯氧基、碳數1～5之烷氧基、碳數1～5之烷基、或NR9
R10
。於此R9
為氫或碳數1～5之烷基，R10
為氫、碳數1～5之烷基、或-C=O)R11
，R11
為氫、苯基、或碳數1～5之烷基。
R3
為氫、羥基、碳數1～5之烷醯氧基、或碳數1～5之烷氧基。
A為-XC(=Y)-、-XC(=Y)Z-、-X-、或-XSO2
-(於此X、Y及Z各獨立為NR4
、S或O。於此R4
為氫、碳數1～5之直鏈或分岐烷基、或碳數6～12之芳基，式中R4
為2以上之場合可相同或不同)。
B為原子價鍵、碳數1～14之直鏈或分岐伸烷基(但可有由碳數1～5之烷氧基、碳數1～5之烷醯氧基、羥基、氟、氯、溴、碘、胺基、硝基、氰基、三氟甲基、及苯氧基而成之群選擇之至少一種以上之取代基取代，也可1～3個亞甲基被羰基取代)、含1～3個雙鍵及/或參鍵之碳數2～14之直鏈或分岐之非環狀不飽和烴(但可有由碳數1～5之烷氧基、碳數1～5之烷醯氧基、羥基、氟、氯、溴、碘、胺基、硝基、氰基、三氟甲基及苯氧基而成之群選擇之至少一種以上之取代基取代，也可1～3個亞甲基被羰基取代)、或含1～5個硫醚鍵、醚鍵及/或胺基鍵之碳數1～14之直鏈或分岐之飽和或不飽和烴(但雜原子可不直接於A結合，而有1～3個亞甲基被羰基取代)。
R5
為氫或具有任一下述骨架之有機基
(但這些之式中Q為N、O或S，T為CH2
、NH、S或O，1為0至5之整數，m及n各獨立為0至5之整數，m與n之合計為5以下，各有機基可有由碳數1～5之烷基、碳數1～5之烷氧基、碳數1～5之烷醯氧基、羥基、氟、氯、溴、碘、胺基、硝基、氰基、異硫氰酸酯、三氟甲基、三氟甲氧基及亞甲基二氧基而成之群選擇之至少一種以上之取代基取代)。
R6
為氫，R7
為氫、羥基、碳數1～5之烷氧基、碳數1～5之烷醯氧基，或R6
與R7
一起為-O-、-CH2
-、或-S-。
R8
為氫、碳數1～5之烷基、或碳數1～5之烷醯基。
R12
及R13
皆為氫，或任一方為氫而他方為羥基，或一起為氧基。
又式(1)包含(+)體、(-)體、(±)體]式(1)中之點線和實線之二重線為雙鍵或單鍵，以單鍵較佳。
本發明之皮膚性狀改善治療藥於式(1)化合物中，以既示之式(I)化合物或其藥理容許酸加成鹽為有效成分含有較佳。式(I)中之點線和實線之二重線為雙鍵或單鍵，以單鍵較佳。
式(I)中，R1
為碳數4~7之環烷基烷基。其中R1
以環丙基甲基、環丁基甲基、環戊基甲基或環己基甲基較佳，特以環丙基甲基較佳。
R2
為碳數1~5之直鏈或分岐烷基。R2
以甲基，乙基或丙基較佳。其中以甲基較佳。
B為-CH=CH-。B以反型之-CH=CH-較佳。
式(I)化合物以R1
為環丙基甲基，R2
為甲基，B為反型之-CH=CH-之化合物，即以(-)-17-(環丙基甲基)-3,14β
-二羥基-4,5α
-環氧基-6β
-[N-甲基-反-3-(3-呋喃基)丙烯醯胺基]嗎啡喃特佳，但本發明不受此限定。
這些式(I)化合物可依專利第2525552號公報之方法製造。式(1)化合物中，R12
及R13
皆為氫者可依專利第2525552號公報記載之方法製造。式(1)化合物中，R12
及R13
一起為氧基之化合物可以例如依文獻(Hererocycle,63,865(2004),Bioorg.Med.Chem.Lett.,5,1505(1995))所得之具有10-氧基之化合物為原料，由此依Chem.Pharm.Bull.,52,664(2004)及專利第2525552記載之方法製造。更式(1)化合物中，R12
為羥基而R13
為氫之化合物可依Chem.Pharm.Bull.,52,664(2004)記載之方法製造。
又本發明之皮膚性狀改善治療藥以作為保濕劑、皮膚障壁機能回復促進劑、皮膚乾燥防止劑、肌膚粗糙防止劑使用較佳。本發明雖以經口劑使用較佳，但不拘於此，只要不損及效果則皮膚外用劑等也可使用。
本發明中藥理容許酸加成鹽可為鹽酸鹽、硫酸鹽、硝酸鹽、氫溴酸鹽、氫碘酸鹽及磷酸鹽等無機酸鹽、乙酸鹽、乳酸鹽、檸檬酸鹽、草酸鹽、戊二酸鹽、蘋果酸鹽、酒石酸鹽、富馬酸鹽、苦杏仁酸鹽、馬來酸鹽、苯甲酸鹽或酞酸鹽等有機羧酸鹽、或甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽或莰磺酸鹽等有機磺酸鹽等。其中以鹽酸鹽、氫溴酸鹽、磷酸鹽、酒石酸鹽、或甲磺酸鹽等較佳，當然不限於這些。
又式(I)化合物或其藥理容許酸加成鹽純化至醫藥品用途，必要之安全性試驗合格後，可就此或作成與公知之藥理容許酸、載體、賦形劑等混合之醫藥組成物來經口投與。經口投與之劑型可選擇錠劑、膠囊劑、散劑或顆粒劑等，但當然不限於此。這些製劑可依醫藥品之領域通常施行之周知方法來調製。本發明之皮膚性狀改善治療藥之投與量可基於患者之症狀、年齡、體重、投與方法等而適宜設定，但通常成人每日有效成分之量，於經口投與時為0.1μg～100mg程度，非經口投與時為0.01μg～10mg程度。
本發明之皮膚性狀改善治療藥可單獨投與，又可與其他藥劑例如保濕劑、止癢外用藥、類固醇軟膏等併用來投與。保濕劑可為凡士林、尿素、肝素類似物質軟膏、艾配合軟膏、神經醯胺含有霜劑、山茶油洗液。止癢外用藥可為抗組織胺軟膏或克羅他米通軟膏、強搔癢時，可更與類固醇軟膏併用。本發明之皮膚性狀改善治療藥可利用為保濕劑、皮膚障壁機能回復促進劑、皮膚乾燥防止劑、肌膚粗糙防止劑。
以下舉實施例更詳細說明本發明。
含2.5μg下述構造式(II)之(-)-17-(環丙基甲基)-3,14β
-二羥基-4,5α
-環氧基-6β
-[N-甲基-反-3-(3-呋喃基)丙烯醯胺基」嗎啡喃鹽酸鹽(化合物1)之溶液封入明膠皮膜之軟膠囊，作成經口劑。將此經口劑2膠囊(5.0μg)於血液透析患者中既存治療抵抗性之搔癢患者2名服用，則1名(女性，79歳)服藥開始就搔癢減輕且全體肌膚(尤其足)潤滑，而肌膚美麗。1名(男性，69歳)雖顏色．肌膚質甚惡，但將該經口劑服藥開始後，臉皮粗糙減少而臉色轉佳。1名為該經口劑服用開始4、5日後，由手腕至肩及胸附近之搔癢治癒處起肌膚濕潤，服用終了後，再感搔癢時開始肌膚粗糙。
本發明防止肌膚粗糙、皮膚乾燥、發暗等，作為具有保濕效果之皮膚性狀改善治療藥有用。
Claims (4)
- 一種式(I)化合物或其藥理容許酸加成鹽用以製造防止皮膚乾燥、改善肌膚粗糙、改善伴隨角質肥厚之發暗之改善治療藥之用途，該式(I)化合物係如下，
- 如申請專利範圍第1項之用途，其中式(I)中R1 為環丙基甲基、環丁基甲基、環戊基甲基或環己基甲基，R2 為甲基、乙基或丙基。
- 如申請專利範圍第1項之用途，其中式(I)化合物為(-)-17-(環丙基甲基)-3,14β-二羥基-4,5α-環氧基-6β-[N-甲基-反-3-(3-呋喃基)丙烯醯胺基]嗎啡喃。
- 如申請專利範圍第1至3項中任一項之用途，其中對象患者為血液透析患者。
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- 2008-10-03 EP EP08835121.8A patent/EP2196206B8/en not_active Not-in-force
- 2008-10-03 KR KR1020107007134A patent/KR101173509B1/ko not_active Expired - Fee Related
- 2008-10-03 BR BRPI0817804A patent/BRPI0817804A8/pt not_active IP Right Cessation
- 2008-10-03 US US12/680,908 patent/US20100222309A1/en not_active Abandoned
- 2008-10-03 WO PCT/JP2008/068092 patent/WO2009044883A1/ja not_active Ceased
- 2008-10-03 PL PL08835121T patent/PL2196206T3/pl unknown
- 2008-10-03 MX MX2010003660A patent/MX2010003660A/es not_active Application Discontinuation
- 2008-10-03 TW TW097138034A patent/TWI453020B/zh not_active IP Right Cessation
- 2008-10-03 AU AU2008308005A patent/AU2008308005B2/en not_active Ceased
- 2008-10-03 JP JP2009536121A patent/JP5613417B2/ja not_active Expired - Fee Related
- 2008-10-03 ES ES08835121T patent/ES2748274T3/es active Active
- 2008-10-03 RU RU2010117649/15A patent/RU2440117C1/ru active
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6174891B1 (en) * | 1996-11-25 | 2001-01-16 | Toray Industries, Inc. | Antipruritic agent |
Non-Patent Citations (1)
| Title |
|---|
| Wikstrom B,et al."k-Opioid System in Uremic Pruritus: Multicenter, Randomized,Double-Blind, Placebo-Controlled Clinical Studies",J Am Soc Nephrol 16: 3742–3747, 2005. * |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2010003660A (es) | 2010-08-10 |
| WO2009044883A1 (ja) | 2009-04-09 |
| EP2196206A1 (en) | 2010-06-16 |
| CA2702032C (en) | 2013-04-02 |
| CA2702032A1 (en) | 2009-04-09 |
| JPWO2009044883A1 (ja) | 2011-02-10 |
| EP2196206A4 (en) | 2010-09-22 |
| CN101848714B (zh) | 2014-08-20 |
| JP5613417B2 (ja) | 2014-10-22 |
| RU2440117C1 (ru) | 2012-01-20 |
| AU2008308005A1 (en) | 2009-04-09 |
| KR101173509B1 (ko) | 2012-08-14 |
| KR20100049683A (ko) | 2010-05-12 |
| US20100222309A1 (en) | 2010-09-02 |
| ES2748274T3 (es) | 2020-03-16 |
| EP2196206B1 (en) | 2019-07-17 |
| BRPI0817804A8 (pt) | 2017-04-18 |
| PL2196206T3 (pl) | 2020-02-28 |
| CN101848714A (zh) | 2010-09-29 |
| AU2008308005B2 (en) | 2012-06-07 |
| TW200927116A (en) | 2009-07-01 |
| BRPI0817804A2 (pt) | 2016-10-11 |
| EP2196206B8 (en) | 2019-11-13 |
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