TWI404530B - 包含抗蕈毒鹼劑及β-腎上腺素激動劑之組合 - Google Patents
包含抗蕈毒鹼劑及β-腎上腺素激動劑之組合 Download PDFInfo
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- TWI404530B TWI404530B TW094117908A TW94117908A TWI404530B TW I404530 B TWI404530 B TW I404530B TW 094117908 A TW094117908 A TW 094117908A TW 94117908 A TW94117908 A TW 94117908A TW I404530 B TWI404530 B TW I404530B
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- combination
- agonist
- formoterol
- receptor antagonist
- muscarinic receptor
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Description
本發明係關於特定之抗蕈毒鹼劑及β-腎上腺素激動劑之新穎的組合及其在治療呼吸失調之用途。
β-腎上腺素激動劑特別如β 2-腎上腺素激動劑,及抗蕈毒鹼劑特別如M3抗蕈毒鹼受體之拮抗劑,為二種支氣管擴張藥劑可有效治療呼吸失調,例如氣喘或慢性阻塞性呼吸疾病(COPD)。
已知二種藥劑能組合使用。國際專利申請案WO 0238154及WO 03000241敘述一些此等組合之實例。
藥劑之組合其活性成分藉由已知對治療上有用之不同的生理徑路起作用。通常,治療優勢係因組合可利用較低濃度之各活性組份達成有效治療效用。此能使藥劑之副作用降至最低。因此,組合能調配成使各活性成份以針對細胞中亞臨床濃度存在而非針對目標疾病細胞。組合在對二種成分都起作用之目標細胞仍然有治療效用。
儘管上述之討論已知用於治療呼吸失調之已知的M3蕈毒鹼受體及β-腎上腺素激動劑之組合對心臟具有有害之作用。心臟細胞似乎易受已知之M3蕈毒鹼受體及β-腎上腺素之激動劑影響就如同呼吸道細胞一樣。當二種藥劑都用於組合中時心臟出現較明顯及頻繁之副作用。因此,使用已知的M3蕈毒鹼受體及β-腎上腺素激動劑之組合包含有
害的心臟副作用,例如,頻脈,心悸,類心絞痛病症及心律不整,進而限制此組合之治療價值,特別當病患有潛在之心臟疾病時。
令人驚訝地,現已發現一些特定之M3蕈毒鹼受體拮抗劑(進一步係指本發明之M3拮抗劑)及β 2-腎上腺素激動劑(進一步係指β2-激動劑)之組合比先前技術所提之組合顯著產生較少之心臟副作用,例如頻脈,且於呼吸道中仍然保有強力作用。
因此本發明係提供一組合,其包括(a)β 2-激動劑及(b)M3蕈毒鹼受體拮抗劑,其為3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]辛烷,以具有陰離子X鹽之型式,該陰離子X為醫藥學上可接受之單價或多價酸陰離子。
醫藥學上可接受之單價或多價酸陰離子實例為由無機酸,如鹽酸、氫溴酸、硫酸、磷酸衍生之陰離子,或由有機酸如甲磺酸、醋酸、富馬酸、琥珀酸、乳酸、檸檬酸或馬來酸衍生之陰離子。再者,亦可使用以上所提及之酸混合物。
典型的,M3蕈毒鹼受體拮抗劑為3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷。
通常組合包含活性的成分(a)及(b)形成部分單一醫藥組
合。
為避免疑惑,上述之通式及術語3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]辛烷係指包括解離、部分解離或非解離型式之鹽類,例如水溶液中。化合物之不同鹽類可以溶劑合物的型式存在,亦即,水合物之型式及所有該等形式亦在本發明範疇中。再者,化合物之不同的鹽及溶劑合物可以非晶型式或以不同之同質異形物的型式存在於本發明之範疇內。
本發明亦提供一種包括(a)β2-激動劑及(b)本發明之M3蕈毒鹼受體拮抗劑之產品,作為同時、分開或依序使用以治療人類或動物病患之組合製劑。典型的,該產品係用於同時、分開或依序使用以治療人類或動物病患之呼吸疾病,該呼吸疾病為氣喘、急性或慢性支氣管炎、氣腫、慢性阻塞性肺病(COPD)、氣道過渡反應或鼻炎。
本發明亦提供一種(a)β2-激動劑及(b)本發明之M3蕈毒鹼受體拮抗劑之用途,其係用於製備供同時、協同、分開或依序使用以治療人類或動物病患之呼吸疾病之醫藥品。
本發明亦提供(b)本發明之M3蕈毒鹼受體拮抗劑之用途,其係用於製備與(a)β2-激動劑同時、協同、分開或依序使用以治療人類或動物病患之呼吸疾病之醫藥品。
本發明亦提供一種(a)β2-激動劑之用途,其係用於製備與(b)本發明之M3蕈毒鹼受體拮抗劑同時、協同、分開或依序使用以治療人類或動物病患之呼吸疾病之醫藥品。
一般而言,該呼吸疾病為氣喘或慢性阻塞性肺病
(COPD)。
一般而言,該患有心臟症狀或頻脈加劇症狀之人類或動物病患,例如,已患有心律不整、低或高血壓、心絞痛或類心絞痛病症、心肌梗塞病史、冠狀動脈疾病或年長的病患。較佳的該病患為人類。
本發明亦提供一種醫藥組合,其包括(a)β2-激動劑;及(b)本發明之M3蕈毒鹼受體拮抗劑與(c)醫藥上可接受之載劑或稀釋劑組合。
本發明亦提供一種部件套組,其包括(b)本發明之M3蕈毒鹼受體拮抗劑,以及與(a)[β2-激動劑同時、協共、分開或依序使用以治療患有或易感染呼吸疾病之人類或動物病患之用法說明。
本發明進一步提供一包裝套組,其包括(b)本發明之M3蕈毒鹼受體拮抗劑,及(a)β2-激動劑,係用於同時、協共、分開或依序使用以治療呼吸疾病。
本發明進一部提供如前文所述之組合、產品、部件的套組或包裝組、其中該組合、產品、部件套組或包裝組進一步包括(c)另一活性化合物係選自:(a)PDE IV抑制劑、(b)皮質類固醇、(c)白三烯素D4拮抗劑、(d)egfr-激酶抑制劑、(e)p38激酶抑制劑及(f)NK1受體激動劑,作為同時、分開或依序使用。一般而言,另外的活性化合物(c)係選自由(a)PDE IV抑制劑及(b)皮質類固醇組成之群。
本發明組合、產品、部件套組或包裝組之具體實例其係包括(b)本發明之M3蕈毒鹼受體拮抗劑,及(a)β2-激動劑作
為僅有之活性化合物。
另一本發明之具體實例係使用(b)本發明之M3蕈毒鹼受體拮抗劑,及(a)β2-激動劑,而不使用其他活性化合物,以製備供同時、協同、分開或依序使用以治療人類或動物病患對M3拮抗作用有反應之呼吸疾病之醫藥品。
用於本發明組合中之較佳的β2-激動劑物為:阿福莫特羅(arformoterol)、班布特羅(bambuterol)、比托特羅(bitolterol)、溴沙特羅(broxaterol)、塞曼特羅(carbuterol)、克侖特羅(clenbuterol)、多培沙明(dopexamine)、酚丙喘寧(fenoterol)、福莫特羅(formoterol)、氯苯胺丙醇(hexoprenaline)、異丁特羅(ibuterol)、異他林(isoetharine)、異丙腎上腺素(isoprenaline)、左沙布特羅(levosalbutamol)、馬布特羅(mabuterol)、美露阿德林(meluadrine)、美他丙特羅(metaprotenerol)、若羅米羅(nolomirole)、異丙喘寧(orciprenaline)、吡布特羅(pirbuterol)、丙卡特羅(procaterol)、茶丙喘寧(reproterol)、利托君(ritodrine)、瑞莫特羅(rimoterol)、沙丁胺醇(salbutamol)、沙甲胺醇(salmefamol)、沙美特羅(salmeterol)、昔本那地(sibenadet)、索托那羅(sotenerot)、磺醯特羅(sulfonterol)、特布他林(terbutaline)、噻拉米特(tiaramide)、妥洛特羅(tulobuterol)、GSK-597901、GSK-159797、GSK-678007、GSK-642444、GSK-159802、HOKU-81、(-)-2-[7(S)-[2(R)-羥基-2-(4-羥基苯基)乙基胺基]-5,6,7,8-四氫-2-萘基氧基]-N,N-二甲基乙醯胺鹽酸鹽單
水化物、卡莫特羅(carmoterol)、QAB-149及5-[2-(5,6-二乙基苯并環戊烷-2-基胺基)-1-羥基乙基]-8-羥基-1H-喹啉-2-酮、4-羥基-7-[2-{[2-{[3-(2-苯氧基乙氧基)丙基]磺醯基}乙基]胺基}乙基]-2(3H)-苯并噻唑酮、1-(2-氟-4-羥基苯基)-2-[4-(1-苯并咪唑基)-2-甲基-2-丁基胺基]乙醇、1-[3-(4-甲氧基苯甲基胺基)-4-羥基苯基]-2-[4-(1-苯并咪唑基)-2-甲基-2-丁基胺基]乙醇、1-[2H-5-羥基-3-氧代-4H-1,4-苯并-8-基]-2-[3-(4-N,N-二甲基胺基苯基)-2-甲基-2-丙基胺基]乙醇、1-[2H-5-羥基-3-氧代-4H-1,4-苯并-8-基]-2-[3-(4-甲氧基苯基)-2-甲基-2-丙基胺基]乙醇、1-[2H-5-羥基-3-氧代-4H-1,4-苯并-8-基]-2-[3-(4-正-丁基氫氧苯基)-2-甲基-2-丙基胺基]乙醇、1-[2H-5-羥基-3-氧代-4H-1,4-苯并-8-基]-2-{4-[3-(4-甲氧基苯基)-1,2,4-三唑-3-基]-2-甲基-2-丁基胺基}乙醇、5-羥基-8-(1-羥基-2-異丙基胺基丁基)-2H-1,4-苯并-3-(4H)-酮、1-(4-胺基-3-氯-5-三氟甲基苯基)-2-第三-丁基胺基)乙醇及1-(4-乙氧基羰基胺基-3-氰基-5-氟苯基)-2-(第三-丁基胺基)乙醇視需要以其消旋異構物、鏡相異構物、非對映異構物及其混合物之形式,及視需要以醫藥藥理上相容之酸加成鹽之形式。
用於本發明組合中之較佳的β2-激動劑為:阿福莫特羅(arformoterol)、班布特羅(bambuterol)、比托特羅(bitolterol)、溴沙特羅(broxaterol)、塞曼特羅(carbuterol)、克侖特羅(clenbuterol)、多培沙明(dopexamine)、酚丙喘寧(fenoterol)、福莫特羅(formoterol)、氯苯胺丙醇
(hexoprenaline)、異丁特羅(ibuterol)、異他林(isoprenaline)、左沙布特羅(levosalbutamol)、馬布特羅(mabuterol)、美露阿德林(meluadrine)、若羅米羅(nolomirole)、異丙喘寧(orciprenaline)、吡布特羅(pirbuterol)、丙卡特羅(procaterol)、(R,R)-福莫特羅(formoterol)、茶丙喘寧(reproterol)、利托君(ritodrine)、瑞莫特羅(rimoterol)、沙丁胺醇(salbutamol)、沙美特羅(salmeterol)、昔本那地(sibenadet)、磺醯特羅(sulfonterol)、特布他林(terbutaline)、妥洛特羅(tulobuterol)、GSK-597901、GSK-159797、KUL-1248、TA-2005及QAB-149視需要以其消旋異構物、鏡相異構物、非對映異構體及其混合物之形式,及視需要以藥理上相容之酸加成鹽形式。
因為本發明之M3拮抗劑具有長作用期間,其最好與長效活性之β2-激動劑組合(亦稱為LABAs)。因此此組合藥可一天投藥一次。
特佳之LABA為福莫特羅、沙美特羅及GSK-597901、GSK-159797、KUL-1248、TA-2005及QAB-149視需要以其消旋異構物、鏡相異構物、非對映異構體及其混合物之形式,及視需要以藥理上相容之酸加成鹽形式。更佳為沙美特羅、福莫特羅及QAB-149,然而更佳為沙美特羅及福莫特羅,特別是沙美特羅羥萘甲酸鹽及福莫特羅富馬酸鹽。
可考慮下列酸代表作為適合形成β2-激動劑之酸加成鹽之實例:鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、醋酸、富馬酸、琥珀酸、乳酸、檸檬酸、馬來酸及三氟醋酸。再者,
上述酸之混合物亦可使用。
本發明較佳之具體實施例為本發明之M3蕈毒鹼受體拮抗劑與選自福莫特羅、沙美特羅、GSK-597901、GSK-159797、KUL-1248、TA-2005及QAB-149之LABA之組合。
本發明一特佳之具體實施例為本發明之M3蕈毒鹼受體拮抗劑與選自福莫特羅、沙美特羅、GSK-597901、GSK-159797、KUL-1248、TA-2005及QAB-149之LABA之組合。
本發明另一具體實施例為由3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷之M3蕈毒鹼受體拮抗劑與選自福莫特羅、沙美特羅、GSK-597901、GSK-159797、KUL-1248、TA-2005及QAB-149之LABA之組合。
根據本發明之一具體實施例,該β2-激動劑為福莫特羅,特別是福莫特羅富馬酸。
根據本發明之另一具體實施例,β2-激動劑為沙美特羅,特別是沙美特羅萘甲酸鹽。
本發明之組合可視需要包含一或多種已知可有效用於治療呼吸失調之另外的活性物質,例如PDE4抑制劑、類固醇或糖化皮質類固醇、白三烯素D4抑制劑、egfr-激酶抑制劑、p38激酶抑制劑及/或NK1-受體拮抗劑。
可與M3-拮抗劑及β2-激動劑組合之適合的PDE4抑制劑實例為登布茶鹼、洛利普南、西潘茶碱、阿羅茶鹼、非明
司特、吡拉米司特、美索普瑞(mesopram)、屈他維林鹽酸、利瑞米拉斯特(lirimilast)、羅氟司特、西洛司特、6-[2-(3,4-二乙氧基苯基)噻唑-4-基]吡啶-2-羧酸、(R)-(+)-4-[2-(3-環戊基氧基-4-甲氧基苯基)-2-苯基乙基]吡啶、N-(3,5-二氯-4-吡啶基)-2-[1-(4-氟苯甲基)-5-羥基-1H-吲哚-3-基]-2-氧代乙醯胺、9-(2-氟苯甲基)-N6-甲基-2-(三氟甲基)腺嘌呤、N-(3,5-二氯-4-吡啶基)-8-甲氧基喹啉-5-甲醯胺、N-[9-甲基-4-氧代-1-苯基-3,4,6,7-四氫吡咯并[3,2,1-jk][1,4]苯并氮呯-3(R)-基]吡啶-4-甲醯胺、3-[3-(環戊基氧基)-4-甲氧基苯甲基]-6-(乙基胺基)-8-異丙基-3H-嘌呤鹽酸鹽、4-[6,7-二乙氧基-2,3-雙(羥基甲基)萘-1-基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮、2-碳甲氧基-4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環已烷-1-酮、順[4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環已烷-1-醇、ONO-6126(Eur Respir J 2003,22(Suppl.45):Abst 2557)及在PCT專利申請案第WO 03/097613號和PCT/EP03/14722及在西班牙專利申請案第P200302613號所申請之化合物。
可與M3-拮抗劑及β2-激動劑組合之適合的類固醇藥及糖化皮質類固醇實例為潑尼松龍、甲潑尼龍、地塞米松、萘非可特、地氟可特、醋酸鹵潑尼松、布地奈德、丙酸倍氯米松、氫化可體松、曲安奈德、氟西奈德、氟可龍、氯可托龍、醋丙甲潑尼龍、地塞米松palmitoate、替泼尼旦、醋酸氫化可體松、潑尼卡酯、阿氯米松二丙酸鹽、鹵米松、磺庚甲潑尼龍、糠酸莫米松、利美索龍、法呢酸潑、環索
奈德、地潑羅酮丙酸酯、氟替卡松丙酸酯、丙酯烏倍他索、氯替潑諾、倍他米松丁酸丙酸酯、氟尼縮松、潑尼松、地塞米松磷酸二氫鈉、曲安西龍、倍他米松戊酸鹽、倍他米松、二丙酸倍他米松、醋酸氫化可體松、氫化可體松琥珀酸鈉、潑尼松龍磷酸鈉及氫化可體松。
可與M3-拮抗劑及β2-激動劑組合之適合之LTD4拮抗劑實例為托魯司特、lbudilast、普比司特、普侖司特水合物、扎魯司特、利托司特、維魯司特、硫魯司特、西那司特、依拉司特鈉、孟魯司特鈉、4-[4-[3-(4-乙醯基-3-羥基-2-丙基苯氧基)丙基磺醯基]苯基]-4-氧代丁酸、[[5-[[3-(4-乙醯基-3-羥基-2-丙基苯氧基)丙基]硫基]-1,3,4-噻二唑-2-基]硫基]醋酸、9-[(4-乙醯基-3羥基-2-正丙基苯氧基)甲基]-3-(1H-四唑-5-基)-4H-吡啶并[1,2-a]嘧啶-4-酮、5-[3-[2-(7-氯喹啉-2-基)乙烯基]苯基]-8-(N,N-二甲基胺甲醯基)-4,6-二硫辛酸鈉鹽、3-[1-[3-[2-(7-氯喹啉-2-基)乙烯基]苯基]-1-[3-(二甲基胺基)-3-氧代丙基硫基]甲基硫基]丙酸鈉鹽、6-(2-環已基乙基)-[1,3,4]噻二唑并[3,2-a]-1,2,3-三唑并[4,5-d]嘧啶-9(1H)-酮、4-[6-乙醯基-3-[3-(4-乙醯基-3-羥基-2-丙基苯基硫基)丙氧基]-2-丙基苯氧基]丁酸、(R)-3-甲氧基-4-[1-甲基-5-[N-(2-甲基-4,4,4-三氟丁基)胺甲醯基]吲哚-3-基甲基]-N-(2-甲基苯基磺醯基)苯甲醯胺、(R)-3-[2-甲氧基-4-[N-(2-甲基苯基磺醯基)胺甲醯基]苯基]-1-甲基-N-(4,4,4-三氟-2-甲基丁基)吲哚-5-甲醯胺、(+)-4(S)-(4-羧基苯基硫基)-7-[4-(4-苯氧基丁氧基-)苯基]-5(Z)-庚烯酸及
於PCT專利申請案號PCT/EP 03/12581中所申請之化合物。
可與M3-拮抗劑及β2-激動劑組合之適合的egfr-激酶抑制劑實例為帕立非明、西妥昔單抗、吉非替尼、角質化細胞生長因數、鹽酸阿撲嗎啡、canertinib二鹽酸、酪氨酸蛋白激酶抑制劑和N-[4-(3-氯-4-氟苯基胺基)-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基胺基)-2(E)-丁醯胺。
可與M3-拮抗劑及β2-激動劑組合之適合p38激酶抑制劑實例為噻唑乙二碳酸鹽乙二磺酸、激酶抑制劑、5-(2,6-二氯苯基)-2-(2,4-二氟苯基硫基)-6H-嘧啶并[3,4-b]嗒-6-酮、4-醯胺基-N-(第三-丁基)苯甲醯胺、SCIO-469(描述於Clin Pharmacol Ther 2004,75(2):Abst PII-7及描述於Circulation 2003,108(17,Suppl.4):Abst 882之VX-702。
可與M3-拮抗劑及β2-激動劑組合之適合NK1-受體拮抗劑實例為苯磺諾匹坦銨、達匹坦、藍內比坦(lanepitant)、福佛比坦(vofopitant)鹽酸、止敏吐、伊錯比坦(ezlopitant)、N-[3-(2-戊基苯基)丙醯基]-羥丁胺醯基-N-甲基-2,3-去氫酪胺醯基-白胺醯-D-苯基丙胺醯基-allo-羥丁胺醯基-天門冬醯胺基-絲胺酸-1.7-O-3.1內酯、1-甲基吲哚-3-基羰基-[4(R)-羥基]-L-脯醯胺基-[3-(2-萘基)]-L-丙胺酸N-苯甲基-N-甲醯胺、(+)-(2S,3S)-3-[2-甲氧基-5-(三氟甲氧基)苯甲基胺基]-2-苯基哌啶、(2R,4S)-N-[1-[3,5-雙(三氟甲基)苯甲醯基]-2-(4-氯苯甲基)哌啶-4-基]喹啉-4-甲醯胺,3-[2(R)-[1(R)-[3,5-雙(三氟甲基)苯基]乙氧基-]-3(S)-(4-氟苯基)嗎啉-4-基甲基]-5-氧代-4,5-二氫-1H-1,2,4-三唑-1-膦酸雙(N-
甲基-D-葡胺)鹽;[3-[2(R)-[1(R)-[3,5-雙(三氟甲基)苯基]乙氧基]-3(S)-(4-氟苯基)-4-嗎啉基甲基]-2,5-二氫-5-氧代-1H-1,2,4-三唑-1-基]膦酸1-去氧基-1-(甲基胺基)-D-葡萄糖醇(1:2)鹽、1'-[2-[2(R)-(3,4-二氯苯基)-4-(3,4,5-三甲氧基苯甲醯基)嗎啉-2-基]乙基]螺[苯并[c]噻吩-1(3H)-4'-哌啶]2(S)-氧化鹽酸鹽及描述於Eur Respir J 2003,22(suppl.45):Abst P2664之化合物CS-003。
組合中之活性化合物,即本發明M3拮抗劑、β2-激動劑及任何其他視需要之活性化合物可相同的醫藥組合中一起投藥或藉由相同或不同之路徑於不同的組合中以分開、同時、伴隨或依序投藥
在一本發明較佳的具體實施例中組合內之活性化合物,係經由一常用之投遞裝置藉由吸入來投藥,其中之活性化合物可調配於相同或不同的醫藥組合中。
在本發明最佳之具體實施例中,本發明之M3蕈毒鹼受體拮抗劑及β2-激動劑係存在於相同的醫藥組合中並經由一常用之投遞裝置藉由吸入來投藥。
本發明一方面係提供如本文定義之組合其特性在於該活性成份(a)和(b)形成單一醫藥組合之部分。
本發明醫藥組合物可以本身已知之方法混合或處理本發明之M3蕈毒鹼受體拮抗劑、β2-激動劑及其他視需要之添加物及/或載劑而製得。
組合中之活性化合物,即本發明之M3拮抗劑、β2-激動劑及任何其他視需要之活性化合物,依所欲治療疾病之性質
可藉由任何適合之路徑投藥,例如口服(如糖漿、錠劑、膠囊、菱錠劑、控制釋放之備製物、快速溶解之備製物、菱錠劑等);局部給藥(如乳霜、軟膏、乳液、鼻噴劑或噴霧劑等);藉由注射(皮下、皮內、肌肉內,靜脈注射等)或藉由吸入(如乾散劑、溶液、懸浮液等)。
醫藥調配物可方便的以單位劑型存在及可藉由此技藝中已知之來製備。所有之方法包括將活性成份與載劑組合。一般而言,調配物係藉由均勻及緊密的將活性成份與液體載劑或細粉狀之固體載劑組合或與兩者組合來製備,然後若需要將成品做成所欲調配物之形狀。
適合口服投藥之本發明調配物可以分離的單位存在,例如各含有預定量之活性成份之膠囊、藥包或錠劑;如散劑或顆粒劑;如溶於水性液體或非水性液體之溶液或懸浮液;或水基液體乳液或油基液體乳液。活性成份亦可以軟圓塊、舐劑或糊狀物存在。
糖漿之調配物一般是由溶於液體載劑之化合物或鹽類之溶液懸浮液所組成的,該載劑例如乙醇,天然的、合成的、半合成的油例如花生油及橄欖油、甘油或調味水、甜味劑及/或調色劑。
當組合為錠劑之型式,任何常用於製備固體調配物之醫藥載劑皆可使用。該等載劑之實例包括纖維素、硬脂酸酯例如硬脂酸鎂或硬脂酸、滑石、明膠、阿拉伯膠、澱粉、乳糖及蔗糖。
錠劑可能藉由壓縮或模造來製造,可視需要加入一或多
種附加成份。壓縮之錠劑可以適合之機器將自由流動之型式之活性成份例如散劑或顆粒,視需要與結著劑、潤滑劑、惰性稀釋劑、潤滑表面活性或分散劑混合來壓製。模造之錠劑可以適合之機器將含有以惰性液體稀釋劑濕潤及視需要乾燥或過篩之活性成份的散狀混合物製成模。該錠劑可視需要加膜衣或刻痕並可調配成可供調節(即慢性或控制)釋放其中之活成份。
當組合為膠囊之型式時,任何一般之包膠皆合適,例如在硬的明膠膠囊中使用上述之載劑。當組合微軟式明膠膠囊之型式時,可考慮任何常用於製備分散劑或懸浮繼之醫藥載劑,例如水性膠、纖維素、矽酸鹽或油並可併入軟式明膠膠囊中。
以吸入局部遞送至肺部之亁粉組合,可例如以不同的主要包裝系統存在(例如明膠之膠囊及匣心或例如積層鋁箔卷之泡罩)用於吸入輔助器或充氣機中。
調配物之包裝可適合用於單位劑量或多劑量傳送。多劑量而言,調配物可事先計量或計量使用。乾粉吸入器因此分為三種:(a)單一劑量(b)多單位劑量(c)多劑量裝置。
調配物一般包含用於吸入之本發明組合及適合的散劑基底(載劑物質)例如乳糖或澱粉之散劑混合物。較佳的係使用乳糖。每一膠囊或匣心一般可包含介於2 μg及400 μg之各治療活性成份。或者,活性成份可無賦形劑存在
以第一種形式之單一劑量而言,單一劑量已由製造商先計重後放入小容器中,其多半為硬明膠膠囊。膠囊必須從
分裝的盒子或容器中取出並插入吸入器之接收區域。接著,必須打開膠囊或以大頭針或切割的刀片貫穿以使部分之呼吸空氣氣流通過膠囊以承載散劑或於吸入過程中從膠囊穿孔藉由離心力釋放散劑。吸入之後,空膠囊必須再次從吸入輔助器中移出。大多數的情況,為插入及移出膠囊拆卸吸入輔助器是必須的,該些操作對一些病患可能是困難及較有負擔的。其他有關硬明膠膠囊做為吸入之散劑之缺點為(a)預防自環境空氣中吸收濕氣之保護性差,(b)當膠囊已先暴露於極端之相對濕度下後之開啟或穿孔的問題,其導致破碎或鋸齒交錯及(c)可能吸入膠囊之碎片。再者,有許多膠囊吸入器不完全釋放已被報導出(例如Nielsen等人,1997)。
如WO 92/03175中所描述的,許多膠囊吸入輔助器具有一儲藏匣,從該匣各別之膠囊能轉移到一接收室,在此會有穿孔及空間產生。其他膠囊吸入器帶有膠囊室之旋轉儲藏匣,可將其帶入空氣導管用於釋出劑量(例如WO 91/02558及GB 2242134)。其包括多單位藥劑吸入器與泡罩吸入器一起,於圓盤或條帶上具有供應限制次數之單位劑量。
泡罩吸入器提供比膠囊吸入器較佳之醫藥品濕氣防護。藉由表面及泡罩箔穿孔或剝去表面箔來接進散劑。當使用泡罩條帶代替圓盤時,劑量之數量可增加,但是不便於病患更換空條帶。因此,該等裝置與其併入之劑量系統包括用於傳遞條帶及開啟泡罩袋之技術常為可拋棄的。
多劑量吸入器不包含預先定量之散劑調配物。其係由較
大的容器及必須由病患操作之劑量測量原理所組成。該容器承載的多劑量係藉由容量取代各別與大量散劑隔離。多種存在的劑量測量原理,包括可旋轉薄膜(例如EP0069715)或圓盤(例如GB 2041763;EP 0424790;DE 4239402及EP 0674533)、可選轉筒柱(例如EP 0166294;GB 2165159及WO 92/09322)及可旋轉角錐臺(例如WO 92/00771)都有孔穴必須從容器填充散劑。其他多劑量裝置係具有測量夾片(例如US 5201308及WO 97/00703)或帶有局部或圓周的凹部之測量活塞以從容器釋放一定體積之散劑至遞送室或空氣導管,例如EP 0505321、WO 92/04068及WO 92/04928。
可再使用之劑量測量為其中一種主要考慮的多劑量吸入裝置。
散劑調配物必須具有良好及穩定的流動特性,因為劑量測量杯或孔洞大多受重力影響。
就重新填裝單一劑量及多單位劑量吸入器而言,製造商必須保證劑量測量之準確度及再使用能力。一般當裝填劑量之操作次數較低時,另一方面多劑量吸入器則能含有較大數量之劑量。
因為在多劑量裝置中之空氣流經常直接穿過劑量測量之孔洞,及因其大量及精準之劑量測量系統之多劑量吸入器不能被呼吸空氣流攪動,散劑量僅從孔洞載入及在釋出時得到少許的鬆團作用。
因此,分開的分散方法是需要的。然而在實行上,其通常並不是吸入器設計的一部分。因在多劑量裝置中之高劑
量,散劑附著在空氣導管內壁及必須降低鬆團作用之次數及/或在不影響在元件中藥劑殘留下,必須可正常清洗這些部件。許多的多劑量吸入器有可拋棄之藥劑容器,其可於開立的藥劑數目使用後更換(例如WO 97/000703)。就該等具有可拋棄藥劑容器之半長效多劑量吸入器而言,甚至必須更嚴格要求防止藥劑累積。
除了透過乾粉吸入器給藥外,本發明組合可經由操作推進的氣體或藉由所謂噴霧器投藥,由此醫藥活性物質之溶液能於高壓下噴灑出而產生可吸入顆粒之霧氣。這些噴霧器之優點為推進的氣體在使用能完全分散開。
此等噴霧器係描述於,例如,PCT專利申請案號WO 91/14468及國際專利申請案號WO 97/12687,其內容列入本文之參考。
以吸入局部遞送至肺部之噴灑組合可例如調配成水溶液或懸浮液或由壓力包遞送之噴霧例如,使用適合液化推進劑之一定量劑量吸入器。適合吸入用之噴霧組合可為懸浮液或溶液且通常包含活性成份及適合之推進劑例如氟碳化合物或含氫之氯氟碳化合物或其混合物,特別是氫氟烷類,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷,特別是1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟正丙烷或其混合物。二氧化碳或其他適合的氣體亦可做為推進劑。噴霧組合可不含推進劑以外之賦形劑或可視需要包含本項技藝中以知之額外的調配賦形劑例如表面活性劑如油酸或卵磷脂及共溶劑如乙醇。加壓之調配物一般可保存於以閥門關閉
並固定在帶有一出口之發動器的罐中(如鋁合金罐)。
以吸入投藥之醫藥品所欲的係具有控制之顆粒大小。吸入支氣管系統之最適合的顆粒大小通常為1-10 μ,較佳為2-5 μ。當吸入到小氣管時,具有超過20 μ大小之顆粒通常太大。為了要達到此顆粒大小,當在製造活性成份之顆粒時可藉由習用方法例如超細粉粒或超臨界流體技術來降低大小。可以氣體分類或過篩將所欲的部份分離出。較佳的,該顆粒為晶體。
因為其差的流動性及極易結塊之傾向,以超細粉粒散劑來達成高產率是困難的。為了改進散劑組合之效能,在吸入器中的顆粒必須大,但是當釋出到呼吸道中時則要小。因此,通常會使用例如乳糖、甘露醇或葡萄糖之賦形劑。賦形劑顆粒大小通常需較大於在本發明中之吸入醫藥品。當賦形劑為乳糖時一般係以研磨過的乳糖,較佳的為晶體阿爾發乳糖單水合物。
加壓力之噴霧組合通常係填進裝置有閥門(特別是測量活閥門)之罐中。罐中可視需要塗覆塑膠物質例如描述於W096/32150中之氟碳化合物聚合物。罐子可將裝設一適合口腔遞送之發動器。
典型的用於鼻部傳送之組合包括上述用於吸入之組合及進一步包括非加壓之組合,其為溶於惰性媒液(例如水)中之溶液或之懸浮液,視需要與習用之賦形劑例如緩衝劑、抗菌劑、黏液附著劑、彈性及黏性調節藥劑組合,其可以鼻腔幫浦投藥。
一般皮膚及穿透皮膚之調配物包括習用的水性或非水性媒液,例如乳霜、軟膏、乳液或糊膏或為醫藥塗漿、貼布或藥膜的型式。
根據本發明(a)β2-激動劑及(b)M3蕈毒鹼受體拮抗劑可使用之比例為可變的。活性物質(a)及(b)可能可以其溶劑合物或水合物的型式存在。依所選擇的化合物(a)及(b)可用之重量計比例係在本發明之範疇內以各種不同鹽類形式之分子量為基準來變化。根據本發明之醫藥組合可包含(a)及(b),其通常之(b):(a)重量計比例範圍係自1:5至500:1,較佳的為1:10至400:1。
根據本發明特較佳的,下列特定的重量計比例係以3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷表示之化合物(b)及β2-促效劑沙美特羅及福莫特羅之游離鹼為基礎。
根據本發明之醫藥組合可包含(a)及(b)以福莫特羅為例,其(b):(a)之重量比例範圍係自1:10至300:1,較佳地係自1:5至200:1,較佳地為自1:3至150:1,更佳地為自1:2至100:1。
根據本發明含有(a)及(b)組合之醫藥組合,通常投藥係使3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷及茶丙喘共同存在劑量有5至5000 μg,較佳地為自10至2000 μg,更佳地為自15至1000 μg,最好每單次劑量為20 to 800μg。
例如,其上在無限制於本發明之範圍時,以3(R)-(2-羥基
-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷做為(b)及以福莫特羅富馬酸作為(a)之組合中,本發明之組合可包含例如自20至1000 μg之3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷及自2,5至30 μg之福莫特羅富馬酸。
例如,根據本發明活性物質組合可包含3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷及(a)(以沙美特羅為例),(b):(a)之重量比例(b):(a)自約1:30至400:1,較佳地為1:25至200:1,較佳地為1:20至100:1,更佳地為自1:15至50:1。
含有(a)及(b)組合之本發明組合通常投藥係使3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷及茶丙喘共同存在劑量有通常投藥係使3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷及沙美特羅共同存在劑量有5至5000 μg,較佳地為自10至2000 μg,更佳地為自15至1000 μg,更佳地每單次劑量為自20至800μg。
例如,其上在無限制於本發明之範圍時,以3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷做為(b)及以沙美特羅羥萘甲酸鹽作為(a)之組合中,本發明之組合可包含例如自20至1000 μg之3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷及自15至300 μg之沙美特
羅羥萘甲酸鹽。
就本發明組合上述可應用之可能劑量實例,應了解係指每單次應用之劑量。然而,這些實例不應被認為排除多次投予本發明組合之可能性。依照醫療的需求,病患能接受多次吸入給藥。例如病患可接受本發明之組合例如於每個治療日早上二或三次(例如使用散劑吸入器、MDI等二或三次噴氣)。如上述劑量之實例應了解僅為每單次應用之劑量實例(即每次噴氣),本發明組合之多次應用則為上述多次劑量之實例。本發明組合之應用可例如每天一次,或視抗膽鹼劑之作用期間每天二次,或每2或3天一次。
較佳地組合係為單位劑型,例如錠劑、膠囊或計量之噴霧劑量,可使病患可投與單一劑量。
每一劑量單位適合的係包含自20 μg至1000 μg及較佳地自50 μg至300μg之本發明M3拮抗劑或其醫藥上可接受之鹽類,以及1μg至300 μg,較佳地自5 μg至100μg之本發明β2激動劑。
個活性成份之量需為達到療效之劑量,當然係依特定的活性物、投藥的方法、治療的對象,及所欲治療之特定的疾病而不同。
活性成分可一天投予1至6次,足以產生需要之作用。較佳地,活性成分係一天投藥一或二次。
預期所有活性藥劑應同時投予,或在非常接近的時間內投予。或者,一或二種活性成份可在早上服用而其他的活性成份同一天稍後服用。或另一種情況,每天服用二次一
或二種活性成份而其他的活性成份則每天服用一次,或者與其中一種一天服用兩次的劑量同時獲分開服藥。較佳地為至少二種活性成份成份一起服用,而更佳地為全部活性成份於同時服用。較佳地為至少二種,而更佳地為全部活性成份以混合物來投藥。
根據本發明活性物質之組合,較佳的係藉由吸入器幫助(特別是乾散劑吸入器)以吸傳送組合之型式投藥,然而,任何其他形式或非經腸或口服亦可用。本處,使用吸入組合為具體較佳之應用形式,特別是治療阻塞性肺部疾病或氣喘病。
引用下列製劑形式作為調配物實例:
上述組合為本發明之較佳具體實例之特定實例,其中本發明之M3拮抗劑係與β2激動劑組合。對於本項技藝中已知
之M3抗劑及β2促效劑之組成物,此等新穎之組合具有顯著的治療優勢。
特而言之,本發明之M3拮抗劑與β2激動劑例如沙美特羅或福莫特羅組合,比噻托溴銨與沙美特羅或福莫特羅治療上之同等組合,明顯及一致地產生較少副作用,如頻脈。
下列比較之實例描述了包含本發明最佳M3拮抗劑,即3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷之組合的優點特性。
三隻公小獵犬重16-19 Kg來自"Centre d'Elevage du domaine des Souches"(CEDS,Mezilles,France)豢養於標準溫度、濕度、光線循環之條件。動物餵養標準實驗室食物並無限制水。
動物在實驗之前禁食約18小時沒有限制水。每一隻狗從狗屋帶出,秤重量,並以吊帶衣拉調帶至進行實驗的房間。
左頭部靜脈插管用以投予試驗物質並心電圖儀導線連接到動物以記錄ECGs(及計算心跳率)。
每一隻狗接受所有治療(或媒液即鹽水溶液濃度0.9%)及至少6天之沖淡期。以總量0.5 ml/kg之組合或媒劑灌注3分鐘來給藥。於投藥結束時及投藥後每15分鐘至5小時以具有程式AcqKnowledge III(版本3.5.3)之電腦資料取得系統MP100WSW(Biopac Systems,Inc Santa Barbara,USA)評估對心跳速率之作用。
進行初步的實驗以研究3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷(以下稱化合物1)塞托溴銨、沙美特羅及福莫特羅對心跳速率之作用以便於辨識出以組合給藥之最合適劑量(即其產生次最大運動心跳率增加量)(資料沒有顯示)。選擇之劑量如下:
●化合物1:10及100 μg/kg
●塞托溴銨:10 μg/kg
●沙美特羅:3 μg/kg
●福莫特羅:0.3 μg/kg.
所研究之下列組成
●化合物1為10 μg/kg加福莫特羅0.3 μg/kg
●化合物1為10 μg/kg加沙美特羅3 μg/kg
●化合物1為100 μg/kg加沙美特羅3 μg/kg
●塞托溴銨為10 μg/kg加福莫特羅0.3μg kg
●塞托溴銨為10 μg/kg加沙美特羅3 μg/kg
就每次治療,在最大心律作用降低至50%(t50%)之前,亦測量心臟速率最大增加量及所使用時間。
使用單因子變異數分析(one-way ANOVA)以Newman-Keuls作資料事後檢定之統計分析簡述於表1,其顯示於心率最大作用間並無差異及且該作用期間:(a)不同於塞托溴銨加福莫特羅p<0.01;(b)不同於塞托溴銨加沙美特羅p<0.01;(c)不同於塞托溴銨加沙美特羅p<0.05。
實驗結果總結於表1及圖1至3顯示下列作用:雖然差距在統計上並不顯著,但化合物1(10 μg/kg)之組合加福莫特羅比噻托溴銨加福莫特羅產生較小增加之心跳率。(圖1)
化合物1(10 μg/kg)加福莫特羅引起之促心律作用降至低
於50%之最大增加量需要40±18分鐘,而噻托溴銨加福莫特羅則需要155±26分鐘才能達到。該差距在統計上較顯著。(圖1)
化合物1(10 μg/kg)之組合加沙美特羅也產生比噻托溴銨加沙美特羅較小增加之心跳率。該差距在統計上並不顯助。(圖2)
化合物1(10 μg/kg)加沙美特羅引起之促心律作用降至低於50%之最大增加量需要25±10分鐘,而噻托溴銨加沙美特羅則需要130±10分鐘才能達到。差距在統計上較顯著。(圖2)。
化合物1之組合在高劑量下(100 μg/kg)加沙美特羅產生最大頻脈效用僅略大於噻托溴銨組合在以低10倍劑量加沙美特羅所引起的效用。該微小差距在統計上並不顯著。(圖3)。
化合物1之組合在高劑量下(100 μg/kg)加沙美特羅所產生的促心律作用之期間在統計上短於(t50%=65±18分鐘)噻托溴銨之組成物其在低10倍劑量下(10 μg/kg)加沙美特羅(t50%=130±10分鐘)所產生之效用。(圖3)。
這些結果證實本發明M3抗劑與LABAs組合比市售之M3拮抗劑,如噻托溴銨與LABAs之組合產生較低的心臟副作用。
因此,本發明之組合具有治療上之優勢性,使其特別適合用於治療各種病患之呼吸疾病,包括那些有潛在心臟症狀之病患。
圖1顯示時間過程對0.3 μg/kg福莫特羅與10 μg/kg化合物1或10 μg/kg噻托溴銨之組合於心跳速率之效應。媒劑之效用亦顯示作為參考。
圖2顯示時間過程對3 μg/kg沙美特羅與10 μg/K之化合物1或10 μg/kg噻托溴銨之組合於心跳速率之效應。媒劑之作用亦顯示作為參考。
圖3顯示時間過程對3 μg/kg沙美特羅與100 μg/kg化合物1或10 μg/kg噻托溴銨之組合於心跳速率之效應。媒劑之作用亦顯示作為參考。
Claims (17)
- 一種組合,其含有(a)β2-激動劑及(b)M3蕈毒鹼受體拮抗劑,該M3蕈毒鹼受體拮抗劑為3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]辛烷,以具有陰離子X鹽之型式,該陰離子X為醫藥學上可接受之單價或多價酸陰離子。
- 根據請求項1之組合,其中該M3蕈毒鹼受體拮抗劑(b)為3(R)-(2-羥基-2,2-二噻吩-2-基乙醯氧基)-1-(3-苯氧基丙基)-1-氮陽離子雙環[2.2.2]溴辛烷。
- 根據請求項1或2之組合,其中該β2-激動劑為長效型β2激動劑。
- 根據請求項1或2之組合,其中該β2激動劑係由阿福莫特羅、班布特羅、比托特羅、溴沙特羅、塞曼特羅、克侖特羅、多培沙明、酚丙喘寧、福莫特羅、氯苯胺丙醇、異丁特羅、異丙腎上腺素、左沙布特羅、馬布特羅、美露阿德林(meluadrine)、若羅米羅(nolomirole)、異丙喘寧、吡布特羅、丙卡特羅、(R,R)-福莫特羅、茶丙喘寧、利托君、瑞莫特羅(rimoterol)、沙丁胺醇、沙美特羅、昔本那地(sibenadet)、磺醯特羅、特布他林、妥洛特羅、GSK-597901、GSK-159797、KUL-1248、TA-2005及QAB-1491組成之群中選出,視需要以其消旋異構物、鏡相異構物、非對映異構體及其混合物之形式,及視需要為其藥理上相容之酸加成鹽形式。
- 根據請求項4之組合,其中該β2激動劑係由福莫特羅、沙 美特羅及QAB-149組成之群中選出,視需要以其消旋異構物、鏡相異構物、非對映異構體及其混合物之形式,及視需要為其藥理上相容之酸加成鹽形式。
- 根據請求項5之組合,其中該β2激動劑係為福莫特羅富馬酸。
- 根據請求項5之組合,其中該β2激動劑為沙美特羅羥萘甲酸鹽。
- 根據請求項1或2之組合,其特徵在於該活性成份(a)及(b)形成單一醫藥組合之部份。
- 根據請求項1或2之組合,其進一步含有(c)另一活性化合物,其係選自:(i)PDE IV抑制劑、(ii)皮質類固醇、(iii)白三烯素D4拮抗劑、(iv)egfr-激酶抑制劑、(v)p38激酶抑制劑及(vi)NK1受體激動劑供同時、分開或連續使用。
- 根據請求項9之組合,其中該活性化合物(c)係由(i)PDE IV抑制劑和(ii)皮質類固醇組成之群中選出。
- 一種如請求項1及3至7項中任一項所定義之(a)β2激動劑及如請求項1或2所定義之(b)M3蕈毒鹼受體拮抗劑之用途,其係備製供同時、協同、分開或依序使用以治療病患之呼吸疾病之醫藥品,其中該呼吸疾病為氣喘、急性或慢性支氣管炎、氣腫、慢性阻塞性肺病(COPD)、氣道過敏反應或鼻炎。
- 根據請求項11之用途,其中該呼吸疾病為慢性阻塞性肺病(COPD)。
- 一種作為組合製劑之產品,其含有如請求項1及3至7項中 任一項所定義之(a)β2激動劑及(b)如請求項1或2所定義之M3蕈毒鹼受體拮抗劑,係供同時、協同、分開或依序使用以治療患有或易感染如請求項11或12所定義之呼吸疾病之病患。
- 如請求項13之產品,其進一步含有一如請求項9或10所定義之活性成分(c)。
- 一種包裝組,其含有如請求項1或2所定義之(b)M3蕈毒鹼受體拮抗劑與如請求項1及3至7項中任一項所定義之(a)β2激動劑,係供同時、協同、分開或依序使用以治療如請求項11或12所定義之呼吸疾病。
- 如請求項15之包裝組,其進一步含有一如請求項9或10所定義之活性成分(c)。
- 根據請求項11之用途,其中該病患係已患有心臟症狀或會因頻脈加劇所致症狀。
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