TW201801728A - 匹莫苯坦(pimobendan)用於在患有由二尖瓣疾病所致之無症狀心臟衰竭之患者中減小心臟大小及/或延遲臨床症狀之發作的用途 - Google Patents
匹莫苯坦(pimobendan)用於在患有由二尖瓣疾病所致之無症狀心臟衰竭之患者中減小心臟大小及/或延遲臨床症狀之發作的用途 Download PDFInfo
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- TW201801728A TW201801728A TW106111320A TW106111320A TW201801728A TW 201801728 A TW201801728 A TW 201801728A TW 106111320 A TW106111320 A TW 106111320A TW 106111320 A TW106111320 A TW 106111320A TW 201801728 A TW201801728 A TW 201801728A
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- heart failure
- asymptomatic
- preclinical
- patients
- mitral valve
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Abstract
本發明係關於匹莫苯坦(pimobendan),其係用於在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳充血性心臟衰竭的患者中減小心臟大小及/或延遲臨床症狀之發作,及/或在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳充血性心臟衰竭的患者中延遲心臟衰竭、較佳充血性心臟衰竭之發作的方法中,其中該患者較佳係哺乳動物,更佳係人類、狗、貓或馬,且最佳係狗。
Description
本發明係關於醫學,尤其是獸醫學領域。特定而言,本發明係關於匹莫苯坦之用途,其係用於在患有由(黏液瘤性)二尖瓣疾病[(M)MVD]及/或慢性心臟瓣膜病(CVHD;亦稱為慢性瓣膜病,CVD)及/或心房心室瓣膜功能不全(AVVI)所致之無症狀(隱發性,臨床前)心臟衰竭(HF)的患者中減小心臟大小,及/或用於在患有由(m)MVD及/或CVHD/CVD及/或AVVI所致之無症狀(隱發性,臨床前)HF的患者中延遲臨床症狀之發作,及/或延遲由(黏液瘤性)二尖瓣疾病[(M)MVD]及/或慢性心臟瓣膜病(CVHD;亦稱為慢性瓣膜病,CVD)及/或心房心室瓣膜功能不全(AVVI)所致之心臟衰竭之發作。
心臟衰竭劃分為不同階段,其由不同分級體系界定,例如國際小動物心臟健康委員會(ISACHC)、紐約心臟協會(NYHA)功能性分級體系及目前使用的根據2009年美國獸醫內科醫學院(ACVIM)之共識聲明的分級。 根據國際小動物心臟健康委員會(ISACHC)體系的分級: I級:無症狀(亦稱為隱發性或臨床前) IA級: 無針對潛在心臟病之代償之跡象(放射照相或心臟超音波偵測不到體積過荷或壓力過荷) IB級: 針對潛在心臟病之代償之臨床徵象(放射照相或心臟超音波偵測到體積過荷或壓力過荷) II級: 休息或輕度運動時具有臨床徵象的輕度至中度心臟衰竭(需要治療) III級: 晚期心臟衰竭;嚴重充血性心臟衰竭之臨床徵象 IIIA級: 可家庭治療 IIIB級: 需要住院 紐約心臟協會(NYHA)功能性分級體系: I級: 描述患有無症狀心臟病(例如,存在慢性心臟瓣膜病(CVHD)但即使在運動時亦無明顯的臨床徵象)的患者。 II級: 描述患有僅在劇烈運動期間產生臨床徵象的心臟病的患者。 III級: 描述患有在常規日常活動或輕度運動時產生臨床徵象的心臟病的患者。 IV級: 描述患有即使在休息時亦產生嚴重臨床症狀的心臟病的患者。 ACVIM體系描述心臟病及心臟衰竭之四個基本階段: A階段: 患者具有患心臟病的高風險但目前無可識別的結構性心臟病症(例如,每隻無心雜音的查爾斯國王騎士獵犬(Cavalier King Charles Spaniel))。 B階段: 患者患有結構性心臟病(例如,存在二尖瓣反流之典型雜音),但從未發展出由心臟衰竭(由於對於預後及治療的重要臨床含義,所以委員會進一步將B階段再分為B1及B2階段)引起的臨床徵象。 B1階段: 無回應於CVHD的心臟重塑作用之放射照相或心臟超音波跡象的無症狀患者。 B2階段: 患有如藉由左側心臟擴大之放射照相或心臟超音波結果證明的血液動力學上顯著的瓣膜反流的無症狀患者。 C階段: 過去或現在具有與結構性心臟病相關的心臟衰竭之臨床徵象的患者。 D階段: 患有具有由「標準療法」難以治療的CVHD引起的心臟衰竭之臨床徵象的末期疾病的患者。 心臟病變開始於ISACHC I級、NYHA I級及ACVIM B2階段,其中存在心雜音或心室擴大,但無臨床症狀(ISACHC I級或無症狀/隱發性/臨床前階段)。在疾病之進展過程中,臨床症狀變得明顯(ISACHC II級或III級,NYHA II級、III級或IV級,ACVIM C階段及D階段)。 (M)MVD或CVHD/CVD或AVVI心臟衰竭之已知進展與心臟大小之增大相關。由心臟內形態變化所致的心臟重塑作用通常視為風險因素且與導致心臟衰竭之病理生理變化之惡化有關。心臟衰竭療法之一個目標係減小心臟大小且延遲心臟之形態變化。 一種用於治療心臟衰竭的已知醫藥活性化合物係匹莫苯坦(4,5-二氫-6-[2-(4-甲氧基苯基)-1H-苯并咪唑-5-基]-5-甲基-3(2H)-噠嗪酮),其揭示於EP 0 008 391中且具有下式:。 匹莫苯坦係用於治療動物之起源於例如擴張型心肌症(DCM)或二尖瓣疾病(MVD)的充血性心臟衰竭(CHF)的熟知化合物。在日本,匹莫苯坦亦經批准作為用於人類心臟血管治療之藥品。 若干公開案揭示匹莫苯坦在治療動物心臟衰竭方面之用途,諸如以下公開案。 WO 2005/092343描述諸如匹莫苯坦之PDE-III抑制劑於減小患有心臟衰竭之患者之心臟大小的用途,然而未提及患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者。 Lombard及同事(Lombard CW等人,J Am Anim Hosp Assoc 2006, 42: 249-261)揭示在治療狗之臨床獲得性心房心室瓣膜病時匹莫苯坦對比貝那普利(benazepril)之臨床效果。 WO 2007/054514係針對諸如匹莫苯坦之PDE-III抑制劑於治療無症狀(亦稱為隱發性或臨床前)心臟衰竭之用途,然而未提及患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者。 Häggström J等人(J Vet Intern Med 2008, 22: 1124-1135)描述了匹莫苯坦或貝那普利鹽酸鹽對患有由天然產生之黏液瘤性二尖瓣疾病引起的臨床充血性心臟衰竭的狗之存活時間的影響,然而未提及患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者。 Summerfield NJ及同事(Summerfield NJ等人,J Vet Intern Med 2012, 26: 1337-1349)係關於匹莫苯坦在患有臨床前擴張型心肌症(DCM)的杜賓犬(Doberman Pinscher)預防充血性心臟衰竭或猝死之效果方面的臨床研究。然而,他們未提及患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者。 Häggström J等人(J Vet Intern Med 2013, 27: 1452-1462)描述匹莫苯坦及貝那普利在患有臨床黏液瘤性二尖瓣疾病及充血性心臟衰竭的狗中之短期血液動力學及神經內分泌作用。然而,他們未提及患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者。 網際網路網站www.epictrial.com係針對EPIC試驗,一個探究匹莫苯坦在延遲由二尖瓣疾病(MVD)所致之充血性心臟衰竭之臨床症狀的發作方面之作用的研究。然而,在本專利申請案之優先權日,此試驗仍在進行中且未公開研究結果。 然而,若干其他公開案係關於匹莫苯坦治療之不利心臟作用,諸如以下公開案。 Schneider P等人(Exp Toxic Pathol 1997, 49: 217-224)描述在雌性米格魯犬(Beagle dog)中靜脈內投與的匹莫苯坦之相當的心臟毒性。 Tissier R及同事(Tissier R等人,Cardiovascular Toxicology 2005, 5(1): 43-51)揭示在接受長期(long-term/chronic)臨床匹莫苯坦療法的兩隻狗中,不利作用加劇了二尖瓣反流及心肌肥大。 Amsallem E等人(Cochrane Database Syst Rev 2005, 25: 1)發現,磷酸二酯酶抑制劑、尤其諸如匹莫苯坦,係與人類患者顯著升高17%的死亡率相關且另外顯著加劇心臟死亡、猝死、心律不整及眩暈。作者得出結論,應避免心臟衰竭患者長期使用磷酸二酯酶抑制劑。 Chetboul V及同事(Chetboul V等人,J Vet Intern Med 2007, 21: 742-753)展示一項關於在患有輕度退行性無症狀二尖瓣疾病的狗中匹莫苯坦及貝那普利單一療法之比較性不利心臟作用的前瞻性的、受控制的、盲法的且隨機化的研究之結果。 Ouellet M等人(J Vet Intern Med 2009, 23: 258-263)描述匹莫苯坦對患有無症狀二尖瓣疾病的狗之心臟超音波值的影響。然而此研究未能鑑定在將匹莫苯坦加入ACE抑制劑治療之後在二尖瓣反流之嚴重度方面的有利長期變化。 因此,本發明之根本目標係提供一種克服如上文所述之先前技術之問題的醫藥治療。
本發明係關於用於以下之方法中之匹莫苯坦:在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭,更佳由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭的患者中減小心臟大小及/或延遲臨床症狀之發作,及/或在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲心臟衰竭之發作,較佳在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作,更佳在患有由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作。在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中減小心臟大小及/或延遲臨床症狀之發作及/或在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲(充血性)心臟衰竭之發作的相應方法,及用於製備用於在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中減小心臟大小及/或延遲臨床症狀之發作及/或在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲心臟衰竭、較佳充血性心臟衰竭之發作的醫藥組合物/藥劑的用途亦意欲在本發明之範疇內。 本發明進一步關於用於以下之方法中的匹莫苯坦:在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭,更佳由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭的患者中減小心臟大小及延遲臨床症狀之發作,及在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲心臟衰竭之發作,較佳在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作,更佳在患有由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作。在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中減小心臟大小及延遲臨床症狀之發作及/或在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲(充血性)心臟衰竭之發作的相應方法,及用於製備用於在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中減小心臟大小及延遲臨床症狀之發作及在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲心臟衰竭、較佳充血性心臟衰竭之發作的醫藥組合物/藥劑的用途亦意欲在本發明之範疇內。 根據本發明之匹莫苯坦之醫藥用途的優點如下: - 延長不呈現充血性心臟衰竭之臨床症狀的臨床前(亦稱為無症狀或隱發性)期 - 延遲充血性心臟衰竭(之臨床症狀)之發作 - 與安慰劑治療相比增加經治療患者之存活時間 - 提高經治療患者之生活品質 - 與基線(即治療開始之前)相比減小經治療患者之心臟大小 - 改進經治療患者之心臟功能/輸出 - 降低患者之由心臟原因所致之心源性猝死/安樂死 - 降低達到充血性心臟衰竭之風險 藉由在全因死亡率分析中在匹莫苯坦組中觀察到較長存活期,任何先前產生的關於藥物治療之安全性的擔憂應得以減輕。在所觀察到的可能不良事件之比率或類型方面,各組之間不存在差異。儘管存在以下事實:匹莫苯坦組中之狗在研究中度過了較長時間且因而較長期間處於經歷不良事件之風險下。
在進一步詳細描述本發明之實施例之前,應注意,如本文及所附申請專利範圍中所使用,除非上下文清楚地另外規定,否則單數形式「一個」、「一種」及「該」包括複數指代。 除非另外定義,否則本文中所使用之所有技術及科學術語具有與本發明所屬領域之一般技術者通常所理解的相同之含義。除非另外規定或為熟習此項技術者以其他方式知曉,否則所有給出的範圍及值可存在1至5%之變化,因此,在說明書及申請專利範圍中通常省略術語「約」。儘管可使用與本文所述類似或等效之任何方法及材料來實施或測試本發明,但現描述較佳方法、裝置及材料。出於描述及揭示如在可結合本發明使用的公開案中所報導的物質、賦形劑、載劑及方法的目的,本文提及的所有公開案以引用的方式併入本文中。不應將本文中之任何內容解釋為承認本發明無權先於憑藉先前發明之此類揭示內容。 如上文及下文所用之術語「患者」係指患有(充血性)心臟衰竭的動物或人。術語「患者」涵蓋哺乳動物,諸如靈長類,包括人類。除靈長類之外,還有各種其他哺乳動物可根據本發明之方法治療。例如,可治療哺乳動物,包含但不限於:馬、狗、貓、或馬類、犬類、貓類物種。較佳係人類患者、狗、貓及馬。人類患者係患有心臟衰竭的女性或男性個體。通常此類個體係兒童、青少年、成人或老年人,其年齡在6歲與80歲之間,較佳在30歲與65歲之間。最佳係狗。 如上文及下文所用之術語「心臟衰竭」,較佳「充血性心臟衰竭」,係指任何心臟收縮病症或疾病。臨床表現通常為心臟細胞及分子組分之變化及驅動體內恆定控制的介體之變化的結果。心臟衰竭,較佳充血性心臟衰竭,通常伴隨著心臟大小之增大及心臟功能之退化。 如上文及下文所用之術語「心臟大小減小」係指患者之心臟大小減小,此係使用心臟超音波診斷且可根據由James W. Buchanan等人(Buchanan JW等人,J Am Vet Med Assoc 1995, 206(2), 194-199)提出的放射照相方法來測定且以椎體心臟大小之相對變化表示。較佳地,相比於基線,亦即在匹莫苯坦治療開始之前,更佳在用匹莫苯坦治療10至100天內,甚至更佳約30至40天內,最佳約35天內,該患者之相對心臟大小減小至少5%,較佳至少10%、15%、20%、25%或至少30%。 如上文及下文所用之術語「由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)(充血性)心臟衰竭」係指歸因於/繼發於MVD,但尚無任何(充血性)心臟衰竭之臨床症狀的任何心臟收縮病症或疾病。特定而言,其係指ISACHC I級(IA級及/或IB級)、NYHA I級及ACVIM B2階段之心臟衰竭。 術語「延遲臨床症狀之發作」及「延長在臨床症狀發作前之時間」在上文及下文中可互換地使用,且係指自診斷出患者之心臟形態變化起至由二尖瓣疾病(MVD)所致之心臟衰竭、較佳充血性心臟衰竭之臨床症狀開始之間的時間段。特定而言,其係指延長自ISACHC I級(IA級及/或IB級)、NYHA I級及ACVIM B2階段之仍無症狀(隱發性,臨床前)心臟衰竭至ISACHC II級且進一步至III級(IIIA級及/或IIIB級)、NYHA II級、III級及IV級及ACVIM C階段及D階段之臨床明顯心臟衰竭,較佳充血性心臟衰竭的時間。 為免歧義,在本發明過程中,醫學適應症術語「二尖瓣疾病(MVD)」、「黏液瘤性二尖瓣疾病(MMVD)」、「慢性心臟瓣膜病(CVHD)」、「慢性瓣膜病(CVD)」及「心房心室瓣膜功能不全(AVVI)」皆可互換地使用。至於ISACHC I級(IA級及/或IB級)、NYHA I級及ACVIM B2階段心臟衰竭,其皆彼此同義且具有相同醫學含義。 如上文及下文所用之術語「降低達到充血性心臟衰竭之風險」係指經歷臨床明顯心臟衰竭、較佳充血性心臟衰竭之相對風險。較佳地,相對風險減小了至少5%,較佳至少10%、15%、20%、25%或至少30%。 如本文所用之術語「有效量」意指在以單一劑型投與匹莫苯坦時,足以達成在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭(HF)的患者中減小心臟大小及/或達成在患有由MVD所致之無症狀(隱發性,臨床前)HF的患者中延遲臨床症狀之發作及/或達成在患有由MVD所致之無症狀(隱發性,臨床前)HF的患者中延遲心臟衰竭、較佳充血性心臟衰竭之發作的量。 在一個態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳由二尖瓣疾病MVD所致之無症狀(隱發性,臨床前)充血性心臟衰竭,更佳由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭係屬於ISACHC I級、較佳ISACHC IA級或IB級之階段,更佳係屬於ISACHC IB級、NYHA I級及ACVIM B2階段之階段。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中匹莫苯坦治療實現患者之已病理性擴大的心臟之心臟大小減小。換言之,此類患者患有ISACHC I級(IA級及/或IB級)、NYHA I級及ACVIM B2階段之由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭且已具有病理性擴大的心臟(例如藉助於心臟超音波圖可見),但尚未顯示心臟衰竭,較佳充血性心臟衰竭之任何臨床症狀。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中匹莫苯坦治療與安慰劑治療或非匹莫苯坦治療相比實現患者之存活時間延長。就此而言,非匹莫苯坦治療係指一種比較治療,其中代替匹莫苯坦或安慰劑,對應的患者組接受除匹莫苯坦之外的有效藥劑成分。較佳此類匹莫苯坦治療與安慰劑治療或非匹莫苯坦治療相比,實現患者之存活時間延長至少30天,更佳至少2個月,甚至更佳至少3個月,甚至更佳至少4個月,甚至更佳至少5個月,甚至更佳至少6個月,甚至更佳至少7個月,甚至更佳至少8個月,甚至更佳至少9個月,甚至更佳至少10個月,甚至更佳至少11個月,甚至更佳至少12個月,甚至更佳至少13個月,甚至更佳至少14個月,甚至更佳至少15個月。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中匹莫苯坦治療實現不呈現充血性心臟衰竭之臨床症狀之臨床前期延長,實現充血性心臟衰竭之(臨床症狀之)發作延遲,與安慰劑治療相比增加經治療患者之存活時間,提高經治療患者之生活品質,與基線(即治療開始之前)相比引起經治療患者之心臟大小減小,改進經治療患者之心臟功能/輸出,減少患者之由心臟原因所致之心源性猝死/安樂死及/或降低達到充血性心臟衰竭之風險。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中患者係哺乳動物,較佳人類、狗、貓或馬,更佳狗。 當然,匹莫苯坦之給藥方案將視已知因素而定,諸如藥效學特徵及其模式及投藥途徑;接收者之物種、年齡、性別、健康、醫學病況及體重;症狀之性質及程度;並行治療之種類;治療之頻率;投藥途徑、患者之腎及肝功能以及所期望的效果。醫師或獸醫可確定預防、對抗、延遲或遏止病症之進展所需的藥物有效量且開具該有效量藥物之處方。 藉助於一般指導,當出於指定效果使用時,匹莫苯坦之每日口服劑量將在約0.2毫克/公斤至0.6毫克/公斤體重SID之間的範圍內,尤其是每天每公斤體重投與0.2毫克至0.6毫克匹莫苯坦(EU)及每天每公斤體重投與0.5毫克匹莫苯坦(US)。較佳地,每日匹莫苯坦劑量係按兩個0.1毫克/公斤至0.3毫克/公斤體重之劑量,較佳兩個0.1毫克/公斤至0.3毫克/公斤體重之劑量每12小時(EU),更佳兩個0.25毫克/公斤體重之劑量每12小時(USA)投與。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中匹莫苯坦以0.2毫克/公斤至0.6毫克/公斤體重SID之日劑量,尤其是每天每公斤體重投與0.2毫克至0.6毫克匹莫苯坦(EU)及每天每公斤體重投與0.5毫克匹莫苯坦(US)來投與。較佳地,每日匹莫苯坦劑量係以兩個0.1毫克/公斤至0.3毫克/公斤體重之劑量,較佳兩個0.1毫克/公斤至0.3毫克/公斤體重之劑量每12小時(EU),更佳兩個0.25毫克/公斤體重之劑量每12小時(USA)投與。 根據本發明之另一態樣,匹莫苯坦結合至少一種第二有效藥劑成分(API)一起投與。此類至少一種第二API較佳係選自由以下組成之群:諸如ACE抑制劑的後負荷減緩劑(動脈擴張劑)、諸如利尿劑的前負荷減緩劑(靜脈擴張劑)、血小板抑制劑、β阻斷劑及血管收縮素II拮抗劑、醛固酮拮抗劑、抗心律不整劑(若出現心律不整)及/或利尿劑,特定而言, - 其中ACE抑制劑係選自由以下組成之群:奧馬曲拉(omapatrilat)、MDL100240、阿拉普利(alacepril)、貝那普利、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普利拉(enalaprilat)、福辛普利(fosinopril)、福辛普利拉(fosinoprilat)、咪達普利(imidapril)、賴諾普利(lisinopril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、雷米普利拉(ramiprilat)、乙酸色拉新(saralasin acetate)、替莫普利(temocapril)、群多普利(trandolapril)、群多普利拉(trandolaprilat)、西那普利(ceranapril)、莫西普利(moexipril)、喹那普利拉(quinaprilat)及/或螺普利(spirapri);及/或 - 其中後負荷減緩劑(動脈擴張劑)係選自由以下組成之群:聯胺肼、鈣離子通道阻斷劑地爾硫卓(diltiazem)、維拉帕米(verapamil)及氨氯地平(amlodipine)、硝普鹽(nitroprusside)及磷酸二酯酶抑制劑,諸如西地那非(sildenafil);及/或 - 其中β阻斷劑係選自由以下組成之群:比索洛爾(bisoprolol)、卡維地洛爾(carvedilol)、美托洛爾(metoprolol)、普萘洛爾(propranolol)、阿替洛爾(atenolol)、艾司洛爾(esmolol)、及/或噻嗎洛爾(timolol);及/或 - 其中血小板抑制劑係選自由以下組成之群:阿司匹林(aspirin)、氯吡格雷(clopidogrel)、Xa因子抑制劑、肝素及低分子量肝素;及/或 - 其中血管收縮素II拮抗劑係選自由以下組成之群:乙酸色拉新、坎地沙坦(candesartan)、沙坦西(cilexetil)、纈沙坦(valsartan)、坎地沙坦、洛沙坦鉀(losartan potassium)、依普羅沙坦(eprosartan)、依貝沙坦(irbesartan)、他索沙坦(tasosartan)、泊米沙坦(pomisartan)及/或替米沙坦(telmisartan);及/或 - 其中醛固酮拮抗劑係選自由以下組成之群:螺內酯、胺苯喋啶(triampterene)、依普利酮(eplerenone)、坎利酮(canrenone)、坎利酮鉀(potassium canrenone);及/或 - 其中抗心律不整劑係選自由以下組成之群:胺碘酮(amiodarone)、溴苄胺(bretylium)、丙吡胺(disopyramide)、多非利特(dofetilide)、氟卡尼(flecainide)、伊布利特(ibutilide)、美西律(mexiletine)、妥卡尼(tocainide)、普魯卡因胺(procainamide)、利多卡因(lidocaine)、普羅帕酮(propafenone)、地爾硫卓、維拉帕米(verapamil)、地高辛(digoxin)、洋地黃(digitalis)、奎尼丁(quinidine)及/或索他洛爾(sotalol);及/或 - 其中利尿劑係選自由以下組成之群:呋喃苯胺酸(furosemide)、螺內酯、托拉塞米(torasemide)、布美他尼(bumetanide)、依他尼酸(etacrynic acid)、阿佐塞米(azosemide)、莫唑胺(muzolimine)、吡咯他尼(piretanide)、曲帕胺(tripamide)、苄氟噻嗪(bendroflumethazide)、氯噻嗪、氫氯噻嗪、氫氟噻嗪、甲基氯噻嗪、多噻嗪、三氯甲噻嗪、氯噻酮(chlorthialidone)、吲達帕胺(indapamide)、美托拉宗(metolazone)、喹乙唑酮(quinethazone)、乙氧唑啉(etozolin)、胺苯喋啶(triamterene)、及/或胺氯吡脒(amiloride);及/或 - 其中前負荷減緩劑(靜脈擴張劑)係選自由硝化甘油、硝普鹽及異山梨酯(isorbide)組成之群;及/或 - 其中正性肌力藥係選自由以下組成之群:多巴酚丁胺、地高辛、洋地黃、多巴胺、氨利酮(amrinone)及米利酮(milrinone);及/或 - 其中超極化活化的環核苷酸選通的(HCN)通道阻斷劑或負性變時劑係選自由西洛雷定(cilobradine)、伊伐佈雷定(ivabradine)及腺苷組成之群。 較佳地,匹莫苯坦與一或多種選自由一或多種ACE抑制劑及一或多種利尿劑組成之群的API一起投與。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中匹莫苯坦係在投與一或多種額外的有效藥劑成分之前、期間或之後投與,該一或多種額外的有效藥劑成分選自由ACE抑制劑,較佳貝那普利;及利尿劑,較佳呋喃苯胺酸組成之群。更佳地,匹莫苯坦與貝那普利及呋喃苯胺酸並行投與。 匹莫苯坦可以如錠劑、咀嚼錠劑、咀嚼片、膠囊(其中之每一者包括持續釋放或定時釋放的調配物)、丸劑、粉劑、粒劑、酏劑、酊劑、懸浮液、溶液、糖漿及乳液之口服劑型投與。其亦可以靜脈內(快速注射或輸注)、腹膜內、皮下或肌肉內形式投與,均使用為一般熟習醫藥技術者所熟知之劑型。其可以單獨投與,但通常將與基於所選投與途徑及標準醫藥實踐選擇的藥學載劑一起投與。 在另一態樣中,本發明係關於根據上文及下文所揭示的態樣及較佳實施例使用的匹莫苯坦,其中匹莫苯坦經口或非經腸,較佳經口,更佳以錠劑或膠囊形式經口,最佳以錠劑形式經口投與。 匹莫苯坦可經由局部使用適合的鼻內媒劑以鼻內形式投與,或使用經皮皮膚貼劑經由經皮途徑投與。當然,當以經皮傳遞系統形式投與時,劑量投與將在整個給藥方案中為連續而非間斷的。 匹莫苯坦通常以與根據預期投藥形式(即口服錠劑、膠囊、酏劑、糖漿及其類似物)適當選擇且與習知醫藥實踐相符之適合醫藥稀釋劑、賦形劑及/或載劑(在本文中統稱為醫藥載劑)之混雜物形式投與。 舉例而言,針對以錠劑或膠囊形式經口投與,活性藥物組分可與以下口服、無毒、醫藥學上可接受之惰性載劑組合,諸如乳糖、澱粉、蔗糖、葡萄糖、甲基纖維素、硬脂酸鎂、磷酸二鈣、硫酸鈣、甘露醇、山梨醇及其類似物;針對以液體形式經口投與,口服藥物組分可與以下任何口服、無毒、醫藥學上可接受之惰性載劑組合,諸如乙醇、甘油、水及其類似物。此外,當需要或必要時,亦可將適合的黏合劑、潤滑劑、崩解劑及著色劑併入混合物中。適合的黏合劑包括澱粉、明膠、天然糖(諸如葡萄糖或β-乳糖)、玉米甜味劑、天然及合成膠(諸如阿拉伯膠、黃蓍膠或海藻酸鈉)、羧甲基纖維素、聚乙二醇、蠟及其類似物。用於此等劑型之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及其類似物。崩解劑包括但不限於澱粉、甲基纖維素、瓊脂、膨潤土、三仙膠及其類似物。 匹莫苯坦亦可以脂質體傳遞系統,諸如小單層囊泡、大單層囊泡及多層囊泡之形式投與。脂質體可由多種磷脂形成,諸如膽固醇、硬脂胺或磷脂醯膽鹼。 匹莫苯坦亦可以脂質包衣包覆形式作為固體醫藥調配物之一部分投與(參見例如WO 2015/082389)。 匹莫苯坦亦可結合可溶性聚合物作為靶向藥物載劑。此類聚合物可包括經軟脂醯基殘基取代的聚乙烯吡咯啶酮、哌喃共聚物、聚羥基丙基甲基丙烯醯胺苯酚、聚羥乙基天冬醯胺苯酚或聚氧化乙烯聚離胺酸。 此外,匹莫苯坦可結合以下適用於達成藥物控制釋放的一類可生物降解聚合物,舉例而言,聚乳酸、聚乙醇酸、聚乳酸與聚乙醇酸之共聚物、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯、及水凝膠之交聯或兩性嵌段共聚物。 適合投與的劑型(醫藥組合物)每劑量單位可含有約1 mg至約100 mg活性成分。 在此等醫藥組合物中,活性成分通常將以按組合物之總重量計約0.5-95重量%之量存在。 明膠膠囊可含有活性成分及粉末狀載劑,諸如乳糖、澱粉、纖維素衍生物、硬脂酸鎂、硬脂酸及其類似物。類似稀釋劑可用於製造壓製錠劑。錠劑及膠囊皆可製造為持續釋放產物以提供藥物經數小時時段之連續釋放。壓製錠劑可包覆糖衣或包覆膜衣以掩蓋任何令人不愉快的味道且保護錠劑不受大氣影響,或包覆腸溶包衣以便在胃腸道中選擇性崩解。 用於經口投與之液體劑型可含有著色劑及調味劑以提高患者接受性。一般而言,水、適合之油、生理鹽水、水性右旋糖(葡萄糖)及相關糖溶液及二醇(諸如丙二醇或聚乙二醇)係適合非經腸溶液之載劑。用於非經腸投與之溶液較佳含有活性成分之水溶性鹽、適合的穩定劑及(若需要)緩衝物質。單獨或組合之抗氧化劑,諸如亞硫酸氫鈉、亞硫酸鈉或抗壞血酸,係適合的穩定劑。亦使用檸檬酸及其鹽及EDTA鈉。另外,非經腸溶液可含有防腐劑,諸如氯化苯甲烴銨、對羥基苯甲酸甲酯或丙酯及氯丁醇。 適合的醫藥載劑描述於本領域中之標準參考文獻Remington's Pharmaceutical Sciences,Mack Publishing Company中。 在前述第二API中之兩者或更多者與匹莫苯坦一起投與的情況下,鑒於當組合投與時API之相加或協同效應,典型的日劑量及典型劑型中之各組分之量通常可相對於單獨投與時API之常規劑量減少。 尤其當以單個劑量單元形式提供時,組合的API之間可能存在化學相互作用。出於此原因,當匹莫苯坦與至少一種第二API以單一劑量單元形式組合時,其調配成使得儘管API係組合在單一劑量單元中,但API之間的物理接觸係最小化的(即減少的)。舉例而言,一種API可包覆腸溶包衣。藉由對API中之一者包覆腸溶包衣,不僅可能使經組合的API之間的接觸最小化,而且可能控制此等組分中之一者在胃腸道中的釋放,使得此等組分中之一者不在胃中釋放,而是在腸道中釋放。API中之一者亦可包覆可實現在整個胃腸道中持續釋放且亦使經組合的API之間的物理接觸最小化的材料。 此外,持久釋放之組分可額外包覆腸溶包衣,使得此組分之釋放僅在腸道中發生。另一方法將涉及組合產品之調配,其中一種組分包覆有持續釋放及/或腸釋放聚合物,且另一組分亦包覆有諸如低黏度級別之羥丙基甲基纖維素(HPMC)的聚合物或此項技術中已知的其他適合材料,以便進一步隔開活性組分。聚合物包衣用以針對與另一組分之相互作用形成額外屏障。實例
以下實例用以進一步說明本發明;但不應將其視為對本文所揭示的本發明之範疇的限制。實例 1 - 期間分析資料
先前研究已提出,匹莫苯坦治療顯著降低患有CHF的狗之病案死亡率及發病率。匹莫苯坦治療在延遲狗之由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭之進展方面的潛在益處尚未闡明。匹莫苯坦係具強效正性心肌收縮及血管舒張作用的苯并咪唑噠嗪酮。此前負荷及後負荷減小之組合作用連同正性心肌收縮支持一起使得患有由二尖瓣疾病所致之隱發性心臟衰竭的狗之心臟之心臟大小及填充壓力減小。 向患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的狗投與匹莫苯坦,使得充血性心臟衰竭之臨床徵象之發作前的時間與安慰劑相比延長約359天(12.0個月)且存活時間(全因死亡率)與安慰劑相比延長約168天(5.6個月)。因而,用匹莫苯坦治療處於心臟衰竭之臨床前期的狗產生改善結果。實例 2 - 最終研究結果之初步分析
360隻狗之盲法、安慰劑對照的研究之最終結果之初步分析顯示,向患有MMVD且具有心臟擴大之心臟超音波圖及放射照相證明的狗投與匹莫苯坦引起臨床前時期延長且此係安全且良好耐受的。 在匹莫苯坦組中達至主要終點之中值時間係1228天(95% CI 856-NA)且在安慰劑組中係766天(95% CI 667-875) (P=0.0038)。臨床前期延長約15個月顯示實質性臨床益處。 如由全因死亡率所確定,匹莫苯坦組的總存活期亦顯著長於安慰劑組(P=0.012),且此亦顯示顯著臨床益處。 在研究之最初35天內量測時,與安慰劑組相比,匹莫苯坦亦引起心臟大小減小(P<0.0001)。 同時,最終研究結果已公開(Boswood A等人,J Vet Intern Med 2016, 30(6): 1765-1779)。參考文獻
(1) Amsallem E et al., Cochrane Database Syst Rev 2005, 25: 1 (2) Boswood A et al., J Vet Intern Med 2016, 30(6): 1765-1779 (3) Buchanan JW et al., J Am Vet Med Assoc 1995, 206(2), 194-199 (4) Chetboul V et al., J Vet Intern Med 2007, 21: 742-753 (5) EP 0 008 391 (6) Häggström J et al., J Vet Intern Med 2008, 22: 1124-1135 (7) Häggström J et al., J Vet Intern Med 2013, 27: 1452-1462 (8) Lombard CW et al., J Am Anim Hosp Assoc 2006, 42: 249-261 (9) Ouellet M et al., J Vet Intern Med 2009, 23: 258-263 (10) Schneider P et al., Exp Toxic Pathol 1997, 49: 217-224 (11) Summerfield NJ et al., J Vet Intern Med 2012, 26: 1337-1349 (12) Tissier R et al., Cardiovascular Toxicology 2005, 5(1): 43-51 (13) WO 2005/092343 (14) WO 2007/054514 (15) WO 2015/082389 (16) www.epictrial.com
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Claims (12)
- 一種匹莫苯坦(pimobendan)之用途,其係用於製造用於以下的藥劑:在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭,更佳由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭的患者中減小心臟大小及/或延遲臨床症狀之發作,及/或在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲心臟衰竭之發作,較佳在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作,更佳在患有由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作。
- 一種匹莫苯坦之用途,其係用於製造用於以下之藥劑:在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭,更佳由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭的患者中減小心臟大小及延遲臨床症狀之發作,及在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲心臟衰竭之發作,較佳在患有由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作,更佳在患有由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)心臟衰竭的患者中延遲充血性心臟衰竭之發作。
- 如請求項1或2之用途,其中該由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)心臟衰竭,較佳由二尖瓣疾病(MVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭,更佳由黏液瘤性二尖瓣疾病(MMVD)所致之無症狀(隱發性,臨床前)充血性心臟衰竭係屬於ISACHC I級、較佳ISACHC IA級或IB級之階段,更佳屬於ISACHC IB級、NYHA I級及ACVIM B2階段之階段。
- 如請求項1或2之用途,其中相比於基線,亦即匹莫苯坦治療開始之前,較佳在用匹莫苯坦治療10至100天內,更佳約30至40天內,最佳約35天內,該匹莫苯坦治療實現該患者之已病理性擴大的心臟之心臟大小減小,較佳減小至少5%,更佳至少10%、15%、20%、25%或至少30%。
- 如請求項1或2之用途,其中該匹莫苯坦治療與安慰劑治療或非匹莫苯坦治療相比,實現該患者之存活時間延長至少30天,更佳至少2個月,甚至更佳至少3個月,甚至更佳至少4個月,甚至更佳至少5個月,甚至更佳至少6個月,甚至更佳至少7個月,甚至更佳至少8個月,甚至更佳至少9個月,甚至更佳至少10個月,甚至更佳至少11個月,甚至更佳至少12個月,甚至更佳至少13個月,甚至更佳至少14個月,甚至更佳至少15個月。
- 如請求項1或2之用途,其中該匹莫苯坦治療實現不呈現充血性心臟衰竭之臨床症狀的臨床前期延長,實現充血性心臟衰竭之(臨床症狀之)發作延遲,與安慰劑治療相比增加經治療患者之存活時間,提高經治療患者之生活品質,引起經治療患者之心臟大小與基線(亦即,治療開始之前)相比減小,改進經治療患者之心臟功能/輸出,減少患者之由心臟原因所致之心源性猝死/安樂死及/或降低達到充血性心臟衰竭之風險。
- 如請求項1或2之用途,其中該患者係哺乳動物,較佳係人類、狗、貓或馬,更佳係狗。
- 如請求項1或2之用途,其中匹莫苯坦之日劑量係0.2毫克/公斤至0.6毫克/公斤體重,較佳0.5毫克/公斤體重。
- 如請求項8之用途,其中該匹莫苯坦日劑量係按兩個0.1毫克/公斤至0.3毫克/公斤體重之劑量,較佳兩個0.1毫克/公斤至0.3毫克/公斤體重之劑量每12小時,更佳兩個0.25毫克/公斤體重之劑量每12小時投與。
- 如請求項1或2之用途,其中該藥劑係用於經口或非經腸投與,較佳經口投與,更佳以錠劑或膠囊形式經口投與,最佳以錠劑形式經口投與。
- 如請求項1或2之用途,其中該藥劑進一步包含一或多種選自由ACE抑制劑,較佳貝那普利(benazepril);及利尿劑,較佳呋喃苯胺酸組成之群的額外的有效藥劑成分,或該藥劑係在投與該一或多種額外的有效藥劑成分之前、期間或之後投與。
- 如請求項11之用途,其中該藥劑進一步包含貝那普利及/或呋喃苯胺酸,較佳貝那普利及呋喃苯胺酸,或該藥劑係與貝那普利及/或呋喃苯胺酸,較佳貝那普利及呋喃苯胺酸並行投與。
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Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
ES2924478T3 (es) | 2012-03-15 | 2022-10-07 | Boehringer Ingelheim Vetmedica Gmbh | Formulación de comprimidos farmacéuticos para el sector médico veterinario, método de producción y uso de los mismos |
CN113181110A (zh) | 2013-07-19 | 2021-07-30 | 勃林格殷格翰动物保健有限公司 | 含有防腐的醚化的环糊精衍生物的液体水性药物组合物 |
WO2015082389A1 (en) | 2013-12-04 | 2015-06-11 | Boehringer Ingelheim Vetmedica Gmbh | Improved pharmaceutical compositions of pimobendan |
US10537570B2 (en) * | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
EP4034099A4 (en) * | 2019-10-23 | 2023-10-25 | Piedmont Animal Health Inc. | FORMULATION OF PIMOBENDANE AND METHOD OF USE |
WO2022073954A1 (en) | 2020-10-08 | 2022-04-14 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan in the anaesthesia of non-human mammals |
WO2023006718A1 (en) | 2021-07-28 | 2023-02-02 | Boehringer Ingelheim Vetmedica Gmbh | Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in non-human mammals excluding felines, in particular canines |
Family Cites Families (133)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1045031A (en) | 1963-04-30 | 1966-10-05 | Iwao Kawakami | Dentifrice |
US3574859A (en) | 1968-07-05 | 1971-04-13 | Carl M Kosti | Process for the treatment of hypertrophied gums |
US3822349A (en) | 1969-06-02 | 1974-07-02 | C Kosti | Vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue |
CA950833A (en) | 1971-02-02 | 1974-07-09 | Carl M. Kosti | Composition for the treatment of hypertrophied oral tissue |
GB1338169A (en) | 1971-03-09 | 1973-11-21 | Smith Kline French Lab | Ureas thioureas and guanidines |
US3832460A (en) | 1971-03-19 | 1974-08-27 | C Kosti | Anesthetic-vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue |
US3839522A (en) | 1971-08-02 | 1974-10-01 | Batley Janss Enterprises | Process for the manufacture of dog bedding |
CH630808A5 (en) | 1976-05-08 | 1982-07-15 | Uscio Heinz D | Process for aromatising pharmaceutical preparations for veterinary medicine |
GB1565966A (en) | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
ES8101067A1 (es) | 1978-08-25 | 1980-12-01 | Thomae Gmbh Dr K | Procedimiento para la preparacion de nuevos bencimidazoles sustituidos en posicion 5 o 6 con un anillo de piridazinona |
DE2841668A1 (de) | 1978-09-25 | 1980-04-10 | Bayer Ag | Medikiertes tierfutter auf basis lebermehl |
US4256743A (en) | 1979-02-22 | 1981-03-17 | President And Fellows Of Harvard College | Inhibition of bone resorption with H1 -blocking antihistamines |
JPS6056143B2 (ja) | 1979-08-02 | 1985-12-09 | 山之内製薬株式会社 | アミジン誘導体ならびにその製造法 |
US4293557A (en) | 1979-07-03 | 1981-10-06 | Teikoku Hormone Mfg. Co., Ltd. | Antiulcer phenoxypropylamine derivatives |
US4375547A (en) | 1980-10-02 | 1983-03-01 | Eli Lilly And Company | N-Methyl-N'-2-([(2-dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl 2-nitro-1,1-ethenediamine |
IT1209431B (it) | 1980-11-28 | 1989-07-16 | Angeli Inst Spa | Imidazolilfenil amidine, processi per la loro preparazione e loro impiego farmaceutico, ed intermedi di preparazione. |
DE3124090A1 (de) | 1981-06-19 | 1983-01-05 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue orale dipyridamolformen |
US4704284A (en) | 1982-08-12 | 1987-11-03 | Pfizer Inc. | Long-acting matrix tablet formulations |
DE3237575A1 (de) | 1982-10-09 | 1984-04-12 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue orale mopidamolformen |
GB8313217D0 (en) | 1983-05-13 | 1983-06-22 | Glaxo Group Ltd | Pharmaceutical compositions |
JPS59222406A (ja) | 1983-06-01 | 1984-12-14 | Teijin Ltd | 歯周疾患治療用製剤及びその製造法 |
US4732915A (en) | 1983-11-02 | 1988-03-22 | Alza Corporation | Process for increasing solubility of drug |
DE3346123A1 (de) | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | Pharmazeutische praeparate von in wasser schwerloeslichen oder instabilen arzneistoffen und verfahren zu ihrer herstellung |
GB8400863D0 (en) | 1984-01-13 | 1984-02-15 | Smith Kline French Lab | Chemical compounds |
US6407079B1 (en) | 1985-07-03 | 2002-06-18 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
ZW20586A1 (en) | 1985-10-17 | 1988-05-25 | Smith Kline French Lab | Chemical compounds |
IE63321B1 (en) | 1986-02-03 | 1995-04-05 | Elan Corp Plc | Drug delivery system |
JPH0759496B2 (ja) | 1986-03-25 | 1995-06-28 | ロ−ト製薬株式会社 | 歯周病治療剤 |
JPS62223112A (ja) | 1986-03-25 | 1987-10-01 | Rooto Seiyaku Kk | 歯周病治療剤 |
IT1204901B (it) | 1986-06-25 | 1989-03-10 | Iscofar Sas | Composizioni contenenti acido usnico o suoi derivati atte all'impiego nel trattamento della carie dentaria |
ZA878182B (en) | 1986-11-05 | 1988-05-02 | Merrell Dow Pharmaceuticals Inc. | Enhancement of prazosin |
US4868182A (en) | 1986-11-05 | 1989-09-19 | Merrell Dow Pharmaceuticals Inc. | Enhancement of prazosin |
NL193682C (nl) | 1987-05-14 | 2000-07-04 | Glaxo Group Ltd | Beklede cefuroximaxetilsamenstelling. |
DE3728244A1 (de) | 1987-08-25 | 1989-03-09 | Thomae Gmbh Dr K | Neue (-)-benzimidazole, deren herstellung und diese verbindungen enthaltende arzneimittel |
EP0306846A3 (de) | 1987-09-11 | 1990-05-02 | Dr. Karl Thomae GmbH | Neue synergistische Kombination bestehend aus einem Phosphodiesterase-Hemmer und einem Thromboxan-A2-Antagonisten und deren Verwendung bzw. Herstellung |
SE8704436D0 (sv) | 1987-11-13 | 1987-11-13 | Pm Konsult Handelsbolag | Anvendning av antisekretoriska substanser for nya indikationer |
US4851226A (en) | 1987-11-16 | 1989-07-25 | Mcneil Consumer Products Company | Chewable medicament tablet containing means for taste masking |
US5002935A (en) | 1987-12-30 | 1991-03-26 | University Of Florida | Improvements in redox systems for brain-targeted drug delivery |
DE3804490A1 (de) | 1988-02-12 | 1989-08-24 | Heumann Pharma Gmbh & Co | Substituierte 6-phenyldihydro-3(2h)-pyridazinone, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
DE3805635A1 (de) | 1988-02-24 | 1989-09-07 | Thomae Gmbh Dr K | Verwendung von benzimidazolen zur herstellung eines arzneimittels mit antiischaemischen wirkungen am herzen und dessen kombinationen mit ss-blockern oder bradycardica |
ES2058503T5 (es) | 1988-03-29 | 1999-04-16 | Univ Florida | Formulaciones farmaceuticas para uso parenteral. |
IE62095B1 (en) | 1988-03-29 | 1994-12-14 | Univ Florida | Pharmaceutical formulations for parenteral use |
EP0349657A1 (en) | 1988-06-06 | 1990-01-10 | Carl Richard Thornfeldt | Manufacture of a medicament for the treatment of teething and colic |
GB8824458D0 (en) | 1988-10-19 | 1988-11-23 | Orion Yhtymae Oy | Substituted pyridazinones |
GB8903130D0 (en) | 1989-02-11 | 1989-03-30 | Orion Yhtymae Oy | Substituted pyridazinones |
US5364646A (en) | 1990-01-10 | 1994-11-15 | Dr. Karl Thomae Gmbh | Oral pharmaceutical forms of pimobendan |
DE4001622A1 (de) | 1990-01-20 | 1991-07-25 | Thomae Gmbh Dr K | Orale arzneimittelformen von pimobendan |
DE4001623A1 (de) | 1990-01-20 | 1991-07-25 | Thomae Gmbh Dr K | Verwendung von benzimidazolen zur herstellung eines zur behandlung von akuten und chronischen obstruktiven atemwegserkrankungen geeigneten arzneimittels |
US5188836A (en) | 1990-07-27 | 1993-02-23 | Warner-Lambert Company | Sustained release formulations |
JPH0489428A (ja) | 1990-07-30 | 1992-03-23 | Kao Corp | 多形核白血球活性化剤 |
GB2251615B (en) | 1991-01-03 | 1995-02-08 | Orion Yhtymae Oy | (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]pro panedinitrile |
JPH0570612A (ja) | 1991-09-12 | 1993-03-23 | Toyobo Co Ltd | 二軸配向ポリエステルフイルム |
US5571533A (en) | 1992-02-07 | 1996-11-05 | Recordati, S.A., Chemical And Pharmaceutical Company | Controlled-release mucoadhesive pharmaceutical composition for the oral administration of furosemide |
DE69523912T2 (de) | 1994-05-20 | 2002-06-27 | Janssen Pharmaceutica Nv | Flubendazole-kautabletten für haustiere |
US20030059471A1 (en) | 1997-12-15 | 2003-03-27 | Compton Bruce Jon | Oral delivery formulation |
JPH11228302A (ja) | 1998-02-18 | 1999-08-24 | Taisho Technos Co Ltd | 抗菌防黴組成物 |
US6476078B2 (en) | 1999-08-11 | 2002-11-05 | Sepracor, Inc. | Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction |
JP2002523475A (ja) | 1998-09-02 | 2002-07-30 | アラーガン・セイルズ・インコーポレイテッド | 防腐したシクロデキストリン含有組成物 |
US20040152664A1 (en) | 1998-09-02 | 2004-08-05 | Allergan, Inc. | Prednisolone compositions |
CN1148190C (zh) | 1998-10-23 | 2004-05-05 | 东丽株式会社 | 用于免疫调节的药物组合物 |
WO2000069414A2 (fr) | 1999-05-17 | 2000-11-23 | D.B.F. | Granules contenant une substance vegetale et leur procede de preparation |
FR2793688B1 (fr) | 1999-05-21 | 2003-06-13 | Ethypharm Lab Prod Ethiques | Microgranules gastroproteges, procede d'obtention et preparations pharmaceutiques |
US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
GB2356346A (en) | 1999-11-19 | 2001-05-23 | Mars Uk Ltd | Food product for oral delivery of a pharmaceutical agent to a non-human animal comprising encapsulated particles of said agent distributed within the product |
WO2001056562A1 (fr) | 2000-02-04 | 2001-08-09 | Takeda Chemical Industries, Ltd. | Compositions d'emulsions stables |
JP4107842B2 (ja) | 2000-03-01 | 2008-06-25 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ポリビニルアルコールを配合した速崩壊性錠剤 |
WO2001097861A2 (en) | 2000-06-21 | 2001-12-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
WO2002000197A1 (en) | 2000-06-27 | 2002-01-03 | Vectura Limited | Method of making particles for use in a pharmaceutical composition |
US6620439B1 (en) | 2000-10-03 | 2003-09-16 | Atul M. Mehta | Chrono delivery formulations and method of use thereof |
UA80393C2 (uk) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Фармацевтична композиція, яка містить інгібітор фде 4, диспергований в матриці |
WO2002049645A1 (en) | 2000-12-18 | 2002-06-27 | Novartis Ag | Therapeutic combination of amlodipine and benazepril |
EP1247456A3 (en) | 2001-02-28 | 2003-12-10 | Pfizer Products Inc. | Palatable pharmaceutical compositions for companion animals |
WO2002070511A1 (en) | 2001-03-02 | 2002-09-12 | Bristol-Myers Squibb Company | Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same |
WO2003012030A2 (en) | 2001-08-01 | 2003-02-13 | University Of Utah, Technology Transfer Office | Isoform-selective inhibitors and activators of pde3 cyclic |
US6669955B2 (en) | 2001-08-28 | 2003-12-30 | Longwood Pharmaceutical Research, Inc. | Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin |
MXPA04008173A (es) | 2002-02-22 | 2004-11-26 | Pharmacia Corp | Formulaciones de farmaco antibiotico oftalmico que contienen un compuesto de ciclodextrina y cloruro de cetil piridinio. |
US20030190343A1 (en) | 2002-03-05 | 2003-10-09 | Pfizer Inc. | Palatable pharmaceutical compositions for companion animals |
DE10209982A1 (de) | 2002-03-07 | 2003-09-25 | Boehringer Ingelheim Pharma | Oral zu applizierende Darreichungsform für schwerlösliche basische Wirkstoffe |
CO5400144A1 (es) | 2002-03-11 | 2004-05-31 | Novartis Ag | Compuestos organicos |
AR040017A1 (es) | 2002-05-17 | 2005-03-09 | Novartis Ag | Combinacion de compuestos organicos |
AU2003223071A1 (en) | 2002-05-23 | 2003-12-12 | Pfizer Inc. | Pharmaceutical combination of PDE5 inhibitors with ACE inhibitors |
SI21223A (sl) | 2002-06-19 | 2003-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Farmacevtska formulacija s stabiliziranim amorfnim donepezilijevim kloridom |
DE10228049A1 (de) | 2002-06-24 | 2004-01-15 | Merck Patent Gmbh | Flüssige Zubereitung enthaltend Oligopeptide |
US20040037869A1 (en) | 2002-08-16 | 2004-02-26 | Douglas Cleverly | Non-animal product containing veterinary formulations |
EP1554267A1 (en) | 2002-10-07 | 2005-07-20 | Artesian Therapeutics, Inc. | Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity |
JP2006509790A (ja) | 2002-11-27 | 2006-03-23 | アルテシアン セラピューティック,インコーポレイティド | 心不全の治療のための混合されたPDE阻害およびβアドレナリン拮抗薬活性または部分的作用薬活性を有する化合物 |
ES2280835T3 (es) | 2002-12-19 | 2007-09-16 | Pharmacia Corporation | Formulacion no higroscopica que comprende un farmaco higroscopico. |
WO2004058726A2 (en) | 2002-12-23 | 2004-07-15 | Artesian Therapeutics, Inc. | CARDIOTONIC COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST β-ADRENERGIC RECEPTORS AND PHOSPHODIESTERASE |
US20050085446A1 (en) | 2003-04-14 | 2005-04-21 | Babu M.K. M. | Fluoroquinolone formulations and methods of making and using the same |
WO2005035505A2 (en) | 2003-09-30 | 2005-04-21 | Artesian Therapeutics, Inc. | Compounds with phosphodiesterase inhibiting and calcium channel blocking activities |
DE102004011512B4 (de) | 2004-03-08 | 2022-01-13 | Boehringer Ingelheim Vetmedica Gmbh | Pharmazeutische Zubereitung enthaltend Pimobendan |
US8980894B2 (en) * | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
EP1579862A1 (en) * | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
JP2005281283A (ja) | 2004-03-31 | 2005-10-13 | Akira Matsumori | ベンズイミダゾール系薬剤の併用医薬 |
BRPI0509592A (pt) | 2004-05-06 | 2007-09-25 | Cydex Inc | formulações de sabor mascarado, contendo sertralina e ciclodextrina de éter de sulfoalquila |
FI20040675A0 (fi) | 2004-05-12 | 2004-05-12 | Orion Corp | Menetelmä sydämen hypertrofian hoitoon ja estoon |
CN1976751A (zh) | 2004-06-28 | 2007-06-06 | H.隆德贝克有限公司 | 释放化学物质的多孔物品 |
NZ534939A (en) | 2004-08-26 | 2007-04-27 | Bomac Research Ltd | Injectable formulation comprising an anthelmintic compound with complexing compound for improved solubility |
US20080255134A1 (en) | 2004-11-30 | 2008-10-16 | Artesian Therapeutics, Inc. | Cardiotonic Compounds With Inhibitory Activity Against Beta-Adrenergic Receptors And Phosphodiesterase |
CA2588949A1 (en) | 2004-11-30 | 2006-06-08 | Artesian Therapeutics, Inc. | Compounds with mixed pde-inhibitory and .beta.-adrenergic antagonist or partial agonist activity for treatment of heart failure |
CN1702243A (zh) | 2005-05-31 | 2005-11-30 | 刘坚雄 | 无壁板框架结构装配组合式房屋建筑及其建造方法 |
EP1903039A4 (en) | 2005-06-13 | 2010-09-22 | Takeda Pharmaceutical | INJECTION |
KR20080055956A (ko) | 2005-09-29 | 2008-06-19 | 레프로스 쎄라피우틱스 아이엔씨. | 향상된 생체이용률을 가지며, 스테로이드 유도체와폴리글리콜리세드 글리세리드를 포함하는 제제 |
FR2891459B1 (fr) | 2005-09-30 | 2007-12-28 | Flamel Technologies Sa | Microparticules a liberation modifiee d'au moins un principe actif et forme galenique orale en comprenant |
EP3210605A1 (en) | 2005-11-14 | 2017-08-30 | Boehringer Ingelheim Vetmedica GmbH | Use of pde iii inhibitors for the treament of asymptomatic (occult) heart failure |
JP4572300B2 (ja) | 2006-01-19 | 2010-11-04 | トーアエイヨー株式会社 | ピモベンダン経口投与製剤 |
KR20090010953A (ko) | 2006-03-28 | 2009-01-30 | 자블린 파머슈티칼스 인코포레이티드 | 저 복용량의 비-스테로이드성 항염증성 약물 및 베타-사이클로덱스트린 제형 |
PE20080697A1 (es) | 2006-05-03 | 2008-08-05 | Boehringer Ingelheim Int | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
FR2917975B1 (fr) | 2007-06-26 | 2009-10-16 | Ceva Sante Animale Sa | Compositions et traitement de l'insuffisance cardiaque chez les animaux mammiferes non humains |
EP2057982A1 (en) | 2007-11-09 | 2009-05-13 | Archimedes Development Limited | Intranasal compositions |
EP2106786A1 (de) | 2008-04-04 | 2009-10-07 | Roewer, Norbert, Univ.-Prof. Dr. med. | Pharmazeutische Zubereitung mit permethyliertem Cyclodextrin |
FR2934156B1 (fr) | 2008-07-23 | 2010-09-24 | Virbac | Medicament appetissant a administration orale sous forme solide |
WO2010055119A2 (en) | 2008-11-17 | 2010-05-20 | Novartis Ag | Pharmaceutical composition comprising pimobendan |
PT2370070E (pt) | 2008-11-25 | 2013-11-18 | Boehringer Ingelheim Vetmed | Utilização de pimobendano para o tratamento da cardiomiopatia hipertrófica felina |
US20100166857A1 (en) | 2008-12-30 | 2010-07-01 | Dong Yan | Pharmaceutical dosage forms and methods of manufacturing same |
GB0912646D0 (en) | 2009-07-21 | 2009-08-26 | Jagotec Ag | Improvements in or relating to organic compounds |
EP2417975A4 (en) | 2009-08-31 | 2012-11-14 | Xi An Libang Medical Technology Co Ltd | FULVESTRANT NANOPERLENES / MICROPERLES AND MANUFACTURING METHOD AND USE |
EP2485716A2 (en) | 2009-10-07 | 2012-08-15 | LEK Pharmaceuticals d.d. | Pharmaceutical composition comprising poorly soluble active ingredient and hyperbranched polymer |
NL1037569C2 (en) | 2009-12-18 | 2011-06-21 | Eurovet Animal Health B V | Crystalline pimobendan, process for the preparation thereof, pharmaceutical composition and use. |
EP2338480A1 (en) | 2009-12-22 | 2011-06-29 | LEK Pharmaceuticals d.d. | Coating of particles comprising a pharmaceutically active ingredient with a carbonate salt or phosphate salt |
CA2778748A1 (en) | 2011-06-01 | 2012-12-01 | Nitto Denko Corporation | Particulate preparation and method for producing the same |
JP5813391B2 (ja) | 2011-06-24 | 2015-11-17 | 日東電工株式会社 | 粒子製剤の製造方法 |
MX2014001556A (es) | 2011-08-12 | 2014-03-31 | Boehringer Ingelheim Vetmed | Composicion farmaceutica de sabor enmascarado. |
AU2012101682B4 (en) | 2011-11-20 | 2013-10-24 | Betrola Investments Pty Limited | Formulation |
ES2560052T5 (es) | 2011-12-21 | 2024-06-07 | Elanco Tiergesundheit Ag | Comprimido bicapa que comprende clorhidrato de benazepril y pimobendan |
ES2924478T3 (es) | 2012-03-15 | 2022-10-07 | Boehringer Ingelheim Vetmedica Gmbh | Formulación de comprimidos farmacéuticos para el sector médico veterinario, método de producción y uso de los mismos |
GB201207886D0 (en) | 2012-05-04 | 2012-06-20 | Jagotec Ag | Improvements in or relating to organic compounds |
NZ701609A (en) | 2012-05-18 | 2016-09-30 | Luoda Pharma Pty Ltd | Liquid formulation comprising propylene glycol and an inodilator |
FR3002736B1 (fr) | 2013-03-04 | 2015-06-26 | Virbac | Composition orale nutritionnelle et medicamenteuse a usage veterinaire |
CN113181110A (zh) | 2013-07-19 | 2021-07-30 | 勃林格殷格翰动物保健有限公司 | 含有防腐的醚化的环糊精衍生物的液体水性药物组合物 |
WO2015082389A1 (en) | 2013-12-04 | 2015-06-11 | Boehringer Ingelheim Vetmedica Gmbh | Improved pharmaceutical compositions of pimobendan |
US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
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KR20180127493A (ko) | 2018-11-28 |
AU2017245601B2 (en) | 2020-11-05 |
EP3439660B1 (en) | 2024-05-01 |
WO2017174571A1 (en) | 2017-10-12 |
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EP3439660A1 (en) | 2019-02-13 |
AU2017245601C1 (en) | 2022-02-17 |
KR20220070047A (ko) | 2022-05-27 |
BR112018068448A2 (pt) | 2019-01-22 |
MX2018012201A (es) | 2018-12-10 |
CA3018436A1 (en) | 2017-10-12 |
DK3439660T3 (da) | 2024-06-17 |
JP2020169187A (ja) | 2020-10-15 |
AU2020102685C4 (en) | 2022-03-03 |
LT3439660T (lt) | 2024-06-25 |
US20170290829A1 (en) | 2017-10-12 |
KR102630900B1 (ko) | 2024-01-31 |
FI3439660T3 (fi) | 2024-05-31 |
AU2017245601A1 (en) | 2018-09-06 |
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