TWI740852B - 使用醫藥上活性之經酚性羥基基團聯結之乙醯胺酚二聚體治療疼痛之方法 - Google Patents
使用醫藥上活性之經酚性羥基基團聯結之乙醯胺酚二聚體治療疼痛之方法 Download PDFInfo
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- TWI740852B TWI740852B TW105134362A TW105134362A TWI740852B TW I740852 B TWI740852 B TW I740852B TW 105134362 A TW105134362 A TW 105134362A TW 105134362 A TW105134362 A TW 105134362A TW I740852 B TWI740852 B TW I740852B
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- acetaminophen
- dimer
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Abstract
本發明提供用於治療個體中諸如急性或慢性疼痛之疼痛而不存在肝毒性風險的方法。若投與乙醯胺酚單體，則該個體可能會處於肝毒性風險下。該方法包括投與含有乙醯胺酚二聚體化合物之醫藥組合物，其中兩種乙醯胺酚化合物之酚性羥基基團係經由伸乙基間隔基聯結。
Description
化學上命名為N-乙醯基-對胺酚之乙醯胺酚(式1)在美國為使用最廣泛的藥物之一。
乙醯胺酚為通常以商標名Tylenol®銷售之非處方鎮痛解熱劑。乙醯胺酚歸類為溫和的鎮痛劑。其常用於緩解頭痛及其他輕微疼痛，且為諸多感冒及流感治療物中的主要成分。乙醯胺酚與類鴉片鎮痛劑，諸如可待因(codeine)、羥考酮及氫可酮組合亦可用於管理較為嚴重之疼痛(諸如術後疼痛)且在晚期癌症患者中提供緩解性照護。
當以適當治療劑量投與時，乙醯胺酚視為安全且無害的。不利的是，藥物之誤用及過量可導致肝毒性，且甚至導致死亡。
乙醯胺酚誘導之肝毒性係由肝對乙醯胺酚單體之代謝受損引起。乙
醯胺酚具有單一酚性羥基基團，其賦予光不穩定性且在肝中經受快速的預全身性代謝(首次代謝)，且在腎臟及腸道中達到較低程度。
乙醯胺酚(例如乙醯胺酚單體)經由與硫酸鹽或葡萄糖苷酸結合以形成硫酸酯或葡萄糖苷酸酯來代謝。小百分比之藥物(約5%至10%)藉由CYP450酶(CYP2E1、1A2、2A6及3A4)氧化以形成肝毒性反應性代謝物N-乙醯基-對苯醌亞胺(NAPQI)。NAPQI可藉由與麩胱甘肽、硫氫基供體快速結合來解毒，且在尿液或膽汁中得以消除。然而，若NAPQI過量或若麩胱甘肽儲存減少，例如比正常少70%，則NAPQI共價結合至肝中的蛋白質之半胱胺醯基硫氫基以形成NAPQI-蛋白質加合物。此等NAPQI-蛋白質加合物靶向肝細胞之粒線體蛋白質及離子通道，導致能量產生喪失、離子失衡及細胞死亡。因此，乙醯胺酚之不當代謝可導致肝細胞損傷、肝功能異常、肝壞死及器官衰竭。
確立給藥標準以將肝毒性風險降至最低。根據用於治療疼痛之乙醯胺酚之經口或經直腸劑量的當前FDA準則，用於成人的最大總日劑量為3g，每隔6小時不超過650mg。對於年齡小於12歲及/或體重小於50kg的兒童而言，最大日劑量為75mg/kg，建議劑量為每隔4至6小時每次劑量10mg/kg至15mg/kg但24小時時段內不超過5個劑量。
對於成人及體重等於或小於50kg之兒童的靜脈內給藥而言，最大總日劑量為4g，每隔6小時不超過1g。對於體重小於50kg之兒童而言，最大總日劑量為24小時內75mg/kg(至多3750mg)，不超過15mg/kg。
對於成人而言，藉由經口投與之乙醯胺酚之最小毒性劑量為約7.5g至約10g，且對於兒童而言，為約150mg/kg至約200mg/kg。成人攝取大於150mg/kg或12g乙醯胺酚視為有罹患肝毒性風險的毒性劑量。兒童
之同等毒性劑量為大於250mg/kg至350mg/kg。
不建議乙醯胺酚用於接受藥物後可能罹患肝毒性的個體。需要具有在需要疼痛緩解之個體中導致肝毒性之較低可能性的鎮痛劑。
在一個態樣中，本文提供一種治療若投與乙醯胺酚單體則具有肝毒性風險之患者中的疼痛(急性或慢性疼痛)或發燒的方法。該方法包括向對其有需要之患者投與治療有效量之醫藥組合物，該醫藥組合物包含醫藥上可接受之載劑或賦形劑及具有下式(1)之乙醯胺酚二聚體化合物：
或其醫藥上可接受之鹽或溶劑合物。
在一些實施例中，患者為成人患者。在其他實施例中，患者為兒科(亦即嬰兒、幼兒或青少年)人類患者。兒科患者可為出生到至多18-21歲之個人。患者可經歷發燒。或者，患者可患有疼痛(急性疼痛或慢性疼痛)。在一些實施例中，患者正在接受癌症治療。在其他實施例中，患者患有腸胃酸過多或腸胃逆流病(GERD)。個體可需要緩解性照護。
醫藥組合物亦可包括巴比妥鹽(barbiturate)、類鴉片、抗組織胺、咖啡鹼、苯海拉明(diphenhydramine)、右甲嗎喃、假麻黃素、其生物類似物、其醫藥等效物或其任何組合。在一些實施例中，醫藥組合物經口、經直腸、舌下、皮下、肌肉內、靜脈內、經皮或經黏膜投與。所投與治療有效量可為約500mg至約1000mg。醫藥組合物可調配為經口錠劑或經延長釋放經口錠劑。
在另一態樣中，本文提供一種治療對其有需要之患者中的疼痛(急性
或慢性疼痛)或發燒而不存在肝毒性風險的方法。該方法包括向患者投與治療有效量之醫藥組合物，該醫藥組合物包含醫藥上可接受之載劑或賦形劑及具有下式(1)之乙醯胺酚二聚體化合物：
或其醫藥上可接受之鹽或溶劑合物。
在一些實施例中，患者為成人患者。在其他實施例中，患者為兒科(亦即嬰兒、幼兒或青少年)人類患者。兒科患者可為出生到至多18-21歲之個人。患者可經歷發燒。或者，患者可患有急性疼痛或慢性疼痛。在一些實施例中，患者正在接受癌症治療。在其他實施例中，患者患有腸胃酸過多或腸胃逆流病(GERD)。
醫藥組合物亦可包括巴比妥鹽、類鴉片、抗組織胺、咖啡鹼、苯海拉明、右甲嗎喃、假麻黃素、其生物類似物、其醫藥等效物或其任何組合。在一些實施例中，醫藥組合物經口、經直腸、舌下、皮下、肌肉內、靜脈內、經皮或經黏膜投與。所投與治療有效量可為約500mg至約1000mg。醫藥組合物可調配為經口錠劑或經延長釋放經口錠劑。
本文所提供之醫藥組合物可用作疼痛舒解劑、退燒劑、睡眠助劑、止咳劑、鎮痛劑及/或咳嗽及感冒助劑。因此，組合物可向個體(例如人類個體)投與以治療疼痛(諸如急性疼痛或慢性疼痛)、發燒、睡眠障礙或問題、咳嗽及/或普通感冒。
自以下〔實施方式〕及圖式，本發明之其他目標、特徵及優點對熟習此項技術者將為顯而易見的。
圖1提供乙醯胺酚二聚體之合成途徑。
圖2說明乙醯胺酚二聚體之代謝穩定性。
圖3說明福馬林爪研究中乙醯胺酚二聚體之鎮痛效應。
本申請案根據35 U.S.C.§ 119(e)主張2015年10月26日申請之美國申請案第14/922,362號的優先權之權益，其揭示內容以引用之方式併入本文中。
本發明部分地基於出人意料地發現乙醯胺酚藉由O-烷基化經由其酚性羥基基團之二聚反應，使得活性劑殘基藉由伸乙基聯結基團橋聯，由此產生相對於活性乙醯胺酚單體之獨特優點。
在特徵為單一酚性羥基基團之類鴉片及其他藥劑中，兩種此類藥劑經由此類基團藉由伸乙基聯結基團共價聯結得到均二聚體，其基本上比其母分子對預全身性代謝更加具有耐受性。伸乙基鍵高度穩定且在特定情況中亦產生其他獨特優點。
根據本發明，乙醯胺酚之二聚效應防止形成母化合物之醌代謝物，該醌代謝物在急性及慢性用途中為肝毒性的。另外，阻斷單體之酚性羥基，二聚反應減少活性劑之離子性質，由此潛在地增強穿過血腦障壁輸送且因此鎮痛。
當描述本發明之化合物、組合物、方法及製程時，除非另外指明，否則以下術語具有以下含義。
如本文所用之術語「一(a/an)」或「該」不僅包括一個要素之態樣，且亦包括超過一個要素之態樣。舉例而言，除非上下文另外明確規定，否則單數形式「一(a/an)」及「該」包括複數個指示物。因此，例如關於「細胞(a cell)」係包括複數個此類細胞且關於「藥劑(the agent)」係包括關於一或多個熟習此項技術者已知之藥劑，以及類似情況等。
術語「約」及「大致」一般應意謂鑒於量測之性質或精確度，所量測量之可接受的誤差程度。典型的例示性誤差程度在所給值或值範圍之20百分比(%)內、較佳在10%內且更佳在5%內。替代地且尤其在生物系統中，術語「約」及「大致」可意謂在所給值之數量級內，較佳在5倍內且更佳在2倍內的值。除非另外說明，否則本文中所給之數量為近似值，意謂當未明確陳述時可推斷術語「約」或「大致」。
術語「急性疼痛」係指持續小於3個月至6個月之疼痛。
術語「慢性疼痛」係指持續延長時間段，例如大於三個月至6個月之疼痛，但疼痛之特徵性病徵可早於或晚於此時段出現。慢性疼痛可為輕微的、極痛苦的、間歇性或連續性的。
術語「發燒」係指人類個體體溫升高而處於約37.7℃(99.9℉)下或超過約37.7℃(99.9℉)。
術語「感染性發燒」係指由感染性病因、病症或疾病導致或與其相關之發燒。此類發燒之常見病因包括上呼吸道及下呼吸道感染、腸胃感染、泌尿道感染及皮膚感染。與感染性疾病相關之非限制性病原體包括病毒、細菌、真菌、酵母菌、原蟲、線蟲及其他寄生蟲。
術語「非感染性發燒」係指由發炎性或贅生性(癌症)病症或疾病導致或與其相關之發燒。非感染性發燒並非歸因於感染性病因、病症或疾病。
在一些情況下，非感染性發燒係由藥物、免疫接種、熱衰竭、曬傷及其類似原因導致。
術語「治療有效量」係指足以改善靶向病症或症狀的治療劑之量。舉例而言，對於所給參數，治療有效量將展示至少5%、10%、15%、20%、25%、40%、50%、60%、75%、80%、90%或至少100%之增加量或減少量。治療功效亦可表示為「成倍」增加或減少。舉例而言，治療有效量可具有超過對照至少1.2倍、1.5倍、2倍、5倍或大於5倍之效應。
術語「治療(treating/treatment)」及其衍生詞係指治療患者，諸如哺乳動物(尤其人類或動物)中疾病或醫學病況(諸如疼痛)，其包括：改善疾病或醫學病況，亦即消除患者中疾病或醫學病況或使其消退；遏制疾病或醫學病況，亦即減緩或遏制患者中疾病或醫學病況發展；或緩解患者中疾病或醫學病況之症狀。術語涵蓋預防性治療疾病或病況以便預防或降低獲取或罹患特定疾病或病況之風險，或預防或降低疾病/病況復發之風險。
術語「投與(administering/administration)」及其衍生詞係指可用於使得藥劑或組合物能夠遞送至生物作用之所需位點的方法。此等方法包括(但不限於)非經腸投與(例如靜脈內、皮下、腹膜內、肌肉內、血管內、鞘內、鼻內、玻璃體內、輸注及局部注射)、經黏膜注射、經口投與、以栓劑形式投與及局部投與(例如貼片、洗劑、乳膏、軟膏及其類似物)。熟習此項技術者將知曉投與治療有效量之本發明化合物以預防或減輕與疾病或病況相關之一或多種症狀的其他方法。
術語「醫藥上可接受之」載劑、稀釋劑或賦形劑為可與調配物之其他成分相容且對其接受者無害的載劑、稀釋劑或賦形劑。
如本文所用之術語「組合物」意欲涵蓋包含呈指定量之指定成分之
產品，以及直接或間接由呈指定量之指定成分之組合而產生之任何產物。
術語「肝毒性(hepatotoxicity)」或「肝毒性(hepatic toxicity)」係指由化學物、藥物或有毒物質導致之肝損傷或肝損害。肝損傷會導致器官不恰當地運作。
術語「個體」、「個人」或「患者」係指動物，諸如哺乳動物，包括(但不限於)靈長類動物(例如人類)、母牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠及其類似動物。
本文提供緩解若投與乙醯胺酚單體藥物則處於肝毒性風險或懷疑有肝毒性風險之個體(例如人類個體)中之發燒及/或疼痛的方法。個體可具有比正常健康個人更高的風險。該等方法包括投與使得疼痛減輕或退燒的有效量之含有本文所述之乙醯胺酚二聚體及醫藥上有效之載劑或賦形劑的組合物。該方法部分地基於發現與乙醯胺酚單體相比，乙醯胺酚二聚體較不可能誘導肝毒性。因此，尤其對於處於乙醯胺酚誘導之肝毒性風險下的個體而言，含有乙醯胺酚二聚體之組合物要優於乙醯胺酚單體。
若服用乙醯胺酚單體則處於肝毒性風險下之個體包括產生過量NAPQI之彼等個體、體內麩胱甘肽儲存減少之彼等個體及CYP酶活性增加之彼等個體。在一些實施例中，麩胱甘肽儲存減少係由以下各者導致或與以下各者相關：年齡較大、飲食受限、潛在肝病或腎病或營養狀況不佳(例如空腹、進食障礙、囊腫性纖維化、胃腸炎、慢性酒精中毒或病毒性病況)。CYP酶活性增加可與例如以下各者相關：長期飲酒、抽菸或服用諸如異菸肼(isoniazid)、利福平(rifampin)、苯妥英(phenytoin)、苯巴比
妥(phenobarbital)、巴比妥鹽(barbituate)、卡馬西平(carbamazepine)、三甲氧苄二胺嘧啶-磺胺甲基異噁唑(trimethoprim-sulfamethoxazole)及齊多夫定(zidovudine)之藥物。在一些實施例中，處於肝毒性風險下之個體攜有一或多種使個體易患病況之基因突變。或者，個體具有與潛在肝功能異常相關之病況，諸如肝病，包括(但不限於)酒精性肝病、非酒精性脂肪肝病、脂肪肝病、肝硬化、肝癌、吉伯氏症候群(Gilbert's syndrome)、布-吉症候群(Budd-Chiari syndrome)、甲狀腺素運載蛋白相關遺傳性澱粉樣變性(transthyretin-related hereditary amyloidosis)、原發性硬化性膽管炎、片吸蟲病及肝炎。
在一些實施例中，處於肝毒性風險下之個體，例如成人個體或兒科個體包括接受重複投與高劑量之乙醯胺酚單體的個體、在一縮短時間間隔接受重複投與適當治療劑量的個體、發燒個體及經口攝入量減少之個體。在一些情況下，乙醯胺酚中毒或毒性係因重複誤用、不當給藥、非故意性多次過量給藥及攝入具有另一肝毒性藥物之乙醯胺酚所導致。
在攝入乙醯胺酚單體之後的個體肝毒性風險可使用Rumack-Matthew列線圖測定，該Rumack-Matthew列線圖描繪相對於攝入時間的乙醯胺酚之血清濃度。Rumack-Matthew列線圖為第一時間點係在注射後4小時處的半對數曲線圖。血清乙醯胺酚水準低於列線圖上Rumack-Matthew線或治療線之個體無肝毒性風險或具有低肝毒性風險。另一方面，乙醯胺酚水準高於列線圖上Rumack-Matthew線或治療線之個體具有肝毒性風險或具有高肝毒性風險或具有肝毒性。參見例如Rumack及Matthew,Pediatrics,1975,55(6)：871-6。
在一些實施例中，處於肝毒性風險下之個體會經歷由乙醯胺酚毒性
導致之一或多種肝毒性症狀。此類症狀之非限制性實例包括在乙醯胺酚攝入之後約0.5小時至約24小時出現的食慾不振、噁心、嘔吐、不適、疲乏、皮膚蒼白及/或發汗；在攝入之後約18小時至約72小時出現的腹痛、腹部壓痛、肝腫大、食慾不振、噁心、嘔吐、心動過速、低血壓及/或排尿減少；及持續噁心、嘔吐、腹痛、脆弱肝邊緣(tender hepatic edge)、肝壞死及與黃疸、凝血病、低血糖及肝性腦病、急性腎衰竭相關之功能異常。
一般而言，最可能受益於本文所述之化合物或組合物之患者為肝功能受損使得依賴代謝而消除的藥物為禁忌的彼等患者。彼等患者可為罹患肝硬化、非酒精性脂肪變性肝炎(NASH，其中肝發炎且具有脂肪沈積)或甚至類似於NASH之非酒精性脂肪肝病或自其恢復的某種患者。另一類別患者包括經歷癌症療法，諸如化學療法或放射療法之彼等患者。特定言之，經歷化學療法之患者通常患有一般的「全系統」虛弱。將受益的又一類別患者為患有腸胃酸過多或腸胃逆流病(GERD)之彼等患者。由於乙醯胺酚二聚體不會刺激腸胃黏膜，所以當用於鎮痛時，其為比NSAIDS更佳之替代物。本發明之化合物及組合物可為選擇用於所有此等類別之患者的鎮痛解熱藥物。
在一些實施例中，診斷或測定接受本文所述之化合物或組合物的個體具有乙醯胺酚誘導之肝毒性。可基於來自分析之結果來作出此類診斷以評估例如個體肝功能、腎功能及血清或血漿中之乙醯胺酚水準。舉例而言，可進行各種臨床測試，包括肝功能測試，諸如丙胺酸胺基轉移酶(ALT)分析、天冬胺酸胺基轉移酶(AST)分析、膽紅素分析及鹼性磷酸酶分析；腎功能測試，諸如電解質分析、BUN分析及肌酸酐分析；尿分
析；及ECG。
在一些實施例中，接受本文所述之化合物或組合物的個體已接受N-乙醯半胱胺酸(NAC)以治療肝毒性。用於乙醯胺酚之解毒劑NAC可在攝入乙醯胺酚之後8小時或大於8小時內向患有肝毒性之個體投與。可經口或靜脈內投與NAC。
在某些實施例中，本文提供包含乙醯胺酚二聚體之醫藥組合物。醫藥組合物可進一步包含醫藥上可接受之載劑。說明性醫藥上可接受之載劑及調配物描述如下。
醫藥組合物亦包括巴比妥鹽(例如布他比妥(butalbital))、類鴉片(例如可待因、氫可酮、羥考酮、曲馬多(tramadol)、芬太尼(fentanyl)、氫嗎啡酮、麥啶(meperidine)、***(methadone)及嗎啡鹼)、抗組織胺(H1拮抗劑、H1反向促效劑、H2抗組織胺、H3抗組織胺、H4抗組織胺及其類似物)、咖啡鹼、苯海拉明、右甲嗎喃、假麻黃素、其衍生物、其生物類似物、其等效物或其任何組合。在一些實施例中，醫藥組合物包括80%至95%乙醯胺酚二聚體及5%至20%布他比妥。在其他實施例中，醫藥組合物包括70%乙醯胺酚二聚體、15%布他比妥及15%咖啡鹼。在一些實施例中，醫藥組合物包括60%乙醯胺酚二聚體、15%布他比妥、15%咖啡鹼及10%可待因。在一個實施例中，醫藥組合物含有85%至95%乙醯胺酚二聚體及5%至15%可待因。組合物可含有90%至95%乙醯胺酚二聚體及5%至10%氫可酮、90%至95%乙醯胺酚二聚體及5%至10%羥考酮或90%至95%乙醯胺酚二聚體及5%至10%曲馬多。醫藥組合物可包括80%至90%乙醯胺酚二聚體及10%至20%苯海拉明。在一些情況下，醫藥組合物包括68.5%
乙醯胺酚二聚體、15%苯海拉明、7.5%右甲嗎喃及10%假麻黃素。
本文揭示之醫藥組合物可包含醫藥上可接受之載劑。在某些態樣中，藉由所投與之特定組合物且藉由用於投與組合物之特定方法部分測定醫藥上可接受之載劑。因此，存在多種本發明之醫藥組合物之適合調配物(參見例如REMINGTON'S PHARMACEUTICAL SCIENCES，第18版，Mack Publishing Co.,Easton,PA(1990))。
如將瞭解，可在任何或所有本文所論述之組合物及治療方法中使用二聚體之醫藥上可接受之鹽代替二聚體或除該二聚體以外，亦使用二聚體之醫藥上可接受之鹽。因此，在特定實施例中，二聚體之醫藥上可接受之鹽(亦即二聚體中任一者之任何醫藥上可接受之鹽)用於本發明之方法中。此等鹽可例如在化合物之最終分離及純化期間原位製備或藉由使呈游離鹼形式之經純化化合物單獨地與適合有機酸或無機酸反應且分離因此形成之鹽來製備。在一些實施例中，二聚體之醫藥上可接受之鹽使用以下各者製備：乙酸、褐藻酸、鄰胺基苯甲酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、甲酸、反丁烯二酸、糠酸、半乳糖醛酸、葡萄糖酸、葡糖醛酸、麩胺酸、乙醇酸、氫溴酸、鹽酸、羥乙基磺酸、乳酸、順丁烯二酸、蘋果酸、杏仁酸、甲磺酸、黏液酸、硝酸、雙羥萘酸、泛酸、苯乙酸、磷酸、丙酸、柳酸、硬脂酸、丁二酸、對胺基苯磺酸、硫酸、酒石酸或對甲苯磺酸。可用於本文所述之方法中的醫藥上可接受之鹽的進一步描述參見例如S.M.Berge等人，「Pharmaceutical Salts」,1977,J.Pharm.Sci.66：1-19，其以全文引用之方式併入本文中。
本發明之二聚體可以非溶劑化形式以及與醫藥上可接受之溶劑(諸如水、乙醇及其類似物)之溶劑化形式存在。一般而言，出於本發明之目
的，溶劑化形式視為等效於非溶劑化形式。在一特定實施例中，二聚體之溶劑化形式為水合物。
一般而言，鹽形式可改良所得治療劑之存放期。合適的鹽合成可提供結晶、較不易於氧化且易於操作之產物。可製備各種鹽以提供穩定且結晶化合物。若干實例為鹽酸鹽、硫酸鹽、對甲苯磺酸鹽、甲磺酸鹽、丙二酸鹽、反丁烯二酸鹽及抗壞血酸鹽。
在某些特定實施例中，此類醫藥組合物調配為經口錠劑或膠囊、經延長釋放之經口錠劑或膠囊(硬明膠膠囊、軟明膠膠囊)、舌下錠劑或膜、經延長釋放之舌下錠劑或膜、液體溶液、糖漿、注射用溶液及經皮貼片。下文較詳細地描述說明性醫藥上可接受之載劑及調配物。
本發明之醫藥組合物以與劑型相容之方式且以將在治療上可有效緩解發燒或疼痛(例如急性或慢性疼痛)之此類量投與。待投與之量視多種因素而定，包括例如個人之年齡、體重、身體活動及膳食以及疼痛之階段或嚴重性。在某些實施例中，劑量大小亦可藉由特定個人中伴隨投與治療劑的任何不良副作用之存在、性質及程度來測定。
本文所提供之二聚體可以諸如以下製劑之習知形式向個體經口投與：膠囊、微膠囊、錠劑、顆粒、粉末、糖衣錠、丸劑、栓劑、經口懸浮液、糖漿、經口凝膠、噴霧、溶液及乳液。適合調配物可藉由常用方法使用諸如以下習知有機或無機添加劑來製備：賦形劑(例如蔗糖、澱粉、甘露醇、山梨醇、乳糖、葡萄糖、纖維素、滑石、磷酸鈣或碳酸鈣)、黏合劑(例如纖維素、甲基纖維素、羥甲基纖維素、聚丙基吡咯啶酮、聚乙烯吡咯啶酮、明膠、***膠、聚乙二醇、蔗糖或澱粉)、崩解劑(例如澱粉、羧甲基纖維素、羥丙基澱粉、經低取代之羥丙基纖維素、碳酸氫鈉、
磷酸鈣或檸檬酸鈣)、潤滑劑(例如硬脂酸鎂、輕質無水矽酸、滑石或月桂基硫酸鈉)、調味劑(例如檸檬酸、薄荷腦、甘胺酸或橙粉)、防腐劑(例如苯甲酸鈉、亞硫酸氫鈉、對羥基苯甲酸甲酯或對羥基苯甲酸丙酯)、穩定劑(例如檸檬酸、檸檬酸鈉或乙酸)、懸浮劑(例如甲基纖維素、聚乙烯吡咯啶酮或硬脂酸鋁)、分散劑(例如羥丙基甲基纖維素)、稀釋劑(例如水)及底蠟(例如可可脂、白凡士林或聚乙二醇)。
乙醯胺酚二聚體化合物可例如呈貼片形式經皮投與。適合調配物可使用諸如(但不限於)以下習知添加劑來製備：滲透或吸收增強劑、聚合物(例如丙烯酸酯、聚丙烯酸酯、丙烯酸聚烷酯、聚醯胺、聚酯、聚碳酸酯、聚醯亞胺、聚苯乙烯、丙烯腈丁二烯苯乙烯、聚丙烯腈、聚丁二烯、聚(對苯二甲酸伸丁酯)、聚(醚碸)、聚(醚)酮、聚乙烯、聚(乙二醇)、聚(對苯二甲酸伸乙酯)、聚丙烯、聚四氟乙烯、苯乙烯-丙烯腈樹脂、聚(對苯二甲酸伸丙酯)、聚胺基甲酸酯、聚乙烯醇縮丁醛、聚氯乙烯、聚偏二氟乙烯、普維酮、聚(乙烯基吡咯啶酮)、聚氯丁二烯、氟彈性體、氯磺化橡膠、羥丙甲纖維素、聚烯烴彈性體、聚丙烯醯胺、氯化聚乙烯、聚醚碸、耐綸、液晶聚合物、聚對苯二甲酸伸乙酯(PET)、聚苯碸、聚鄰苯二甲醯胺聚乙烯醇衍生物、聚乙二醇、乙烯乙酸乙烯酯、聚甲基丙烯酸甲酯、纖維素衍生物(諸如乙基纖維素、羥丙基甲基纖維素)、糖衍生物(膠狀物)(包括山梨醇及甘露醇之衍生物)、聚矽氧油及聚矽氧油衍生物、聚矽氧烷(包括抗胺聚矽氧烷及矽氧烷)、聚合物載劑(例如丙烯酸酯、普維酮及矽氧烷)、抗氧化劑、填充劑及其類似物。聚合物載劑亦可包含惰性載劑組分，諸如抗黏著劑、增黏劑及塑化劑以達成適用於聚合物載劑之柔軟度、可撓性及黏性以使得組合物能夠黏附至皮膚表面，且因此提供恆定
遞送。經皮調配物之額外描述見於例如Walters,KA.DERMATOLOGICAL AND TRANSDERMAL FORMULATIONS.Boca Raton：CRC Press,2002中。
液體劑型可藉由以下方法製備：在載劑，諸如水性鹽水(例如0.9%w/v氯化鈉)、水性右旋糖、甘油、乙醇及其類似物中溶解或分散乙醯胺酚二聚體化合物及視情況選用之一或多種醫藥上可接受之佐劑以形成例如用於經口、局部或靜脈內投與之溶液或懸浮液。在一些實施例中，液體劑型為無菌的。
治療有效劑量亦可以凍乾形式提供。此類劑型可包括緩衝液(例如碳酸氫鹽)用於在投與之前復原，或緩衝液可包括於凍乾劑型中以用例如水復原。凍乾劑型可進一步包含適合血管收縮劑，例如腎上腺素。凍乾劑型可在注射器中提供，視情況與用於復原之緩衝液組合封裝，使得經復原劑型可即刻向個人投與。
用於製備此類劑型之方法為一般熟習此項技術者所已知(參見例如REMINGTON'S PHARMACEUTICAL SCIENCES，第18版，Mack Publishing Co.,Easton,PA(1990))。劑型通常包括習知醫藥載劑或賦形劑且可額外包括其他藥劑、載劑、佐劑、稀釋劑、組織滲透增強劑、增溶劑及其類似物。可根據特定劑型及投藥途徑藉由此項技術中熟知之方法定製合適賦形劑(參見例如REMINGTON'S PHARMACEUTICAL SCIENCES,同上)。
視個體疼痛之嚴重程度及個體年齡而定，本發明之化合物及組合物可經口、非經腸(例如肌肉內、腹膜內、靜脈內、腦室內、腦池內注射或輸注、皮下注射或植入)、吸入、經鼻、經***、經直腸、舌下或局部投
與途徑來投與。另外，化合物及抗體可單獨或一起調配於含有適合於各投與途徑之習知無毒性醫藥上可接受之載劑、佐劑及媒劑的適合單位劑型中。本發明亦涵蓋投與呈積存劑調配物形式之化合物。
對於治療發燒或急性或慢性疼痛而言，乙醯胺酚二聚體之合適劑量水準一般為每天約0.001至100毫克/公斤患者體重，其可呈單一或多個劑量形式投與。較佳地，劑量水準為每天約0.01mg/kg至約50mg/kg；更佳每天約0.05mg/kg至約10mg/kg。適合的劑量水準可為每天約0.01mg/kg至50mg/kg，每天約0.05mg/kg至10mg/kg，或每天約0.1mg/kg至5mg/kg。在此範圍內，劑量可為每天0.005mg/kg至0.05mg/kg、每天0.05mg/kg至0.5mg/kg、每天0.5mg/kg至5.0mg/kg或每天5.0mg/kg至50mg/kg。
對於經口投與而言，乙醯胺酚二聚體可以錠劑形式提供，該等錠劑含有1.0毫克至1000毫克活性成分，尤其1.0mg、5.0mg、10.0mg、15.0mg、20.0mg、25.0mg、50.0mg、75.0mg、100.0mg、150.0mg、200.0mg、250.0mg、300.0mg、400.0mg、500.0mg、600.0mg、750.0mg、800.0mg、900.0mg、及1000.0mg之活性成分，以針對待治療患者用劑量進行症狀性調整。
在一些實施例中，向個體投與之治療有效量為約500mg至約1000mg，例如約500mg、約600mg、約700mg、約800mg、約900mg或約1000mg。在其他實施例中，向個體投與之治療有效量為約500mg至約1000mg，例如約500mg至約900mg、約500mg至約800mg、約500mg至約700mg、約500mg至約600mg、約900mg至約1000mg、約800mg至約1000mg、約700mg至約1000mg、約600mg至約1000mg、約600
mg至約700mg、約700mg至約800mg或約800mg至約900mg。
乙醯胺酚二聚體或其組合物可每天投與1至6次，例如每天1次、2次、3次、4次、5次或6次。換言之，化合物可每隔24小時投與一次、每隔12小時投與一次、每隔8小時投與一次、每隔6小時投與一次或每隔4小時投與一次。或者，乙醯胺酚二聚體或其組合物可每隔4至6小時或每隔6至8小時投與。
提供以下實例來加以說明，但並非限制所主張之發明。
如圖1中所示合成化合物。
在3頸圓底燒瓶中將乙醯胺酚(1當量)及碳酸鉀(4當量)溶解於無水DMF(10體積)中。將混合物加熱至60℃且添加1,2-二溴乙烷(4當量)。在60℃下攪拌反應混合物16h且TLC分析展示乙醯胺酚消耗量。混合物用MTBE稀釋，冷卻至10℃且用水洗滌。分離有機相，經硫酸鎂乾燥，過濾且濃縮。藉由矽膠層析純化粗產物，得到純產物3。產率：65%。
將化合物3(1當量)、乙醯胺酚(1.2當量)及碳酸鉀(3當量)溶解於無水DMF(10體積)中且在60℃下加熱混合物且將其攪拌14小時。TLC分析展示中間物3之消耗量。混合物用MTBE稀釋且在15℃至20℃用水下洗滌。分離有機相，經硫酸鎂乾燥，過濾且濃縮。藉由矽膠層析純化粗產物，得到純產物4。產率：78%。1H NMR(300MHz,DMSO-d6)：2.14(s,6H,CH3),4.38(t,4H,CH2),6.80(d,4H,Ar),7.44(d,4H,Ar),9.15(s,2H,
NH)。
表1中之醫藥組合物可用於本發明二聚體之經口錠劑。
向患者投與之本文所提供之二聚體劑量變化可相當廣泛且可經受健康照護從業者之判斷。劑量可視個體之年齡、體重及醫學病況以及投與類型而適當地變化。在一個實施例中，每天給與一次劑量。在任何所給情況中，本文所提供二聚體之量將視諸如活性組分之溶解性、所用調配物及投藥途徑之因素而定。對於「治療有效劑量」，吾人意謂在統計學上顯著數目之患者中產生可觀且有利效應的劑量。在某些實施例中，患者為哺乳動物。在更具體實施例中，患者為人類。在某些特定實施例中，患者可為馴養哺乳動物，諸如狗、貓或馬。
用於處於由乙醯胺酚單體導致之肝毒性風險下之患者的較佳經口投與劑量例如為約500mg至約1000mg，較佳為500mg至約800mg、更佳約600mg。表2提供與單體相比用於較佳適應症的根據本發明二聚體之例示性劑量。
乙醯胺酚二聚體可與一或多種用作睡眠助劑、止咳劑(咳嗽抑制劑)、鎮痛劑以及咳嗽及感冒藥之其他化合物組合。表3中提供乙醯胺酚二聚體與至少一種醫藥化合物之例示性組合。組合中乙醯胺酚二聚體之百分比可為總體之50%至99%。組合中乙醯胺酚二聚體之經口投與劑量可為約500mg至1000mg。在一些情況下，含有85%乙醯胺酚二聚體及15%布他比妥之組合物可用於緩解疼痛或發燒且作為睡眠助劑。在其他情況下，含有85%乙醯胺酚二聚體、15%布他比妥、15%咖啡鹼及10%可待因之組合物可用作止咳劑。
鎮痛劑組合可作為經口錠劑、液體溶液、糖漿、注射液或經皮貼片投與。睡眠助劑組合或咳嗽及感冒助劑組合可作為經口錠劑、液體溶液或糖漿投與。
使用Tecan®液體處置系統或等效物，在37±1℃下在含有磷酸鉀緩衝液(50mM，pH 7.4)、MgCl2(3mM)及EDTA(1mM，pH 7.4)之0.2mL培育混合物(最終體積)中用輔因子NADPH產生系統以96孔板格式中所指示之最終濃度進行用人類肝微粒體(例如1毫克蛋白質/毫升)培育上文所述
之乙醯胺酚二聚體(例如1μM)。NADPH產生系統由NADP(1mM，pH 7.4)、葡萄糖-6-磷酸鹽(5mM，pH 7.4)及葡萄糖-6-磷酸脫氫酶(1單位/毫升)組成。將乙醯胺酚二聚體溶解於甲醇水溶液(甲醇0.5% v/v或小於0.5% v/v)中。反應通常藉由添加輔因子開始，且在四個指定時間點(例如至多60分鐘)處藉由添加相等體積之中止試劑(例如乙腈，含有內標物之0.2mL)中止。零時培育充當100%值以測定基質之損失%。樣品經受離心(例如在10℃下，920×g持續10分鐘)且藉由LC-MS/MS分析清液層部分。用微粒體及標記物基質(例如丙咪嗪、普萘洛爾(propranol)、特非那定(terfenadine)及維拉帕米(verapamil))，以監測基質損失)作為陽性對照進行額外培育以測定測試系統是否具有代謝能力。
以上樣品藉由LC-MS/MS方法分析。在各培育溶液下進行樣品分析。藉由比較實驗時程內峰值比率來測定結果(通常報導為「剩餘的母體%」)。
用實驗室資訊管理系統，諸如GALILEO LIMSTM(Thermo Fisher Scientific Inc.)及報導工具(例如SAP® Crystal Reports®)及試算表電腦程式Microsoft® Excel®或其等效物計算資料。基於分析物/內標物(IS)峰面積比率使用LIMS、Analyst® Instrument Control及資料處理軟體(Data Processing Software)(AB SCIEX)或其等效物估算未變化之母化合物之量(以測定各培育中剩餘的大致基質%)。
結果在圖2中展示且指示乙醯胺酚二聚體在微粒體酶存在下相對穩定長達分析之持續時間。微粒體酶通常負責諸如乙醯胺酚之藥物代謝。
二聚體在微粒體存在下在存在或不存在輔因子下為穩定的。分析在1小時處終止，因為酶在37℃之培育溫度下超過1小時後通常為不穩定的。
程序：將稱重為23±3g之雄性ICR小鼠各分成8組。在向一個後爪投與福馬林之次種植器注射液(0.02ml 2%溶液)之前，所有測試物質及媒劑對照在非空腹小鼠中經腹膜內投與。在福馬林攻擊之後，以5分鐘時間間隔持續約35分鐘記錄後爪舔舐時間作為測試化合物之鎮痛活性量測。表4中提供研究設計。表5及表6中提供資料。
施用單因子ANOVA接著進行鄧尼特測試(Dunnett's test)來進行媒劑對照與經測試化合物處理之組之間的比較。
圖3展示與媒劑、嗎啡鹼、乙醯胺酚單體及乙二醇醚丁基原啡因相比乙醯胺酚二聚體(ORP-105)之鎮痛效應。與接受其他處理之小鼠相比，接受乙醯胺酚二聚體之彼等小鼠具有最短平均舔舐時間。結果展示乙醯胺酚二聚體為有效的鎮痛劑。其效應快速且大於2×乙醯胺酚單體之效應。乙醯胺酚二聚體之鎮痛效應類似於嗎啡鹼之鎮痛效應。資料展示投與乙醯胺酚二聚體可減輕疼痛，包括諸如即時c纖維介導階段中之急性傷痛刺激及第二階段中出現之敏感。
應理解，本文所述之實例及實施例僅出於說明之目的，且根據其而進行之各種修改或變化將由熟習此項技術者提出且包括在本申請案之精神及範圍內及隨附申請專利範圍之範疇內。在某種程度上，在優先權申請案與本申請案之間存在衝突，任何不一致應有利於本申請案來解決。本文中所引用之所有公開案及專利出於所有目的以全文引用之方式併入本文中。
Claims (6)
- 一種醫藥組合物之用途，其包含醫藥上可接受之載劑或賦形劑及具有下式(1)之乙醯胺酚二聚體化合物：
- 如請求項1之用途，其中該個體正經歷急性疼痛。
- 如請求項1之用途，其中該個體正經歷慢性疼痛。
- 如請求項1之用途，其中該個體患有胃食道逆流病(gastroesophageal reflux disease)。
- 如請求項1之用途，其中該個體患有癌症。
- 如請求項1之用途，其中該醫藥組合物進一步包含巴比妥鹽(barbiturate)、類鴉片、抗組織胺、咖啡鹼、苯海拉明(diphenhydramine)、右甲嗎喃、假麻黃素或其組合。
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| Title |
|---|
| EDWARD LAU, "Handbook of Modern Pharmaceutical Analysis", Chp. 5: Preformulation Studies, Published by Academic Press, 2001. |
| RAMESH KUMAR, SANDEEP JAIN and NEELAM JAIN., "Synthesis and evaluation of acetaminophen derivatives as analgesic, antipyretic and anti-inflammatory agents", Der Pharma Chemica, 2013, 5(3), page 73~78. |
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