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TWI581811B - 包含非晶質形式之阿戈美拉汀（ａｇｏｍｅｌａｔｉｎｅ）之安定調配物及含有其之醫藥組合物 - Google Patents

包含非晶質形式之阿戈美拉汀（ａｇｏｍｅｌａｔｉｎｅ）之安定調配物及含有其之醫藥組合物 Download PDF

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TWI581811B
TWI581811B TW102131714A TW102131714A TWI581811B TW I581811 B TWI581811 B TW I581811B TW 102131714 A TW102131714 A TW 102131714A TW 102131714 A TW102131714 A TW 102131714A TW I581811 B TWI581811 B TW I581811B
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agomelatine
formulation
disease
disorders
amorphous form
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TW102131714A
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TW201412348A (zh
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大衛 樂法格
麥可 林曲
希席兒 波蕊爾
菲利普 樂迪葉
珍 曼紐 皮恩
羅穎
單漢濱
沈裕輝
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施維雅藥廠
中國上海醫藥工業研究院
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Priority claimed from PCT/CN2012/081250 external-priority patent/WO2014040228A1/en
Priority claimed from FR1259064A external-priority patent/FR2995896B1/fr
Application filed by 施維雅藥廠, 中國上海醫藥工業研究院 filed Critical 施維雅藥廠
Publication of TW201412348A publication Critical patent/TW201412348A/zh
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Description

包含非晶質形式之阿戈美拉汀(AGOMELATINE)之安定調配物及含有其之醫藥組合物
本發明係關於式(I)之阿戈美拉汀(agomelatine)或N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺之安定非晶質形式，
其製備方法以及含有其之醫藥組合物。
阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基)]乙醯胺具有頗具價值之藥理特性。
事實上，其具有雙重特徵，一方面，作為褪黑激素能系統之受體之激動劑，且另一方面，作為5-HT2C受體之拮抗劑。該等特性為其於中樞神經系統中且尤其在治療嚴重抑鬱症、季節性情感病症、睡眠病症、心血管疾病、消化系統疾病、因時差引起之失眠及疲勞、食欲病症及肥胖症中提供活性。
阿戈美拉汀、其結晶形式、其複合物、其共晶體、其與醫藥上可接受之酸或鹼之加成鹽、其製備及其於治療中之用途已闡述於專利申請案EP0447285、WO2005/077887、WO2007/015003、WO2007/015002、WO2007/015004、WO2010/097052、 WO2010/102554、CN101955440、WO2011/050742、CN102050756、WO2011/006387、WO2011/075943、CN101774937、WO2011/006387、CN101870662及CN102030673中。
此外，阿戈美拉汀作為活性成份具有極低生物利用度且由此大的個體間變化性之缺點。此低生物利用度部分地與阿戈美拉汀於水中之溶解度有關，其於25℃下小於0.15mg/ml。
鑒於此化合物之醫藥價值及其差的生物利用度，非晶質形式似乎係可能之策略，此乃因已知固體化合物之非晶質形式較其相應結晶形式具有較好之溶解特性。
申請人現已發現阿戈美拉汀具有非晶質狀態，其玻璃態轉變溫度已藉由掃描量熱分析或DSC(「示差掃描量熱法」)於-6℃下經量測。高於此溫度，活性成份經歷向結晶形式之轉變。因此，於環境溫度下保持呈非晶質狀態之阿戈美拉汀係不可能的。
因此，所提出之技術問題係使阿戈美拉汀之非晶質形式於調配物中可用，該調配物與其於醫藥工業中之使用、尤其於慣用條件下在安定性及儲存方面相容。
熟悉此項技術者已知之解決方案係由形成活性成份於固體基質中之分散液組成，該固體基質圍繞該等分子且防止其形成晶格。活性成份於基質內越稀，非晶質形成越多。後果是含有非晶質活性成份之錠劑之大小隨基質實質上增加，對於必須吞嚥其之患者而言，此構成主要弊端。因此，另一挑戰在於最小化所用有利於活性成份同時仍防止晶格形成之基質之量。
已利用存於環糊精或海藻糖中之阿戈美拉汀實施測試，該等環糊精或海藻糖通常用於形成「主體-客體」類型之複合物，但不可能以隨時間安定的方式獲得所尋求類型之複合物。
申請人現已發現可以可再現及工業上可行之方式獲得呈非晶質形式之阿戈美拉汀之安定調配物。此新的安定形式允許設想其於醫藥工業中之用途。此外，其允許高活性成份含量，此獲得與患者所服用完全相容之最終大小之調配物。
由此，本發明係關於阿戈美拉汀之安定非晶質形式。「安定」應理解為當其經受溫度及濕度之變性儲存條件達至少一週時保持阿戈美拉汀之非晶質形式。本發明之溫度及濕度變性條件將係常用的，例如40℃/75% RH(相對濕度)、30℃/65% RH、50℃、70℃......。
更具體而言，本發明係由阿戈美拉汀在有機聚合物中之固體分散液組成，應理解阿戈美拉汀佔分散液之至少30重量%。可端視所選擇之有機聚合物而定增加阿戈美拉汀之此重量%。阿戈美拉汀之重量%為固體分散液之30%至50%、且較佳30%至40%係較佳的。出人意料地，即使在彼等高活性成份含量下，阿戈美拉汀之非晶質形式亦以隨時間安定之方式保持。此外，除通常活性成份之非晶質化可預期改良溶解速率之外，所獲得之阿戈美拉汀之溶解度亦極大增加遠超出結晶阿戈美拉汀所量測之溶解度，其中其至少增至3倍而且於一些情形下增加8倍。此結果完全出人意料，此乃因儘管此領域之許多出版物闡述藉由設計安定固體分散液來改良活性成份之生物醫藥性能(溶解度、溶解速率)，但此係針對小於20%之活性成份之裝載量(Lin等人，International Journal of Pharmaceutics,1996,127,261-272)。
出人意料地，活性成份之溶解度之增加維持達至少4小時。
用於本發明中之聚合物尤其係關於甲基丙烯酸化合物或乙烯基或纖維素聚合物。
更具體而言，本發明所用之聚合物係關於聚甲基丙烯酸酯或甲基丙烯酸之共聚物，其對應於甲基丙烯酸與丙烯酸酯或甲基丙烯酸酯之完全聚合共聚物。此等聚甲基丙烯酸酯通常稱作優特奇(Eudragit®) 並可呈粉劑或顆粒之形式。在市售之不固Eudragit®產品中，彼等用於本發明上下文中之較佳者係Eudragit® L產品，尤其Eudragit® L100及L100-55或Eudragit® EPO。此等聚合物特別地適於所有範圍之阿戈美拉汀裝載量(阿戈美拉汀之重量%)。
本發明之乙烯基聚合物尤其係關於聚乙烯酯，例如聚乙酸鄰苯二甲酸乙烯酯；基於聚乙烯吡咯啶酮之均聚物或共聚物，諸如聚維酮(Povidones)(Povidone® K30、共聚維酮(Plasdone®)S630)、科利當(Kollidon)VA64亦或沙魯加(Soluplus®)。聚維酮將用於低於50重量%之阿戈美拉汀之裝載量。
在本發明所用之纖維素化合物中，可提及纖維素醚或纖維素酯，諸如羥丙基甲基纖維素(HPMC)、且尤其HPMC乙醯基琥珀酸酯。
本發明亦係關於用於獲得於聚合物內具有高含量非晶質形式之阿戈美拉汀之安定調配物之方法。根據本發明之方法，將藉由任一方法所獲得並以任何結晶形式、複合物、共晶體或與醫藥上可接受之酸或鹼之加成鹽存在之式(I)化合物與所選擇聚合物於一或多種允許獲得成份之完全溶解之溶劑中混合，並隨後於減壓下將溶劑全部蒸發掉。
本發明所用之溶劑係彼等能夠溶解阿戈美拉汀及所選擇聚合物者；較佳者係極性質子或非質子溶劑，諸如丙酮、醇且尤其甲醇及乙醇、水、二氯甲烷、乙酸乙酯或彼等溶劑之混合物。於環境溫度下攪拌或藉由加熱混合物實施溶解，直至成份完全溶解為止。於減壓下於環境溫度下或藉由加熱實施溶劑之蒸發，直至溶劑完全蒸發為止。
用於製備於聚合物內具有高含量非晶質形式之阿戈美拉汀之安定調配物之方法之有利實施例係由混合並預摻和藉由任一方法所獲得且以任何結晶形式、複合物、共晶體或與醫藥上可接受之酸或鹼之加成鹽存在之式(I)化合物與所選擇之聚合物組成，並隨後將此混合物引入至螺距及溫度隨混合物黏度之函數選擇之擠出機中以獲得擠出物，隨後將其切成期望大小並隨後視情況研磨。
較佳地，將於50rpm與200rpm之間、尤其於75rpm與150rpm之間實施螺桿之旋轉。
所選擇之擠出溫度將隨所得成份之混合物黏度之函數且將介於90℃與200℃之間且包含90℃及200℃。
於用於獲得本發明之阿戈美拉汀之安定非晶質形式之方法中，可使用藉由任一方法所獲得並以任何結晶形式、複合物、共晶體或與醫藥上可接受之酸或鹼之加成鹽存在之式(I)化合物。
在本發明之方法中，阿戈美拉汀裝載量係大於或等於30重量%且尤其自30重量%至50重量%變化、較佳自30%至40%。
由此所獲得之安定非晶質形式在治療褪黑激素能系統病症中具有價值且對中樞神經系統及微循環展示實質活性，此使其可確立其在治療下列病症中之有效性：壓力、睡眠病症、焦慮症、嚴重抑鬱症、季節性情感病症、躁鬱症、廣泛性焦慮病症、心血管疾病、消化系統疾病、因時差引起之失眠及疲勞、精神分裂症、恐慌發作、憂鬱症、食欲病症、肥胖症、失眠、疼痛、精神病症、癲癇、糖尿病、帕金森氏疾病(Parkinson's disease)、老年性癡呆、與正常或病理性老化相關之各種病症、偏頭痛、記憶力喪失、阿茲海默氏病(Alzheimer's disease)以及腦循環病症。在活性之另一領域中，於治療中阿戈美拉汀之非晶質形式似乎可用於性功能失調中，其具有抑制排卵及免疫調節特性且其可潛在地用於癌症治療中。
阿戈美拉汀之安定非晶質形式較佳將用於治療嚴重抑鬱症、季節性情感病症、躁鬱症、廣泛性焦慮病症、睡眠病症、心血管疾病、消化系統疾病、因時差引起之失眠及疲勞、食欲病症及肥胖症。
獲得阿戈美拉汀之安定非晶質形式具有使得製備一致且可再現組合物之醫藥調配物成為可能之優點，該等醫藥調配物具有隨時間之極佳安定性。
因此，根據本發明可獲得具有高含量之阿戈美拉汀之非晶質形式之固體醫藥組合物，其尤其可藉由經口、經頰、舌下、經眼、直腸、陰道或非經腸途徑投與。
此等醫藥組合物可由聚合物內之阿戈美拉汀之固體分散液構成，而除包裝以外無需任何其他處理操作。然而若需要，該等醫藥組合物可藉由研磨或藉由製粒用於填充至膠囊中或用於壓縮進行處理或可經塗佈。
本發明之醫藥組合物亦可視情況包括(例如)選自下列之群之藥理學上可接受之賦形劑：黏結劑、崩解劑(disintegrating agents,disintegrants)、潤滑劑、稀釋劑、抗氧化劑、芳香劑、著色劑、防腐劑、甜味劑及抗黏著劑。
在本發明之醫藥組合物中，尤其可提及錠劑或糖衣丸、顆粒、舌下錠劑、膠囊、菱形錠劑、栓劑、乳膏、軟膏、皮膚凝膠、可注射製劑、可飲用之懸浮液及口香糖。
較佳地，本發明之醫藥組合物含有相對於調配物之總重量至少25重量%之阿戈美拉汀。
有用劑量可根據病症之性質及嚴重程度、投與途徑及患者之年齡及體重而變化。劑量在每天0.1mg至1mg阿戈美拉汀間變化，一或多次投與。
下文之實例闡述本發明但不以任何方式對其進行限制。
A.藉由溶解-蒸發獲得阿戈美拉汀之安定非晶質形式之一般程序
將阿戈美拉汀及所選擇之聚合物放置於具有3ml溶劑之10-ml小瓶中。將混合物於40℃下攪拌30分鐘直至完全溶解為止並獲得均質溶液。將溶劑於減壓下於40℃下達30分鐘蒸發掉。將所獲得之殘餘物於真空中於環境溫度下(20℃)最終乾燥過夜(12小時)以得到阿戈美拉汀之安定非晶質形式。對於每一測試，於變性條件下於40℃及75% RH下、於40℃及75% RH下隨後50℃以及於70℃下測試非晶質形式之安定性。
所產生之各個實例及所獲得之結果陳述於下表中：
以舉例方式，於各種安定性條件下(於40℃75% RH下1週、於40℃/75% RH下1週隨後於50℃下1週、於70℃下1週)所記錄之實例10、11、12、19及28之X射線繞射圖分別陳述於圖1、圖2、圖3、圖4及圖5中。
B.藉由擠出獲得阿戈美拉汀之安定非晶質形式之一般方法
將阿戈美拉汀與聚合物於Turbula型混合器中預摻和達10分鐘。將所獲得之混合物手動放置於HAAKE Minilab II Microcompounder型(ThermoFisher)之錐形轉子擠出機(直徑5/14mm)中。擠出速度係100rpm。
所獲得之非晶質形式之安定性係於各種溫度及相對濕度條件下評估：25℃/60% RH於敞口或封閉燒瓶中、30℃/65% RH於敞口或封閉燒瓶中、50℃於敞口燒瓶中。
下表中所給出之所有實例均具有大於至少6週之安定性。
以舉例方式，實例39及40於各種安定性條件(25℃/60% RH於敞口或封閉燒瓶中、30℃/65% RH於敞口或封閉燒瓶中、50℃於敞口燒瓶中)下在3個月結束時所記錄之X射線繞射圖分別陳述於圖6及圖7中。
C.溶解度
利用Crystal16®型裝置於pH 6.8緩衝溶液中於25℃下經4小時之時期同時於700rpm之攪拌速度下實施所獲得之調配物之溶解度研究。已測試各種濃度並藉由濁度檢測監測不溶性粒子之存在。作為參考，阿戈美拉汀於彼等條件下之溶解度係0.14mg/ml。
所獲得之結果陳述於下表中，其陳述i)所觀察到之最大溶解度及於觀察到此最大溶解度時之時間、ii)於4小時時所觀察到之溶解度。
所獲得之結果展示最大溶解度之實質增加。重點係此溶解度增加隨時間而繼續：於4小時時，結果展示其至少增加1.7至8.5之範圍內之因子，此在其再沈澱之前給出吸收活性成份之時間。
D.醫藥組合物
實例42
用於製備每粒含有25mg阿戈美拉汀之1000粒膠囊之配方：
根據實例36製備擠出物並隨後切割成為微型基質並納入至1號膠囊中。
實例43
用於製備每粒含有25mg阿戈美拉汀之1000粒膠囊之配方：
根據實例38製備擠出物並隨後切割成微型基質並納入至1號膠囊中。
實例44
用於製備每粒含有25mg阿戈美拉汀之1000粒膠囊之配方：
圖1：於各種安定性條件(於40℃75% RH下1週、於40℃/75% RH下1週隨後於50℃下1週、於70℃下1週)下所記錄之實例10之X射線繞射圖
圖2：於各種安定性條件(於40℃75% RH下1週、於40℃/75% RH下1週隨後於50℃下1週、於70℃下1週)下所記錄之實例11之X射線繞射圖
圖3：於各種安定性條件(於40℃75% RH下1週、於40℃/75% RH下1週隨後於50℃下1週、於70℃下1週)下所記錄之實例12之X射線繞射圖
圖4：於各種安定性條件(於40℃75% RH下1週、於40℃/75% RH下1週隨後於50℃下1週、於70℃下1週)下所記錄之實例19之X射線繞射圖
圖5：於各種安定性條件(於40℃75% RH下1週、於40℃/75% RH下1週隨後於50℃下1週、於70℃下1週)下所記錄之實例28之X射線繞射圖
圖6：實例39於各種安定性條件(25℃/60% RH於敞口或封閉燒瓶中、30℃/65% RH於敞口或封閉燒瓶中、50℃於敞口燒瓶中)下於3個月結束時所記錄之X射線繞射圖
圖7：實例40於各種安定性條件(25℃/60% RH於敞口或封閉燒瓶中、30℃/65% RH於敞口或封閉燒瓶中、50℃於敞口燒瓶中)下於3個月結束時所記錄之X射線繞射圖

Claims (8)

  1. 一種安定調配物，其包含非晶質形式之式(I)之阿戈美拉汀 (agomelatine)，，其中該阿戈美拉汀分散於基質中，該基質係選自優特奇(Eudragit)L100、優特奇(Eudragit)L100-55、科利當(Kollidon)VA64、沙魯加(Soluplus)、聚乙酸鄰苯二甲酸乙烯酯、共聚維酮(Plasdone)S630、羥丙基甲基纖維素(HPMC)乙醯基琥珀酸酯、共聚維酮(Plasdone)S630及聚乙酸鄰苯二甲酸乙烯酯，其中所使用之阿戈美拉汀之重量百分比係自30%至50%，且其中「安定」應理解為當其經受溫度及濕度之變性儲存條件達至少一週時保持阿戈美拉汀之非晶質形式。
  2. 如請求項1之安定調配物，其中所使用之阿戈美拉汀之重量百分比係自30%至40%。
  3. 一種醫藥組合物，其包括作為活性成份之如請求項1或2之安定調配物自身或與一或多種惰性、無毒且醫藥上可接受之載劑之組合。
  4. 如請求項3之醫藥組合物，其中相對於調配物之總重量阿戈美拉汀之重量百分比係大於或等於25%。
  5. 如請求項3或4之醫藥組合物，其用於製造用於治療褪黑激素能系統之病症的藥劑。
  6. 如請求項3或4之醫藥組合物，其用於製造用於治療以下病症之藥劑：睡眠病症、壓力、焦慮症、季節性情感病症或嚴重抑鬱症、心血管疾病、消化系統疾病、因時差引起之失眠及疲勞、 精神分裂症、恐慌發作、憂鬱症、食欲病症、肥胖症、失眠、疼痛、精神病症、癲癇、糖尿病、帕金森氏疾病、老年性癡呆、與正常或病理性老化相關之各種病症、偏頭痛、記憶喪失、阿茲海默氏疾病、腦循環病症以及性功能失調，且作為排卵抑制劑及免疫調節劑且用於癌症治療中。
  7. 如請求項1或2之安定調配物，其用於治療褪黑激素能系統之病症。
  8. 如請求項1或2之安定調配物，其用於治療睡眠病症、壓力、焦慮症、季節性情感病症或嚴重抑鬱症、心血管疾病、消化系統疾病、因時差引起之失眠及疲勞、精神分裂症、恐慌發作、憂鬱症、食欲病症、肥胖症、失眠、疼痛、精神病症、癲癇、糖尿病、帕金森氏疾病、老年性癡呆、與正常或病理性老化相關之各種病症、偏頭痛、記憶喪失、阿茲海默氏疾病、腦循環病症以及性功能失調，且作為排卵抑制劑及免疫調節劑且用於癌症治療中。
TW102131714A 2012-09-11 2013-09-03 包含非晶質形式之阿戈美拉汀（ａｇｏｍｅｌａｔｉｎｅ）之安定調配物及含有其之醫藥組合物 TWI581811B (zh)

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