TW201302673A - 阿戈美拉汀(agomelatine)之新共結晶,其製備方法及包含其之醫藥組合物 - Google Patents
阿戈美拉汀(agomelatine)之新共結晶,其製備方法及包含其之醫藥組合物 Download PDFInfo
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- TW201302673A TW201302673A TW101120779A TW101120779A TW201302673A TW 201302673 A TW201302673 A TW 201302673A TW 101120779 A TW101120779 A TW 101120779A TW 101120779 A TW101120779 A TW 101120779A TW 201302673 A TW201302673 A TW 201302673A
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- acid
- naphthyl
- methoxy
- ethyl
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- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 65
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- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 18
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 14
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Classifications
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Abstract
本發明係關於阿戈美拉汀(agomelatine)之新共結晶,其包括:-阿戈美拉汀或式(I)之N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺□及-有機酸。
Description
本發明係關於阿戈美拉汀或式(I)之N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺之新共結晶:
其製備方法及包含其之醫藥組合物。
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,作為褪黑激素激導性系統之受體之激動劑,且另一方面,作為5-HT2C受體之拮抗劑。該等特性為其提供在中樞神經系統中且更特定而言在治療嚴重抑鬱症、季節性情感障礙、睡眠障礙、心血管病狀、消化系統病狀、因時差引起之失眠及疲勞、食慾障礙及肥胖症中之活性。
阿戈美拉汀、其製備及其在治療中之用途闡述於歐洲專利說明書EP 0 447 285中。
鑒於該化合物之藥理價值,已實施大量研究工作,使得可分離具有多種優點(特定而言,關於純度、穩定性、再現性及調配物特徵等)之不同多晶型,允許長時間儲存而無需關於溫度、光、濕度或氧濃度之特定條件。
此外,正如意欲投與人類之任一活性成分,能夠控制其
溶解速率以促進其快速或(相反地)緩慢溶解係極為重要的。
申請者現已研發阿戈美拉汀之新共結晶,使得可改變活性成分之溶解速率。與闡述於專利說明書EP 1 564 202中且以商標Valdoxan®出售之市場上有售之形式相比,本發明共結晶之溶解速率加速或遲延。因此,該等具有改變溶解性質之新共結晶使得可考慮與期望用途匹配之新調配物。
共結晶係包括至少兩個藉由非共價相互作用於晶格中結合在一起之中性分子的結晶複合物。溶劑合物與共結晶之間之主要差異與純組份之物理狀態有關:若一種成分在環境溫度下係液體,則該分子複合物係溶劑合物;若所有組份在環境溫度下均係固體,則該複合物由術語「共結晶」表示。溶劑合物與共結晶之間之主要差異係共結晶之穩定性遠大於溶劑合物。共結晶之特徵在於其獲得方法及藉由(例如)X-射線繞射圖展示之有序三維結構。不可預先知道兩種給定成分是否將能夠形成具有特定三維結構之共結晶或將僅產生兩種粉末之並置。該特定三維結構與藉此形成之實體之溶解速率具有直接關係。
更具體而言,本發明係關於由一方面阿戈拉美汀且另一方面有機酸形成之新共結晶。本發明之共結晶包括在環境溫度下呈固體狀態之有機酸。
本發明之有機酸係包含2至10個碳原子之直鏈或具支鏈
酸。其具有一或多個COOH酸官能基,且更佳地,一個、兩個或三個酸官能基。除其酸官能基外,其亦可具有一或多個酮官能基、一或多個羥基官能基及/或一或多個不飽和鍵。
在為本發明共結晶之成分之有機酸中,可提及(舉例而言且不暗示任何限制)對羥基苯甲酸、檸檬酸、草酸、沒食子酸、馬來酸、丙二酸、戊二酸、乙醇酸、酮戊二酸等。
與阿戈美拉汀有關之所用有機酸之比例自0.25至4莫耳當量、較佳地自0.5至2莫耳當量變化。
更特定而言,本發明係關於以下共結晶:阿戈美拉汀/對羥基苯甲酸(2/1)及(1/2);阿戈美拉汀/檸檬酸(1/1);阿戈美拉汀/草酸(2/1);阿戈美拉汀/沒食子酸(2/1);阿戈美拉汀/馬來酸(1/1);阿戈美拉汀/丙二酸(1/1);阿戈美拉汀/戊二酸(1/1);阿戈美拉汀/乙醇酸(1/1);阿戈美拉汀/酮戊二酸(1/1)。
本發明亦係關於獲得阿戈美拉汀及有機酸之共結晶之方法,其中:- 將兩種成分以期望比例混合於有機溶劑中(1當量阿戈美拉汀/0.25至4莫耳當量有機酸);- 攪拌所獲得溶液並視情況在不高於所選溶劑之沸點溫度下加熱;- 邊攪拌邊冷卻混合物,且共結晶自然沈澱或在溶解於第二溶劑後沈澱;
- 過濾並乾燥所獲得沈澱。
在本發明之方法中,所用溶劑較佳地係醇,例如甲醇或第三丁醇;醚,例如二異丙醚或甲基第三丁基醚;或芳族烴,例如甲苯。當使用第二溶劑以促進共結晶沈澱時,有利地選擇苄腈。
替代方法包括共研磨共結晶之兩種成分。共研磨較佳地係在鋼罐中實施。該方法之變化形式包括在共研磨期間添加有機溶劑;在此情形下,然後乾燥所獲得共結晶。在所用溶劑中,可提及(更特定而言)諸如乙醇等醇或諸如二異丙醚等醚。
有利於使用不可氧化球實施研磨。其採用振動研磨,較佳研磨頻率在20 Hz至30 Hz範圍內。振動時間可在15分鐘至3小時範圍內。
另一替代方法包括將包含每一成分之兩種溶液混合且在極低溫度下快速冷凍所得混合物,且隨後在該相同低溫下乾燥藉此獲得之共結晶。這兩種成分宜在有機溶劑或水性-有機溶劑中混合。較佳地在-40℃及-60℃之間,且更佳地於-40℃下進行冷凍及乾燥。
本發明之另一有利方法包括在混合器中混合阿戈美拉汀粉末及所述酸粉末,且隨後藉由無模具之雙螺桿擠出機擠出,直接在擠出機出口處獲得固體顆粒狀產物。較佳地,所用螺桿型態係高剪切型態,其視情況使用混合元件,使得可改良兩種成分之間之表面接觸。螺桿之L/D參數可在10至40之間變化,且旋轉速度可在10 rpm至200 rpm之間
變化。所用溫度在40℃至100℃之間變化。
製備本發明共結晶之方法可使用藉由任一方法(尤指藉由闡述於EP 1 564 202中之方法)獲得之式(I)化合物。
本發明共結晶在穩定性及溶解性(醫藥工業中之兩個必要參數)方面呈現高價值之特性。活性成分之溶解性係可決定其在人體內之吸收速率的重要特徵。其係釋放過程中之重要步驟,對藥品之活性具有重大影響。事實上,為跨過生物膜或被吸收,活性成分必須在吸收位點處以分子態分散於水性介質中(亦即,溶解)。活性成分之溶解速率係由其物理-化學特徵且亦由吸收介質之條件管控。因此,重要的是具有可支配形式,該等形式具有改變之活性成分溶解速率,以便配合期望用途讓活性成分較快或較慢溶解:亦即用於即刻釋放調配物之具有改良溶解性之形式,及用於延緩或延遲釋放調配物之具有較慢溶解之形式。
本發明共結晶滿足該要求,此乃因其可改變阿戈美拉汀之溶解速率,使其比目前以醫藥產品Valdoxan®出售之形式之溶解速率提高或減少至高2倍。更具體而言,在中性(pH 6.8)或酸(0.01 N HCl)條件下,與目前以醫藥產品Valdoxan®出售之形式的溶解速率相比,本發明共結晶可以改變活性成分溶解速率至少25%。因此,相對於目前市場上出售形式之溶解速率,可使用本發明共結晶來研發改良之即刻釋放醫藥形式以及延緩溶解速率之延遲釋放形式。
包括本發明共結晶之醫藥形式基於其針對中樞神經系統
及微循環方面之活性,可用於治療應激壓力、睡眠障礙、焦慮症(尤指廣泛性焦慮症)、強迫症、情緒障礙(尤指雙相障礙)、嚴重抑鬱症、季節性情感障礙、心血管病狀、消化系統病狀、因時差引起之失眠及疲勞、精神分裂症、恐慌發作、憂鬱症、食慾障礙、肥胖症、失眠、疼痛、精神障礙、癲癇、糖尿病、帕金森氏病(Parkinson's disease)、老年性癡呆、與正常或病理性老化相關之多種病症、偏頭痛、記憶喪失、阿茲海默氏病(Alzheimer's disease)、及腦循環病症。在另一活性領域中,本發明共結晶可用於性功能障礙,作為排卵抑制劑,及作為免疫調節劑,及用於癌症治療。
本發明共結晶較佳地用於治療嚴重抑鬱症、季節性情感障礙、睡眠障礙、焦慮症、情緒障礙、心血管病狀、消化系統病狀、因時差引起之失眠及疲勞、食慾障礙及肥胖症。
本發明亦係關於包括作為活性成分之本發明共結晶以及一或多種適當惰性無毒賦形劑之醫藥組合物。在本發明之醫藥組合物中,可提及(更特定而言)彼等適於經口、非經腸(靜脈內或皮下)或經鼻投與者,錠劑或糖衣藥丸、顆粒、舌下錠劑、膠囊、菱形錠劑、栓劑、乳霜、軟膏劑、皮膚用凝膠、可注射製劑、可飲用懸浮液及口香糖。
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變化。劑量在每天一或多次投與0.1 mg至1 g阿戈美拉汀間變化。
下文實例闡述本發明但不以任何方式對其進行限制。
將3 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及2.6 g檸檬酸引入100 ml燒瓶中。添加30 ml MeOH且在環境溫度下攪拌溶液20小時。蒸發至乾燥後,將所獲得白色膠溶解於以3 ml逐份添加之30 ml苄腈中。攪拌所獲得懸浮液直至該膠完全轉化成結晶。在過濾並用20 ml苄腈洗滌後,將所獲得固體在環境溫度下於真空中乾燥。藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角(Bragg's angle)2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:5.21°、12.24°、17.07°、19.38°、20.69°、21.90°、22.81°、27.30°。
熔點:126℃至129℃
將316.59 g阿戈美拉汀及250 g檸檬酸單水化物在Turbula型混合器中混合10分鐘。然後藉由無模具之雙螺旋擠出機擠出以直接在擠出機出口處獲得固體顆粒狀產物。將高剪切螺桿型態與混合元件一起使用以改良兩種成分之間之表面接觸。所用螺桿之L/D參數係19。對於以300 g/h量測之進給速率而言,螺桿之旋轉速度係50 rpm。擠出溫度係55℃。所獲得之共結晶藉由其X-射線粉末繞射圖進行表徵,該圖與藉由程序A獲得之圖相同。
在250 ml燒瓶中,將300.6 mg N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺存於15 ml第三丁醇中之溶液緩慢添加至106 mg
沒食子酸存於35 ml水中之溶液中。將混合物攪拌10分鐘且隨後將溶液冷凍至-40℃且在相同溫度下乾燥2天以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:14.47°、17.68°、19.82°、22.33°、23.93°。
熔點:108℃至110℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及482 mg馬來酸引入25 ml不可氧化罐中。添加兩個直徑為12 mm之不銹鋼球且將該罐封閉。施加頻率為30 Hz之振動60分鐘以產
生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:11.30°、15.40°、17.28°、24.29°。
熔點:73℃至75℃
在250 ml燒瓶中,將300 mg N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺存於15 ml第三丁醇中之溶液緩慢添加至129 mg丙二酸存於35 ml水中之溶液中。將混合物攪拌30分鐘且隨後將溶液冷凍至-40℃且在相同溫度下乾燥2天以產生標
題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:10.47°、11.95°、14.78°、16.05°、22.32°、24.50°、25.05°、25.24°、27.38°、27.91°。
熔點:67℃至68℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及283.8 mg對羥基苯甲酸引入25 ml不可氧化罐中。添加兩個直徑為12 mm之不銹鋼球且將該罐封閉。添加200 μl異丙基醚。施加
頻率為30 Hz之振動60分鐘以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:13.16°、14.91°、17.37°、18.39°、18.93°、19.04°、19.65°、19.96°、20.25°、21.49°、25.00°。
熔點:93℃至95℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及1.14 g對羥基苯甲酸與250 μl二異丙醚一起引入25 ml不可氧化罐中。添加兩個直徑為12 mm之不銹鋼球且將該罐封閉。施加頻率為30 Hz之振動120分鐘以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:9.50°、12.28°、14.00°、15.76°、16.18°、16.62°、17.56°、18.15°、19.96°、21.00°、21.30°、22.00°、22.97°、23.55°、23.76°、24.44°、26.09°、26.82°、28.42°、28.71°、29.85°。
熔點:116℃至118℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及185.5 mg草酸引入25-ml不可氧化罐中。添加兩個直徑為12 mm之不銹鋼球且將該罐封閉。施加頻率為30 Hz之振動15分鐘以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:12.48°、13.80°、14.02°、14.22°、15.30°、15.43°、17.61°、17.82°、19.64°、19.77°、21.53°、21.72°、21.79°、21.97°、24.95°、25.39°、27.36°、27.47°、29.29°、29.77°。
熔點:112.5℃至114.5℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及555 mg戊二酸引入25-ml不可氧化罐中。添加兩個直徑為12 mm之不銹
鋼球且將該罐封閉。施加頻率為30 Hz之振動60分鐘以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:9.59°、10.35°、11.96°、20.57°、21.65°、23.34°。
熔點:74℃至75℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及600 mg酮戊
二酸與500 μl乙醇一起引入25-ml不可氧化罐中。添加兩個直徑為12 mm之不銹鋼球且將該罐封閉。於40℃下乾燥過夜後,施加頻率為30 Hz之振動15分鐘以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:15.36°、16.34°、16.54°、19.24°、23.57°、23.90°、24.41°。
熔點:94℃至96℃
將1 g N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺及319 mg乙醇
酸引入25-ml不可氧化罐中。添加兩個直徑為12 mm之不銹鋼球且將該罐封閉。於40℃下乾燥過夜後,施加頻率為30 Hz之振動15分鐘以產生標題產物,藉由其熔點及以下X-射線粉末繞射圖對其進行表徵,該圖係使用Panalytical Xpert Pro MPD繞射儀(銅對陰極)量測且表示為面間距d、布拉格角2θ(以°±0.2表示)及相對強度(表示為相對於最強線之百分比):
X-射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵:10.29°、14.11°、14.23°、17.98°、18.83°、19.51°、20.61°、23.96°、24.39°、26.44°、28.11°、29.52°。
熔點:75℃至77℃
所獲得共結晶之溶解速率之量測係藉助μDISS分析裝置(pION)在37℃下使用700 rpm之攪拌速度於酸性及中性介質中實施。所獲得結果整理於下表中且表示為與包含於市售Valdoxan®形式中之形式II之阿戈美拉汀所獲得之溶解速率相比共結晶之溶解速率增加之百分比:
所獲得結果顯示,在兩種介質之至少一種(酸性或中性)條件下所測試共結晶之溶解速率在介於33%至97%範圍內增多。
所獲得結果顯示,在兩種測試條件(酸性或中性)之至少一種下,共結晶之溶解速率降低26%至55%。
1000個錠劑之製備配方,每一錠劑含有25 mg阿戈美拉汀:
實例5化合物....................................................50 g乳糖單水合物...................................................115 g硬脂酸鎂..........................................................2 g玉米澱粉..........................................................33 g麥芽糖糊精.......................................................15 g無水膠質二氧化矽.............................................1 g預膠凝玉米澱粉,類型A....................................9 g
1000個錠劑之製備配方,每一錠劑含有25 mg活性成分:實例9化合物.....................................................50 g乳糖單水合物....................................................100 g硬脂酸鎂...........................................................2 g帕維酮(Povidone)...............................................12 g無水膠質二氧化矽..............................................1 g羥丙甲纖維素.....................................................85 g
Claims (24)
- 一種阿戈美拉汀(agomelatine)之共結晶,其特徵在於其包括:阿戈美拉汀或式(I)之N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺
- 如請求項1之共結晶,其中所用該有機酸包含2至10個碳原子。
- 如請求項1或2之共結晶,其中所用該有機酸係對羥基苯甲酸、檸檬酸、草酸、沒食子酸、馬來酸、丙二酸、戊二酸、乙醇酸或酮戊二酸。
- 如請求項1至3中任一項之共結晶,其中與目前以醫藥產品Valdoxan®出售之形式相比,其改變該活性成分溶解速率。
- 如請求項1至4中任一項之共結晶,其中與目前以醫藥產品Valdoxan®出售之該形式之該溶解速率相比,其在中性(pH 6.8)或酸性(0.01 N HCl)條件下可將該活性成分溶解速率改變至少25%。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/對羥基苯甲酸(2/1),其特徵在於其X-射線粉末繞射圖中布拉格角(Bragg's angle)2θ(以°±0.2 表示)為13.16°、14.91°、17.37°、18.39°、18.93°、19.04°、19.65°、19.96°、20.25°、21.49°、25.00°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/對羥基苯甲酸(1/2),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為9.50°、12.28°、14.00°、15.76°、16.18°、16.62°、17.56°、18.15°、19.96°、21.00°、21.30°、22.00°、22.97°、23.55°、23.76°、24.44°、26.09°、26.82°、28.42°、28.71°、29.85°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/檸檬酸(1/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為5.21°、12.24°、17.07°、19.38°、20.69°、21.90°、22.81°、27.30°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/草酸(2/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為12.48°、13.80°、14.02°、14.22°、15.30°、15.43°、17.61°、17.82°、19.64°、19.77°、21.53°、21.72°、21.79°、21.97°、24.95°、25.39°、27.36°、27.47°、29.29°、29.77°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/沒食子酸(2/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為14.47°、17.68°、19.82°、22.33°、23.93°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/馬來酸(1/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為11.30°、15.40°、17.28°、24.29°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/丙二酸(1/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為10.47°、11.95°、14.78°、16.05°、22.32°、24.50°、25.05°、25.24°、27.38°、27.91°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/戊二酸(1/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為9.59°、10.35°、11.96°、20.57°、21.65°、23.34°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/乙醇酸(1/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為10.29°、14.11°、14.23°、17.98°、18.83°、19.51°、20.61°、23.96°、24.39°、26.44°、28.11°、29.52°。
- 如請求項1至5中任一項之共結晶,其係N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺/酮戊二酸(1/1),其特徵在於其X-射線粉末繞射圖中布拉格角2θ(以°±0.2表示)為15.36°、16.34°、16.54°、19.24°、23.57°、23.90°、24.41°。
- 一種獲得如請求項1至15中任一項之共結晶之方法,其特徵在於: 將該兩種成分以期望比例混合於有機溶劑中(1當量阿戈美拉汀/0.25至4莫耳當量有機酸);攪拌該所獲得溶液且視情況在不高於所選溶劑之沸點之溫度下加熱;邊攪拌邊冷卻該混合物,且該共結晶自然沈澱或溶解於第二溶劑中後沈澱;過濾並乾燥該所獲得沈澱。
- 一種製備如請求項1至15中任一項之共結晶之方法,其特徵在於共研磨該兩種成分。
- 一種製備如請求項1至15中任一項之共結晶之方法,其特徵在於將該兩種成分混合於有機溶劑或水性-有機溶劑中且隨後在極低溫度下冷凍並乾燥。
- 一種製備如請求項1至15中任一項之共結晶之方法,其特徵在於將阿戈美拉汀粉末及所述酸粉末在混合器中混合且隨後藉由無模具之雙螺桿擠出機擠出,以直接在該擠出機出口處獲得固體顆粒狀產物。
- 一種醫藥組合物,其包含作為活性成分之如請求項1至15中任一項之共結晶,與一或多種醫藥上可接受之惰性無毒載劑之組合。
- 如請求項20之醫藥組合物,其用於製造用於治療褪黑激素激導性系統之病症的藥劑。
- 如請求項20之醫藥組合物,其用於製造用於治療以下疾病之藥劑:應激壓力、睡眠障礙、焦慮症(尤指廣泛性焦慮症)、強迫症、情緒障礙(尤指雙相障礙)、嚴重抑鬱 症、季節性情感障礙、心血管病狀、消化系統病狀、因時差引起之失眠及疲勞、精神分裂症、恐慌發作、憂鬱症、食慾障礙、肥胖症、失眠、疼痛、精神障礙、癲癇、糖尿病、帕金森氏病(Parkinson's disease)、老年性癡呆、與正常或病理性老化相關之多種病症、偏頭痛、記憶喪失、阿茲海默氏病(Alzheimer's disease),且亦用於腦循環病症中,且亦用於性功能障礙中,及作為排卵抑制劑及免疫調節劑,及用於治療癌症。
- 如請求項1至15中任一項之共結晶,其用於治療褪黑激素激導性系統之病症。
- 如請求項1至15中任一項之共結晶,其用於治療應激壓力、睡眠障礙、焦慮症(尤指廣泛性焦慮症)、強迫症、情緒障礙(尤指雙相障礙)、嚴重抑鬱症、季節性情感障礙、心血管病狀、消化系統病狀、因時差引起之失眠及疲勞、精神分裂症、恐慌發作、憂鬱症、食慾障礙、肥胖症、失眠、疼痛、精神障礙、癲癇、糖尿病、帕金森氏病、老年性癡呆、與正常或病理性老化相關之多種病症、偏頭痛、記憶喪失、阿茲海默氏病,且亦用於腦循環病症中,且亦用於性功能障礙,且用作排卵抑制劑及免疫調節劑,及用於治療癌症。
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FR1101766A FR2976284B1 (fr) | 2011-06-09 | 2011-06-09 | Nouveaux co-cristaux d'agomelatine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
CN201110245039 | 2011-08-25 |
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TW101120779A TWI441803B (zh) | 2011-06-09 | 2012-06-08 | 阿戈美拉汀(agomelatine)之新共結晶,其製備方法及包含其之醫藥組合物 |
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PT2517700E (pt) * | 2011-04-28 | 2013-10-14 | Zentiva Ks | Cocristais farmaceuticamente aceitáveis de n-[2-(7-metoxi- 1-naftil)etil]acetamida e métodos para a sua preparação |
EP2743255B1 (en) | 2012-12-17 | 2016-06-22 | Dr. Reddy's Laboratories Ltd. | Cocrystal of agomelatine with phosphoric acid |
EP2810647A1 (en) * | 2013-06-06 | 2014-12-10 | Zentiva, a.s. | Pharmaceutical formulations comprising agomelatine in the form of agomelatine co-crystal with an organic acid |
EP2810656B1 (en) * | 2013-06-06 | 2017-08-02 | Zentiva, a.s. | Agomelatine formulations comprising agomelatine in the form of co-crystals |
DK3027588T3 (da) * | 2013-07-29 | 2020-07-06 | Servier Lab | Komplekser af agomelatin og sulfonsyre, fremgangsmåde til deres fremstilling og lægemiddelsammensætninger som indeholder dem |
WO2015013865A1 (en) * | 2013-07-29 | 2015-02-05 | Les Laboratoires Servier | Agomelatine sulfonic acids complexes and preparation thereof |
CN105473551B (zh) * | 2013-07-31 | 2019-01-11 | 法国施维雅药厂 | 阿戈美拉汀和对甲苯磺酸的共晶的新形式、其制备方法和包含其的药物组合物 |
KR101404836B1 (ko) | 2014-03-21 | 2014-06-09 | 순천향대학교 산학협력단 | 아고멜라틴의 공결정 및 그의 제조방법 |
KR101470794B1 (ko) | 2014-06-30 | 2014-12-08 | 순천향대학교 산학협력단 | 아고멜라틴 공결정의 제조 방법 및 이를 포함하는 조성물 |
PL3075724T3 (pl) | 2015-03-31 | 2023-12-27 | F.I.S.- Fabbrica Italiana Sintetici S.P.A. | Stała postać agomelatyny |
KR101790411B1 (ko) | 2015-09-25 | 2017-10-26 | 순천향대학교 산학협력단 | 균일한 입도분포를 가지는 아고멜라틴 공결정 분체의 제조방법 |
WO2017115284A1 (en) * | 2015-12-28 | 2017-07-06 | Leiutis Pharmaceuticals Pvt, Ltd. | Novel co-crystal forms of agomelatine |
CA3027297A1 (en) * | 2016-06-13 | 2017-12-21 | Syneurx International (Taiwan) Corp. | Co-crystals of sodium benzoate and uses thereof |
EP3544603A2 (en) * | 2016-11-23 | 2019-10-02 | Bohne Askøy AS | Prevention and/or treatment of chronic fatigue syndrome |
EP3466413A1 (en) * | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Pharmaceutical composition containing agomelatine and process for the preparation thereof |
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FR2658818B1 (fr) * | 1990-02-27 | 1993-12-31 | Adir Cie | Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
AR047553A1 (es) * | 2003-07-04 | 2006-01-25 | Lundbeck & Co As H | La combinacion de un inhibidor de reabsorcion de serotonina y agomelatina |
US20050137247A1 (en) * | 2003-12-22 | 2005-06-23 | The Brigham And Women's Hospital, Inc. | Methods and compositions for treatment of hypertension |
AU2004308962A1 (en) * | 2003-12-24 | 2005-07-14 | Sepracor Inc. | Melatonin combination therapy for improving sleep quality |
FR2866335B1 (fr) * | 2004-02-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'agomelatine |
FR2899472B1 (fr) * | 2006-04-07 | 2008-09-12 | Servier Lab | Utilisation de l'agomelatine pour l'obtention de medicaments destines au traitement du trouble anxiete generalisee |
WO2008035177A2 (en) * | 2006-09-18 | 2008-03-27 | Copharm | Combination of mt1 and mt2 melatonin receptor agonists and a norepinephrine/dopamine reuptake inhibitor |
FR2908995B1 (fr) * | 2006-11-24 | 2009-02-06 | Servier Lab | Utilisation de l'agomelatine pour l'obtention de medicaments destines au traitement du syndrome de smith magenis |
FR2923482B1 (fr) * | 2007-11-09 | 2010-01-29 | Servier Lab | Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
CN101870662B (zh) * | 2010-05-21 | 2013-03-20 | 中山大学 | 结晶型阿戈美拉汀溶剂化物及其制备方法 |
WO2012046253A2 (en) * | 2010-10-08 | 2012-04-12 | Msn Laboratories Limited | Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms |
CN102690210A (zh) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物 |
CN102690209A (zh) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物 |
PT2517700E (pt) * | 2011-04-28 | 2013-10-14 | Zentiva Ks | Cocristais farmaceuticamente aceitáveis de n-[2-(7-metoxi- 1-naftil)etil]acetamida e métodos para a sua preparação |
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