CN110639021A - 阿戈美拉汀的稳定的无定形形式、其制备方法和含有其的药物组合物 - Google Patents
阿戈美拉汀的稳定的无定形形式、其制备方法和含有其的药物组合物 Download PDFInfo
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Abstract
式(I)化合物的稳定的无定形形式:药物。
Description
本申请是申请日为2013年9月11日、优先权日为2012年9月11日的中国专利申请201380046980.2的分案申请。
技术领域
本发明涉及阿戈美拉汀或式(I)的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的稳定的无定形形式:
其制备方法以及含有其的药物组合物。
背景技术
阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺具有有价值的药理学性质。
实际上,其具有双重特性,一方面它是褪黑激素能系统受体的激动剂,另一方面,它是5-HT2C受体的拮抗剂。这些性质使得它在中枢神经系统中具有活性,更特别是在治疗重症抑郁、季节性情感障碍、睡眠障碍、心血管疾病、消化系统疾病、时差导致的失眠和疲惫、食欲障碍和肥胖中具有活性。
阿戈美拉汀、其结晶形式、其复合物、其共晶体、其与可药用酸或碱的加成盐、其制备方法及其在治疗中的用途已经描述在如下专利申请中: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和CN102030673。
而且,阿戈美拉汀是一种具有极低生物利用度且因此具有大的个体间差异的缺点的活性成分。这种低生物利用度部分地与阿戈美拉汀在水中的溶解度有关,所述溶解度为在25℃小于0.15mg/mL。
发明内容
考虑到该化合物的药用价值及其生物利用度差,无定形形式显示是一种可能的策略,因为已知固体化合物的无定形形式具有比其相应结晶形式好的溶出性质。
本申请人现在已经发现:阿戈美拉汀具有无定形状态,已经通过扫描量热分析或DSC(“差示扫描量热法”)测定了其玻璃化转变温度在-6℃处。高于温度时,该活性成分进行向结晶形式的转变。因此,在环境温度下保持阿戈美拉汀为无定形状态是不可能的。
因此,所提出的技术问题是使得能够获得在制剂中的阿戈美拉汀的无定形形式,这与其在制药工业中的应用是相一致的,特别是就稳定性和在常规条件下贮存而言。
本领域技术人员已知的解决方法包括形成活性成分在固体基质中的分散体,所述固体基质包围分子并防止它们形成晶格。活性成分在基质内越稀,无定形的形成就越多。其结果是:含有无定形活性成分的片剂的尺寸由于基质而大量增加,这对于必须吞服它们的患者构成了一个主要缺点。因此,另外的挑战在于使为了活性成分的利益所用的基质的量最低、同时仍然防止了形成晶格。
已经使用阿戈美拉汀在环糊精或海藻糖(它们通常用于形成“主体-客体”类型的复合物)中进行了试验,但是从来不可能以超过时间稳定的方式获得所寻求的复合物类型。
本申请人现在已经发现:以可重现和工业上可行的方式获得无定形形式的阿戈美拉汀的稳定制剂是可能的。这种新的稳定形式允许用于制药工业。而且,其允许高的活性成分含量,产生了与被患者服用完全相符的最终制剂尺寸。
因此,本发明涉及阿戈美拉汀的稳定的无定形形式。“稳定”理解为阿戈美拉汀的无定形形式当经受温度和湿度变性储存条件达至少一周时被保持。本发明的温度和湿度变性条件将是平均的,例如40℃/75%RH(相对湿度)、30℃/65%RH、50℃、70℃等。
更特别地,本发明包括阿戈美拉汀在有机聚合物内的固体分散体,可以理解,阿戈美拉汀占分散体重量的至少30%。根据所选的有机聚合物增加阿戈美拉汀的重量百分比是可能的。其中阿戈美拉汀的重量百分比为30%至50%、更优选30%至40%的固体分散体是优选的。令人惊奇的是,即使在那些高的活性成分含量下,阿戈美拉汀的无定形形式也得以保持——以超过时间稳定的方式。而且,除了采用活性成分的无定形化通常可预期到的溶出速率的改善之外,所获得的阿戈美拉汀溶解度也极大地增加,充分地超过了对结晶阿戈美拉汀所测定的溶解度,其为至少三倍,在一些情况下为乘以因子8。该结果是完全出人意料的,因为虽然本领域中大量出版物描述了通过设计稳定的固体分散体来改善活性成分的生物药剂学性能(溶解度、溶出速率),但是这是用于负荷少于20%的活性成分的(Lin等人,International Journal of Pharmaceutics,1996,127,261-272)。
令人惊奇的是,活性成分的溶解度增加保持了至少4小时。
本发明中所用的聚合物更特别涉及甲基丙烯酸复合物或乙烯基或纤维素聚合物。
更特别地,根据本发明所用的聚合物涉及聚甲基丙烯酸酯或甲基丙烯酸共聚物,甲基丙烯酸共聚物相当于甲基丙烯酸和丙烯酸酯或甲基丙烯酸酯的完全聚合共聚物。这些聚甲基丙烯酸酯通常称为可以是粉末或颗粒形式。在市售的不同产品中,本发明的内容中优选使用的那些是L产品、更特别是L100和L100-55或者是EPO。这些聚合物特别适于所有范围的阿戈美拉汀负荷(阿戈美拉汀的%重量)。
本发明的乙烯基聚合物更特别涉及聚乙烯酯,例如聚醋酸乙烯邻苯二甲酸酯;基于聚乙烯吡咯烷酮的均聚物或共聚物,例如聚维酮(K30、S630)、Kollidon VA64或还有聚维酮将用于负荷少于50%重量的阿戈美拉汀。
在根据本发明所用的纤维素化合物中,可以提及的有纤维素醚或酯如HPMC、更特别是HPMC乙酰基琥珀酸酯。
本发明还涉及用于获得在聚合物内具有高含量的阿戈美拉汀的无定形形式的稳定制剂的方法。根据本发明的方法,将通过任意方法获得并且以任意结晶形式、复合物、共晶体或与可药用酸或碱的加成盐存在的式(I)化合物与所选聚合物在一种或多种溶剂中混合,使将获得的组分完全溶解,然后在减压下完全蒸除溶剂。
根据本发明所用的溶剂是能够溶解阿戈美拉汀和所选聚合物的那些;优选极性质子或非质子溶剂,例如丙酮、醇且更尤其是甲醇和乙醇、水、二氯甲烷、乙酸乙酯或那些溶剂的混合物。溶解是在环境温度下搅拌或通过加热混合物直至组分完全溶解来进行的。溶剂的蒸除是在环境温度下在减压下或通过加热直至溶剂蒸发完全来进行的。
制备在聚合物内具有高含量的阿戈美拉汀的无定形形式的稳定制剂的方法的一个有利实施方案包括将通过任意方法获得并且以任意结晶形式、复合物、共晶体或与可药用酸或碱的加成盐存在的式(I)化合物与所选聚合物混合或预掺和、然后将该混合物引入到其螺矩和温度作为混合物粘度的函数进行了选择的挤出机中以获得挤出物,然后将挤出物切成预期的尺寸,然后任选地研磨。
优选地,螺杆的旋转将在50至200rpm之间进行,更特别在75至150rpm之间进行。
所选的挤出温度将是所得组分混合物的粘度的函数,并且将是包括端值在内的90℃至200℃。
在获得本发明的阿戈美拉汀的稳定无定形形式的方法中,可以使用通过任意方法获得并且以任意结晶形式、复合物、共晶体或与可药用酸或碱的加成盐存在的式(I)化合物。
在本发明的方法中,阿戈美拉汀的负荷大于或等于30%重量,更尤其是在30至50%重量、优选30%至40%之间变化。
由此得到的稳定的无定形形式在治疗褪黑激素能系统疾病中具有价值,并且已经显示出对中枢神经系统和微循环的重要活性,使得能够确立其在治疗下述疾病中的有用性:应激、睡眠障碍、焦虑、重症抑郁、季节性情感障碍、双相性精神障碍、广泛性焦虑症、心血管疾病、消化系统疾病、由于时差导致的失眠和疲劳、精神分裂症、惊恐发作、忧郁症、食欲紊乱、肥胖症、失眠、疼痛、精神障碍、癫痫、糖尿病、帕金森病、老年痴呆、与正常或病理性衰老有关的各种紊乱、偏头痛、记忆丧失、阿尔茨海默病以及还有脑循环疾病。在另一个活性领域中显示:在治疗中阿戈美拉汀的无定形形式可用于性功能障碍,其具有排卵抑制和免疫调节性质,并且其潜在地可以用于治疗癌症。
阿戈美拉汀的稳定的无定形形式将优选用于治疗重症抑郁、季节性情感障碍、双相性精神障碍、广泛性焦虑症、睡眠障碍、心血管疾病、消化系统疾病、由于时差导致的失眠和疲劳、食欲紊乱和肥胖症。
获得阿戈美拉汀的稳定的无定形形式具有使制备具有一致且可重现组成的药物制剂成为可能的优点,其具有超过时间的优良的稳定性。
因此,根据本发明,获得具有高含量的阿戈美拉汀的无定形形式的固体药物组合物是可能的,其尤其可通过口、颊、舌下、眼、直肠、阴道或胃肠道外途径进行施用。
这些药物组合物可以由阿戈美拉汀在聚合物内的固体分散体制成,而没有除包装之外的任何其它加工操作。但是,如果期望的话,所述药物组合物可以通过研磨或通过制粒进行加工用于填充到胶囊中或用于压制或者可以进行包衣。
本发明的药物组合物还可以任选地包含药理学上可接受的赋形剂,所述赋形剂例如选自粘合剂、崩解物质、崩解剂、润滑剂、稀释剂、抗氧化剂、芳香剂、着色剂、防腐剂、甜味剂和抗粘着剂。
在本发明的药物组合物中,可以更特别提及片剂或糖衣剂、颗粒剂、舌下片剂、胶囊剂、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶剂、可注射制剂、可饮用混悬剂和咀嚼胶。
优选地,本发明的药物组合物含有相对于制剂总重量而言至少25%重量的阿戈美拉汀。
有用的剂量可以根据病症的性质和严重性、施用途经及患者的年龄和体重而变化。剂量为每天0.1mg至1g阿戈美拉汀不等,一次或多次施用。
附图简述
图1:在多种稳定性条件(在40℃/75%RH下1周、在40℃/75%RH下1周、然后在50℃下1周、在70℃下1周)下记录的实施例10的X-射线衍射图。
图2:在多种稳定性条件(在40℃/75%RH下1周、在40℃/75%RH下1周、然后在50℃下1周、在70℃下1周)下记录的实施例11的X-射线衍射图。
图3:在多种稳定性条件(在40℃/75%RH下1周、在40℃/75%RH下1周、然后在50℃下1周、在70℃下1周)下记录的实施例12的X-射线衍射图。
图4:在多种稳定性条件(在40℃/75%RH下1周、在40℃/75%RH下1周、然后在50℃下1周、在70℃下1周)下记录的实施例19的X-射线衍射图。
图5:在多种稳定性条件(在40℃/75%RH下1周、在40℃/75%RH下1周、然后在50℃下1周、在70℃下1周)下记录的实施例28的X-射线衍射图。
图6:实施例39的在多种稳定性条件(在敞口或闭口烧瓶中25℃/60%RH,在敞口或闭口烧瓶中30℃/65%RH,在敞口烧瓶中50℃)下在3个月末记录的X-射线衍射图。
图7:实施例40的在多种稳定性条件(在敞口或闭口烧瓶中25℃/60%RH,在敞口或闭口烧瓶中30℃/65%RH,在敞口烧瓶中50℃)下在3个月末记录的X-射线衍射图。
具体实施方式
下述实施例解释说明了本发明,但是不以任何方式限制本发明。
A.通过溶解-蒸发获得阿戈美拉汀的稳定的无定形形式的通用方法
将阿戈美拉汀和所选聚合物置于含有3ml溶剂的10-ml小瓶中。将该混合物于40℃搅拌30分钟直到完全溶解,获得均匀的溶液。在减压下于40℃蒸除溶剂30分钟。最后,将所得残余物在环境温度(20℃)下在真空中干燥过夜(12小时),得到阿戈美拉汀的稳定的无定形形式。对于每个试验,在40℃和75%RH下、在40℃和75%RH下、之后在50℃下以及在70℃下的变性条件下测试了该无定形形式的稳定性。
下表列出了所制备的各实施例和所获得的结果:
例如,图1、图2、图3、图4和图5分别给出了在多种稳定性条件(在40℃/75%RH下1周、在40℃/75%RH下1周、然后在50℃下1周、在70℃下1周)下记录的实施例10、11、12、19和28的X-射线衍射图。
B.通过挤出获得阿戈美拉汀的稳定的无定形形式的通用方法
将阿戈美拉汀和聚合物在Turbula型搅拌器中预掺和10分钟。将所得混合物手动放置于HAAKE Minilab II Microcompounder型(ThermoFisher)的圆锥转子挤出机(直径5/14mm)中。挤出速度为100rpm。
在各种温度和相对湿度条件下评价了所得无定形形式的稳定性:在敞口或闭口烧瓶中25℃/60%RH、在敞口或闭口烧瓶中30℃/65%RH、在敞口烧瓶中50℃。
下表给出的所有实施例均具有长于至少6个星期的稳定性。
例如,图6和图7分别列出了在多种稳定性条件(在敞口或闭口烧瓶中25℃/60%RH、在敞口或闭口烧瓶中30℃/65%RH、在敞口烧瓶中50℃)下在3个月末记录的实施例39和40的X-射线衍射图。
C.溶解度
在25℃下,采用型装置在pH6.8缓冲溶液中历经4小时进行了所得制剂的稳定性研究,搅拌速度为700rpm。测试了各种浓度,通过浊度检测监测了不溶性颗粒的存在。作为参考,阿戈美拉汀在那些条件下的溶解度为0.14mg/mL。
下表列出了所得结果,其列出了:i)所观察到的最大溶解度和观察到该最大溶解度的时间,ii)在4小时观察到的溶解度。
实施例 | 在t分钟观察到的最大溶解度(mg/mL) | 在4小时的溶解度(mg/mL) |
14 | 在5分钟,>0.9 | >0.59 |
20 | 在6分钟,>0.9 | >0.42 |
31 | 在5分钟,>1.5 | >1.20 |
32 | 在45分钟,>1.2 | >0.46 |
33 | 在10分钟,>1.1 | >0.52 |
34 | 在5分钟,>0.67 | >0.24 |
35 | 在5分钟,>0.9 | >0.40 |
36 | 在10分钟,>0.76 | >0.33 |
37 | 在5分钟,>0.79 | >0.32 |
38 | 在5分钟,>0.34 | >0.34 |
39 | 在5分钟,>0.64 | >0.43 |
40 | 在5分钟,>0.53 | >0.29 |
41 | 在5分钟,>0.73 | >0.37 |
所得结果显示最大溶解度显著增加。重点是该溶解度随时间推移是继续增加的:在4小时,结果显示其为至少乘以1.7至8.5的因子,这使得活性成分在再沉淀之前有时间被吸收。
D.药物组合物
实施例42
制备1000粒胶囊的配方,每粒胶囊含有25mg阿戈美拉汀:
阿戈美拉汀...............................................25g
Eudragit L100-55.........................................25g
按照实施例36制备了挤出物,然后将其切成微小基质,引入1号胶囊中。
实施例43
制备1000粒胶囊的配方,每粒胶囊含有25mg阿戈美拉汀:
阿戈美拉汀...............................................25g
Plasdone S630............................................58g
按照实施例38制备了挤出物,然后将其切成微小基质,引入1号胶囊中。
实施例44
制备1000片片剂的配方,每片含有25mg阿戈美拉汀:
挤出物实施例36...........................................50g
玉米淀粉.................................................10g
乳糖.....................................................20g
硬脂酸镁.................................................0.5g
二氧化硅.................................................0.25g
羟丙基纤维素.............................................2.25g。
Claims (8)
1.式(I)的阿戈美拉汀的稳定的无定形形式:
其特征在于阿戈美拉汀如下分散在基质内:
·以30%、40%或50%重量分散在Eudragit L100中的阿戈美拉汀;
·以30%、35%、40%或50%重量分散在Eudragit L100-55中的阿戈美拉汀;
·以30%、35%或40%重量分散在Kollidon VA64中的阿戈美拉汀;
·以30%、35%或40%重量分散在Soluplus中的阿戈美拉汀;
·以30%或40%重量分散在聚醋酸乙烯邻苯二甲酸酯中的阿戈美拉汀;
·以30%重量分散在Plasdone S630中的阿戈美拉汀;或
·以30%重量分散在HPMC乙酰基琥珀酸酯中的阿戈美拉汀。
2.用于获得权利要求1的阿戈美拉汀的稳定的无定形形式的方法,其特征在于将通过任意方法获得并且以任意结晶形式、复合物、共晶体或与可药用酸或碱的加成盐存在的式(I)化合物与所选聚合物在一种或多种溶剂中混合,使将获得的组分完全溶解,然后在减压下完全蒸除溶剂。
3.用于获得权利要求1的阿戈美拉汀的稳定的无定形形式的方法,其特征在于将通过任意方法获得并且以任意结晶形式、复合物、共晶体或与可药用酸或碱的加成盐存在的式(I)化合物与所选聚合物混合和预掺和、然后引入到其螺矩和温度作为混合物粘度的函数进行了选择的挤出机中以获得挤出物,然后将挤出物切成预期的尺寸,然后任选地研磨。
4.药物组合物,包含作为活性成分的权利要求1的阿戈美拉汀的稳定的无定形形式自身或其与一种或多种惰性无毒且可药用的载体的组合。
5.根据权利要求4的药物组合物用于制备治疗褪黑激素能系统疾病的药物的用途。
6.根据权利要求4的药物组合物用于制备治疗睡眠障碍、应激、焦虑、季节性情感障碍或重症抑郁、心血管疾病、消化系统疾病、由于时差导致的失眠和疲劳、精神分裂症、惊恐发作、忧郁症、食欲紊乱、肥胖症、失眠、疼痛、精神障碍、癫痫、糖尿病、帕金森病、老年痴呆、与正常或病理性衰老有关的各种紊乱、偏头痛、记忆丧失、阿尔茨海默病、脑循环疾病和性功能障碍以及作为排卵抑制剂和免疫调节剂以及治疗癌症的药物的用途。
7.根据权利要求1的阿戈美拉汀的稳定的无定形形式用于制备治疗褪黑激素能系统疾病的药物的用途。
8.根据权利要求1的阿戈美拉汀的稳定的无定形形式用于制备治疗睡眠障碍、应激、焦虑、季节性情感障碍或重症抑郁、心血管疾病、消化系统疾病、由于时差导致的失眠和疲劳、精神分裂症、惊恐发作、忧郁症、食欲紊乱、肥胖症、失眠、疼痛、精神障碍、癫痫、糖尿病、帕金森病、老年痴呆、与正常或病理性衰老有关的各种紊乱、偏头痛、记忆丧失、阿尔茨海默病、脑循环疾病和性功能障碍以及作为排卵抑制剂和免疫调节剂以及治疗癌症的药物的用途。
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PCT/CN2012/081250 WO2014040228A1 (en) | 2012-09-11 | 2012-09-11 | Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
FR1259064A FR2995896B1 (fr) | 2012-09-26 | 2012-09-26 | Forme amorphe stabilisee de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent. |
FR12/59064 | 2012-09-26 | ||
CN201380046980.2A CN104619346A (zh) | 2012-09-11 | 2013-09-11 | 阿戈美拉汀的稳定的无定形形式、其制备方法和含有其的药物组合物 |
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