CN101912367A - 伊潘立酮和星状聚合物的贮库制剂 - Google Patents
伊潘立酮和星状聚合物的贮库制剂 Download PDFInfo
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Abstract
本发明涉及伊潘立酮和星状聚合物的贮库制剂，尤其涉及包含作为活性剂的伊潘立酮和生物可降解、生物可相容聚合物的贮库制剂，以及制备微粒贮库制剂的方法。
Description
本申请为2002年10月29日提交的、发明名称为“伊潘立酮和星状聚合物的贮库制剂”的PCT申请PCT/EP02/12073的分案申请，所述PCT申请进入中国国家阶段的日期为2004年4月27日，申请号为02821426.9。
技术领域
本发明涉及药物组合物，特别涉及包含作为活性剂的伊潘立酮和生物可降解、生物可相容的聚合物的贮库制剂(depot formulation)，以及制备微粒贮库制剂的方法。
背景技术
伊潘立酮是1-[4-[3-[4-(6-氟-1，2-苯并异
唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮。本文所用的“伊潘立酮”包括其任何可药用的盐、水合物、溶剂化物和/或立体异构体，以及其任何代谢物，包括所述代谢物的任何盐、水合物、溶剂化物和/或立体异构体。
美国专利No.5,364,866述及化合物伊潘立酮可用作抗精神病剂和镇痛剂。美国专利No.5,955,459述及含有脂肪酸和伊潘立酮的偶联物、用于治疗精神分裂症的组合物。
发明内容
本发明者已发现包含伊潘立酮的贮库制剂，所述伊潘立酮包埋于生物可降解、生物可相容的聚合物中，优选星状聚合物，例如d，l-丙交酯-乙交酯共聚物。因此本发明凭借这种贮库制剂可提供伊潘立酮在例如2至6周内的控制释放。
本发明的包含伊潘立酮和生物可降解、生物可相容的聚合物的贮库制剂可以是微粒的形式。
本文所用的“生物可相容”意指聚合物对人体无毒、可药用且不致癌。本文所用的“生物可降解”意指经体内过程应降解为身体易于处理的产物且不在体内蓄积的材料。
本发明所用的适宜的星状聚合物通常为支链聚酯。本文所用的“星状聚合物”应理解为聚酯的结构是星形的。这些聚酯具有单一的多元醇残基作为中心部分，周围包围着酸性残基链。多元醇部分可以是例如葡萄糖或例如甘露醇。这些酯是已知的且在GB 2,145,422和美国专利No.5,538,739中述及。
使用多羟基化合物、例如多元醇例如葡萄糖或甘露醇作为引发剂可制备星状聚合物。多元醇含有至少3个羟基且分子量高达约20,000道尔顿，多元醇的羟基中至少1个、优选至少2个、例如平均3个是酯基形式，其含有聚交酯或共聚交酯链。通常使用0.2％葡萄糖引发聚合。支链聚酯例如d，l-丙交酯-乙交酯共聚物具有中心葡萄糖部分，该部分具有辐射状直链聚交酯链。本发明优选使用的星状聚合物化合物中的聚酯链优选为α羧酸部分、乳酸和乙醇酸的共聚物或内酯二聚体的共聚物。丙交酯∶乙交酯的摩尔比可为约75∶25至25∶75，例如60∶40至40∶60，更优选55∶45至45∶55，例如55∶45至50∶50。
优选地，支链聚酯，例如具有中心葡萄糖部分、中心葡萄糖部分具有辐射状直链聚交酯链的d，l，-丙交酯-乙交酯共聚物的平均分子量(Mn)为约10,000至200,000道尔顿、优选25,000至100,000道尔顿、特别是35,000至60,000道尔顿，且多分散性为例如1.7至3.0，例如2.0至2.5。Mn 35,000和Mn 60,000的星状聚合物在氯仿中的特性粘度分别为0.36和0.51dl/g。例如Mn 52,000的星状聚合物在氯仿中的粘度为0.475dl/g。
就本发明而言，术语微球、微囊和微粒视为可以互换，表示活性剂被聚合物包埋、优选活性剂分布于整个聚合物中，从而聚合物成为活性剂的骨架。在此情况下优选使用术语微球或更常见的微粒。
以植入剂或微粒的总重为基准，包含于植入剂或微粒中的伊潘立酮的量为约1至约90的重量百分比。
优选地，包含于植入剂或微粒中的伊潘立酮的量为50至80的重量百分比、更优选60至75的重量百分比。
在本发明的一项实施方案中，微粒还含有赋形剂如表面活性剂或溶剂，例如固体溶剂。该赋形剂可加速或进一步延迟活性剂的释放。
本发明组合物的组分在例如Fiedler，H.P.“Lexikon der Hilfsstoffe für Pharmazie，Kosmetik und angrenzende Gebiete”，Editio Cantor Verlag Aulendorf，Aulendorf，Aulendorf，第4修订和增补版(1996)中述及，其内容在此引入作为参考。
尽管微粒可以是不规则形的，但本发明的微粒通常由球形微粒组成。它们可显示光滑至粗糙的表面且可以是致密或多孔样的。微粒的平均粒径为3至300微米、优选10至200微米、更优选10至100微米。
另一方面，本发明提供了制备包含伊潘立酮或其可药用盐和生物可降解、生物可相容的星状聚合物的微粒的方法。所述微粒可通过多种方法制备，例如凝聚法，例如喷雾干燥法或例如溶剂蒸发法。溶剂蒸发法为优选方法，其包括以下步骤：
i)将聚合物和伊潘立酮溶于有机溶剂例如二氯甲烷中，
ii)将表面活性剂例如聚乙烯醇的水溶液和缓冲剂例如磷酸氢二钠混合，
iii)使用静态混合器将步骤i)和步骤ii)的溶液混合以形成乳液，
iv)任选地将乳液加热至升高的温度，例如约30℃至约60℃、优选40℃至50℃，
v)经沉降收集生成的微粒，
vi)任选地洗涤微粒，和
vii)在真空下干燥微粒。
步骤iii)中合并的溶液i)和ii)的比例可以是1∶20至5∶1、优选1∶20至1∶5。
多种溶剂可用于内相如卤代和/或脂肪族或芳香族烃类以及它们与水混溶性液体的混合物。优选地，溶剂为二氯甲烷。
外相中可以使用聚(乙烯醇)、羧甲基纤维素、明胶、聚(乙烯吡咯烷酮)、聚氧乙烯20山梨糖醇酐单油酸酯和聚氧乙烯20山梨糖醇酐单月桂酸酯作为表面活性剂。
本发明的微粒可用于治疗中枢神经系统病症，例如精神病性精神障碍，例如精神分裂症，或例如可用作镇痛剂。
本发明微粒的贮库制剂可经肌内或皮下注射施用。经注射施用的本发明的贮库制剂可在延长的一段时间内、例如2至6周内提供疾病的有效治疗。所述微粒使伊潘立酮得以通过扩散控制释放，因此在延长的一段时间内获得了稳态药物水平。
包埋于聚合物中的活性剂的准确施用量，即贮库制剂例如微粒制剂的准确施用量取决于多个因素，例如待治疗病症、期望的治疗持续时间、活性剂的释放速度和聚合物骨架的可降解性。所需的活性剂的量可基于已知的体外或体内技术确定。当药物充分释放时可重复施用本发明的贮库制剂。
实施本发明的方法所需的剂量可根据例如施用方式和待治疗病症的严重性而改变。例如混悬液形式的大量活性剂，例如高达750或1000mg的活性剂，可单次施用，例如一次注射施用。
本发明方法所制备的微粒以粉末形式贮存。注射施用时将微粒混悬于适宜的介质中。
可在贮库制剂灭菌前或灭菌后进行灌装。本发明制剂和初级包装的灭菌可例如通过例如能量为25-35kGy的γ辐射实现，活性剂和/或微粒不降解。
以下实施例阐述了本发明。
具体实施方式
实施例1至4：药物载荷为20至75重量百分比的微粒
内相是通过将伊潘立酮和d，l，-丙交酯-乙交酯共聚物溶于二氯甲烷中而制备。制备了含磷酸氢二钠(Na2HPO4)的聚乙烯醇水溶液(外相)。
将(内相和外相)溶液过滤并通过静态混合器(实施例1，2，4)泵入盛有聚乙烯醇和磷酸氢二钠水溶液的搅拌容器中(实施例2-4)。搅拌下于90分钟内将制得的溶液加热至40℃至45℃。冷却后使混悬液沉降20分钟。真空下除去水性上清液。任选地，将微粒重新混悬于磷酸氢二钠水溶液中并如上进行处理(加热、冷却、沉降、除去上清液)。用水洗涤微粒约30分钟。沉降20分钟后，除去溶液并用Ultipor过滤器过滤微粒，用水洗涤并在真空下干燥。经测定由此获得的微粒的平均粒径为50至150微米。以上制剂显示了在动物和人中、在超过2周的时间内伊潘立酮在血浆中的持续释放。
虽然已参考一些实施方案对本发明进行了描述，但应理解：在以下权利要求的范围和精神内本领域技术人员可进行改变和修饰。
Claims (14)
1.包含伊潘立酮和生物可降解、生物可相容的聚合物的经肌内或皮下注射施用的贮库制剂，
其中所述的贮库制剂是微粒的形式，
其中所述的聚合物是丙交酯-乙交酯共聚物，
其中伊潘立酮的量为50至80的重量百分比，并且
其中制剂在经肌内或皮下注射施用后在2至6周内提供了有效治疗疾病的伊潘立酮。
2.权利要求1的贮库制剂，其中的聚合物选自直链聚合物、星状聚合物及它们的组合。
3.权利要求1的贮库制剂，其中的聚合物为星状聚合物。
4.权利要求1的贮库制剂，其中的聚合物为直链聚合物。
5.权利要求1的贮库制剂，其中的聚合物为多元醇的丙交酯-乙交酯共聚物。
6.权利要求1的贮库制剂，其中微粒的形状为球形。
7.权利要求5的贮库制剂，其中的聚合物为多元醇的丙交酯-乙交酯共聚物，其中丙交酯和乙交酯的摩尔比为40/60至60/40。
8.权利要求1的贮库制剂，其中伊潘立酮的量为60至75的重量百分比。
9.权利要求1的贮库制剂，其还包含表面活性剂。
10.权利要求1的贮库制剂，其还包含溶剂。
11.权利要求1的贮库制剂，在注射前将微粒混悬于适宜的赋形剂中。
12.包含伊潘立酮和生物可降解、生物可相容的星状聚合物的经肌内或皮下注射施用的微粒，其中所述的聚合物是丙交酯-乙交酯共聚物，其中伊潘立酮的量为50至80的重量百分比，并且其中制剂在经肌内或皮下注射施用后在2至6周内提供了有效治疗疾病的伊潘立酮。
13.制备包含伊潘立酮和生物可降解、生物可相容的星状聚合物的微粒的方法，其中所述的聚合物是丙交酯-乙交酯共聚物，其中伊潘立酮的量为50至80的重量百分比，所述方法包括：
i)将聚合物和伊潘立酮溶于有机溶剂中，
ii)将表面活性剂的水溶液和缓冲剂混合，
iii)用静态混合器将步骤i)和步骤ii)中的溶液混合以形成乳液，
iv)任选地在升高的温度下加热乳液，
v)经沉降收集生成的微粒，
vi)任选地洗涤微粒，和
vii)在真空下干燥微粒。
14.一种包装产品，其包括盛有权利要求1的贮库制剂的容器以及使用所述贮库制剂以治疗患者的精神分裂症的说明书。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103599074A (zh) * | 2013-11-26 | 2014-02-26 | 重庆医药工业研究院有限责任公司 | 一种伊潘立酮缓释微球及其制备方法 |
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| US20030091645A1 (en) | 2003-05-15 |
| JP5067998B2 (ja) | 2012-11-07 |
| CY1111357T1 (el) | 2015-08-05 |
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| BRPI0213564B1 (pt) | 2016-08-02 |
| BR0213564A (pt) | 2004-08-31 |
| ES2436439T3 (es) | 2014-01-02 |
| DE60238780D1 (de) | 2011-02-10 |
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| US20100233217A1 (en) | 2010-09-16 |
| EP1441727A1 (en) | 2004-08-04 |
| WO2003037337A8 (en) | 2004-05-13 |
| CN1578664A (zh) | 2005-02-09 |
| EP2295058B1 (en) | 2013-09-04 |
| ES2358416T3 (es) | 2011-05-10 |
| EP2295058A1 (en) | 2011-03-16 |
| WO2003037337A1 (en) | 2003-05-08 |
| CA2463158C (en) | 2013-07-30 |
| BRPI0213564B8 (pt) | 2021-05-25 |
| ATE493129T1 (de) | 2011-01-15 |
| EP1441727B1 (en) | 2010-12-29 |
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