CN102379866A - 药物组合物和方法 - Google Patents

药物组合物和方法 Download PDF

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CN102379866A
CN102379866A CN2011102282988A CN201110228298A CN102379866A CN 102379866 A CN102379866 A CN 102379866A CN 2011102282988 A CN2011102282988 A CN 2011102282988A CN 201110228298 A CN201110228298 A CN 201110228298A CN 102379866 A CN102379866 A CN 102379866A
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阿希什·查特吉
哈普瑞特·K·桑德夫
纳弗尼特·哈尔戈文达斯·沙阿
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Abstract

本发明提供包含N-(2-氯-6-甲基苯甲酰基)-4-[(2，6-二氯苯甲酰基)氨基]-L-苯丙氨酸-2(二乙基氨基)乙酯和泊洛沙姆188的制剂，其通过热熔法制备。

Description

药物组合物和方法
本申请是国际申请号PCT/EP2007/050144，国际申请日2007年1月8日，进入中国国家阶段日为2008年7月16日，中国申请号2007800024502，发明名称为“药物组合物和方法”的分案申请。 
本发明涉及具有N-(2-氯-6-甲基苯甲酰基)-4-[(2，6-二氯苯甲酰基)氨基]-L-苯丙氨酸-2-(二乙基氨基)乙酯盐酸盐作为活性成分的新制剂，其在下文称为R411。R411具有治疗哮喘的活性。 
R 411可以晶体形式获得并且具有在生理范围内的pH-依赖性的物理化学性质，即溶出度，稳定性和渗透性。 
除了pH影响之外，R 411的溶出度也依赖于抗衡离子的类型和浓度。 
R 411，其具有酯键，也易于进行碱水解(在pH＞6)。pH-依赖性的物理化学性质和有限的渗透性(58x10-6cm2/秒)导致该化合物的较低的和可变的口服生物利用度。在各种动物物种中的生物利用度的范围从6％(在猴中)到20％(在大鼠和狗中)。 
具有pH-依赖性物理化学性质的弱碱对于制剂科学家提出独特的挑战。对于具有溶解率限制的溶解度和生物利用度的药物，其成为了重要的挑战。用于提高生物利用度的一般方法包括减少药物的颗粒大小，使用助溶剂或络合剂，将药物分散在亲水性基质中，使用基于脂质的药物递送系统如自乳化药物递送系统，微乳，胶束系统和固体分散体和分子分散体并且是一些专利文献和专利的来源，例如Choi等.，Drug Dev.Ind.Pharm.，卷29(10)，1085-1094，2003；Yueksel等，Eur.J.Pharm.and Biopharm.(欧洲药物和生物药物杂志)，卷56(3)，453-459，2003和美国专利号6,632,455。 
R411存在的生物利用度问题不仅是由于低溶出度还是由于在胃肠液体中的有限的稳定性。因此，需要规避这两个问题的配制方法。使用泊洛沙姆来基于提高的溶解度来提高生物利用度已经在文献中记载(Reddy等，J.Pharm.Sci(药物科学杂志)，卷65，115-118和1753-1758，1976和Geneidi等.，Pharm.Ind.(药物工业)，42，315-1980)。然而在文献中没有提及即使较慢的溶解，泊洛沙姆也可以提高生物利用度。此外，也没有提及其在药物的化学稳定性或改善药物的食物影响性质上的作用。这些发现形成了本发明的基础。 
为了进一步提高湿敏药物的稳定性，公开了使用内部干燥剂。无水乳糖的吸收-解吸附等温线说明这种形式的乳糖具有在更高的湿度吸收水分的倾向。由于这种吸水性，无水乳糖没有被视为配制湿敏药物的有利的赋形剂(Patel等，Int.J.Pharm(国际药物杂志)，卷64，35-43，Is：1-2，2003和Eur，J.Pharm.And Biopharm.(欧洲药物杂志和生物药学)，卷46，177-182，Is：2，1998)。与文献数据相反的是，将无水乳糖包含在R411制剂中证明对于水分介导的不稳定性是有利的。 
使用ProSolv作为压缩助剂是充分记载的。类似地，其超过其单个成分，微晶纤维素和胶态二氧化硅的物理混合物的优越性也是充分确定的(Drug Dev.Ind.Pharm(药物递送工业药物).，卷30，103-109，Is：1，2004)。然而，它尤其以有利的方式影响溶解稳定性的能力是一个令人惊奇的发现并且被认为是在制剂中进一步增强。 
最后，还包括使用加工方法。可以通过数种方式加工R411泊洛沙姆混合物。然而，为了获得从生物利用度角度看的最大益处，优选通过如熔化制粒和熔体挤出的方法紧密混合。已经在文献中记载了这些技术中的一些的应用。还记载了它们相对于用于湿敏产品的制粒的其它方法的优点(Passerini等，Eur.J.Pharm.Sci(欧洲药物科学杂志).，卷15，71-78，Is：1，2002)。然而，文献仅将其优势限制在最初的化学稳定性，而在R411制剂的情形中，在延长的时间中，观察到在其溶解稳定性形式方面的优势，这是非显而易见的。 
本发明提供R411的以口服剂型存在的药物组合物，其具有改善的药物代谢动力学性能，即提高的生物利用度和降低的食物影响。所述组合物在单位剂量中包含50mg-400mg的R411以及泊洛沙姆188(Lutrol F68 
Figure BDA0000082285630000021
)，其通过熔化制粒或熔体挤出方法制备。还公开了使用辅助赋形剂如ProSolv SMCC50 
Figure BDA0000082285630000022
和无水乳糖以获得稳定性方面的辅助的益处。 
本发明提供用于口服施用R411的药物组合物，其包括，基于组合物的总重量，约50mg-400mg的R411，并且在a重量％基础上，约5-40％的泊洛沙姆188，约1-20％的ProSolv SMCC50 
Figure BDA0000082285630000023
和约20-60％的无水乳糖。 
优选的组合物包含300-400mg的R411，约10-25％的泊洛沙姆188，约2-4％的ProSolv SMCC50 
Figure BDA0000082285630000024
和约30-50％的无水乳糖。 
关于关键赋形剂最优选的组合物显示如下： 
R411                318mg 
泊洛沙姆188         136mg 
无水乳糖            228mg 
ProSolv SMCC50      40mg 
可以按照需要将其它的赋形剂如崩解剂和润滑剂以及填料加入以提高现有技术已知的剂型的生产和/或性能。泊洛沙姆188(Lutrol F68)是氧化乙烯和氧化丙烯的嵌段共聚物并且在NF专题论文中列为泊洛沙姆188。泊洛沙姆以广泛范围的分子量，熔点和亲水性获得，并且通常作为湿润剂用在药物制剂中以提高生物利用度。它们由BASF(NJ，USA)提供。用在本发明中的Lutrol F68
Figure BDA0000082285630000032
具有8400道尔顿范围内的分子量，52°-54℃的熔点和18-29的HLB(亲水性-亲脂性平衡)，并且平均颗粒大小在1微米到500微米范围内。其与R411在制剂中的应用性提供了独特的情形，因为其提供了比常规片剂溶解更慢的基质，却提供了药物的更高的生物利用度，所述药物在小肠中具有不利的溶出度和稳定性。此外，该药物组合物还使食物对产物的药物代谢动力学性质的影响最小化。泊洛沙姆188的优选的物理形式是精细的颗粒物质以获得紧密的混合。次级选择的其它非离子表面活性剂包括维生素E TPGS(Eastman Kodak)，Gelucire 44/14，Gelucire 50/13(Gattefosse，NJ)，Solutol HS15，泊洛沙姆407，泊洛沙姆338，Lutrol F77，Cremophor RH40(BASF，NJ)，蔗糖二棕榈酸酯和蔗糖二硬脂酸酯(Croda，NJ)。 
无水乳糖由Cary生物科学(Cary Biosciences)(IL，USA)或DMV国际(荷兰)获得。其通常用作填充剂，压缩助剂和药物活性剂的载体。由于其吸湿性，不推荐将其与湿敏物质一起使用，然而在这种特定的情形中，其吸湿性赋予提高的溶解稳定性，因为其充当水分清除剂。 
ProSolv SMCC
Figure BDA0000082285630000033
是包含2％胶态二氧化硅和98％微晶纤维素的辅助加工的赋形剂。在制剂中使用的单个赋形剂符合USP/NF的要求。其由JRS供应并且以两个级别获得：关于不同的微晶纤维素的颗粒大小，即50微米和90微米，分别为ProSolv SMCC50
Figure BDA0000082285630000034
和ProSolvSMCC90
Figure BDA0000082285630000035
。将ProSolv作为压缩助剂用在药物制剂中。其在R411制剂中的应用不仅是作为压缩 助剂，它还帮助提高产物的溶解稳定性。这是令人惊奇的发现，因为所有的文献数据显示ProSolv在压缩特性上是优良的，但是，没有提及通过使用辅助加工的赋形剂而不是其单个成分来提高物理稳定性。 
聚合物基质核心制剂还可以包含其它的药用赋形剂如粘合剂，填充剂，稳定剂，压缩助剂，润滑剂，制粒助剂，流动助剂等。膜包衣还可以包含其它的包衣赋形剂如遮光剂，色素，着色剂等。这些物质和使用的量的选择被认为是现有技术已知的。为了使所述膜包衣的硬化和破裂最小化，使用增塑剂与聚合物包衣物质的组合通常是有利的。可以根据本发明使用的增塑剂的实例包括：三醋汀，丙二醇，具有约200到约1,000分子量的聚乙二醇，邻苯二甲酸二丁酯，癸二酸二丁酯，柠檬酸三乙酯，植物油和矿物油，脂肪酸，C6，-C18脂肪酸的脂肪酸甘油酯等。 
根据本发明制备的核心组分可以在常规压片设备、胶囊填充设备或模塑设备上生产。 
附图说明
图1：显示实施例2的湿法制粒方法的示意图。 
图2：显示实施例3的热熔制粒的示意图。 
图3：显示实施例4的热熔挤出方法的示意图。 
图4：显示实施例6的硬明胶胶囊制备的示意图。 
本发明通过下列实施例举例说明，但不限于下列实施例： 
实施例1
N-(2-氯-6-甲基苯甲酰基)-4-[(2，6-二氯苯甲酰基)氨基]-L-苯丙氨酸-2-(二乙基氨基)乙酯盐酸盐(R411)
下列反应方案和步骤产生标题产物： 
Figure BDA0000082285630000051
步骤10产物的制备 
使2-氯-6-氟苯甲醛与正丁胺在回流下在甲苯中反应以制备相应的亚胺中间体。在通过蒸馏浓缩后，用THF稀释反应混合物。通过用在THF中的1.4当量的MeMgCl处理亚胺中间体来获得氯基团的金属-卤素交换。用稀酸水解亚胺基团并且用己烷提取2-氯-6-甲基苯甲醛(10)并且通过真空蒸馏纯化该步骤的产物。 
步骤3产物的制备 
使用DMSO/NaClO2，将2-氯-6-甲基苯甲醛(10)氧化为在乙腈中的2-氯-6-甲基苯甲酸中间体(11)。中和过量的氧化剂并且用甲苯提取需要的酸。通过部分蒸馏甲苯去除在反应混合物中的痕量水。包含2-氯-6-甲基苯甲酸中间体(11)的甲苯溶液直接进行步骤2反应。在存在催化量的N，N-二甲基甲酰胺(DMF)情况下，将草酰氯加入2-氯-6-甲基苯甲酸(11)的甲苯溶液中。在通过蒸馏浓缩后，将水加入以猝灭过量的草酰氯。将得到的2-氯-6-甲基苯甲酰基氯中间体(2)的溶液与4-硝基-L-苯丙氨酸甲酯盐酸盐在乙酸乙酯和氢氧化钠水溶液中合并。通过加入饱和的碳酸氢钠水溶液完成反应。在完成反应后，可以使用硅藻土过滤所述批次。分离所述层并且用水洗涤有机层。通过蒸馏用甲苯替换乙酸乙酯。在冷却并且用己烷稀释混合物后，将步骤3的产物结晶，通过过滤收集，并且用己烷洗涤并且干燥。 
步骤6产物的制备 
将步骤(3)产物通过在四氢呋喃(THF)中的硫化Pt/C催化剂进行氢化，伴随加热以得到步骤4的中间体。在通过过滤去除催化剂后，冷却步骤4的中间体THF溶液，与2，6-二氯苯甲酰氯和氢氧化钠水溶液合并。反应结束后，用另外一份的氢氧化钠水溶液处理步骤5的中间体，得到甲酯的水解。用乙酸异丙酯稀释混合物并且用盐酸酸化。分离水层并且用水洗涤有机层。在替换THF后并且通过蒸馏浓缩乙酸异丙酯后，结晶步骤6的产物，通过过滤收集，洗涤并且干燥。所述物质是与乙酸异丙酯的溶剂合物。 
步骤8产物的制备 
将步骤6产物，2-(二乙基氨基)乙基氯盐酸盐(1当量)和碳酸钠在DMF中的混合物加热到约45℃。完成反应后，将混合物冷却并且与乙酸异丙酯和氯化铵水溶液合并。分离水相并且将其丢弃，用DMF和水洗涤有机层。将该批次用乙酸异丙酯稀释，并且在真空下浓缩以得到游离胺的溶液。测试该批次的水含量。加热该批次，随后通过在表面下加入用氮气稀释的气体氯化氢以沉淀需要的终产物(8)的盐酸盐。将该批次冷却，通过过滤收集，用乙酸异丙酯洗涤并且干燥。可以将终产物解聚(delump)或研磨。 
实施例2
通过湿法制粒方法进行配制 
可以通过常规的湿法制粒方法制备R411药物产品。将典型的组合物和制备方法举例说明如下。称取一定量的R411，泊洛沙姆188，交聚维酮，聚乙烯吡咯烷酮K30，甘露糖醇和富马酸置于高切力制粒机中。用叶轮和左右交叉螺旋，设定在中速将内容物混合约2分钟。通过将需要量的纯水通过液体进料口喷雾加入，同时混合内容物。持续混合直到达到基于功率消耗读数的目标制粒终点。通过Fitz研磨以缓慢速度将获得的颗粒解聚。在～35℃通过流化床干燥将解聚的颗粒干燥直到获得目标水分含量。通过Fitz研磨机研磨干燥的颗粒以获得均一大小的颗粒来进一步加工。将这些颗粒与外部赋形剂如交聚维酮，滑石和硬脂酸镁通过在适合的混合器中混合而混合。使用适合的压片机将该粉末物质压缩成为片剂。将压缩的片剂用在式中显示的薄膜包衣，通过使用适合的片剂包衣设备包被。尽管湿法制粒对于该产物是可能的，由于可能的稳定性问题和加工问题，这是不可行的。由于较窄的制粒终点，该产物的水性湿法制粒存在明显的制备问题。对制粒方法的不充足的控制导致了关于压制和溶解性质的问题。 
湿法制粒 
Figure BDA0000082285630000081
显示湿法制粒的示意图示于图1中。 
实施例3
通过热熔制粒制备制剂
对于该产物的热熔制粒采用低熔点的泊洛沙姆(poloxmaer)188(52°-54℃)。典型的组合物显示在表中并且制备方法显示在示意图中。制备方法由高切力制粒，流化床冷却，研磨，混合，压缩和包衣组成。称取一定量的R411，泊洛沙姆188和交聚维酮(颗粒内)，置于带夹套的高切力制粒机中。将粉末与叶轮和切碎机在中速混合，同时通过循环热水将夹套的温度增加到60℃。将粉末间歇混合直到床的温度达到50℃。当床的温度达到50℃时开始持续混合以确保泊洛沙姆的均匀混合和均匀制粒。持续混合直到达到关于功率消耗的目标制粒终点。通过经过Fitz研磨机将颗 粒解聚。在环境条件下，在流化床中将解聚的颗粒冷却。将冷却的颗粒通过Fitz研磨机研磨以获得均匀的颗粒大小分布。在适合的混合器中，将研磨的颗粒与外部赋形剂如交聚维酮(颗粒外)，富马酸，ProSolv，滑石，无水乳糖和硬脂酸镁混合。使用适合的压片机将混合的颗粒压缩成核心。在通风的包衣锅中，将压缩的片剂使用适合的薄膜包衣进行薄膜涂布。备选地，还可以将颗粒研磨成硬明胶胶囊。 
热熔制粒 
Figure BDA0000082285630000101
显示热熔制粒的示意图示于图2中。 
热熔制粒法使用泊洛沙姆188在52-54℃的熔化性质以影响制粒并且提供对于制粒方法的更有利的控制。一致的制粒提供更稳定的下游加工并且产生可再现的溶出。因此，热熔制粒与常规的水性湿法制粒相反，提供更稳定的产品。 
实施例4
通过热熔挤出法生产的制剂 
可以通过热熔挤出法获得R411的制粒。这是最优选的方法，因为其提供R411与泊洛沙姆188的最紧密的混合，导致更均一和稳定的药物产品。因为热熔挤出法是连续的方法，其还提供在药物产品的放大中的另外的益处。典型的药物组合物提供在表中，生产方法提供在示意图中。 
R411和泊洛沙姆188在适合的混合器(料箱或双壁)中混合在一起。使 用齿轮操纵的进料器以恒速(10-20g/分钟)将混合物进料到适合的挤压器(Leistritz双螺旋挤压器)中，同时将螺旋的转速维持在100-200rpm。该双螺旋挤压器具有适合的螺旋几何形状，并且将压辊温度(对于Micro-1装置的8个辊)维持在30，40，60，70，70，70，70，70℃。使用3mm模从出口收集挤出物，在输送带上空气冷却。使用适合的条件，通过Fitz研磨机研磨收集的挤出物(如在中速下2mm筛)。在适合的混合器中将颗粒与外部赋形剂混合。使用压片机，将最终的混合物压缩成片剂。可以在通风的包衣锅中，使用适合的薄膜包衣包被核心。 
Figure BDA0000082285630000121
显示热熔挤出法的示意图示于图3中。 
实施例5
通过干燥制粒方法(击压(slugging)或滚筒压缩)制备制剂 
该部分提供举例说明通过干燥制粒法生产药物产品的实例。在下面的表中提供典型的药物组合物。在适合的混合器(料箱或双壁)中将R411，泊洛沙姆188，ProSolv SMCC50和硬脂酸镁的部分混合在一起。在击压法中，将该粉末块压缩成约10-15SCU硬度的平面片剂(1”直径)。对于滚筒压缩，将粉末块通过在需要的压力下，在移动的滚筒之间压缩来压缩成带状物。接着使用适合的研磨机(Fitz或共研磨机)研磨所述带状物或压缩块以获得具有平均颗粒大小范围在100-200微米的均一颗粒。在适合的混合器中，将颗粒与外部赋形剂混合。使用压片机将最终的混合物压缩成片剂。在通风包衣锅中，使用适合的薄膜包衣包被核心。 
制粒方法 
实施例6
在硬明胶胶囊中包含泊洛沙姆188的制剂 
通过如在前面实施例如湿法制粒，熔化制粒，熔体挤出或滚筒压缩的任何方法中获得的颗粒与外部赋形剂(如需要)混合并且填充到适合的大小硬壳胶囊中。在下面显示简单的实例，其中R411，泊洛沙姆188，交聚维酮和聚乙烯吡咯烷酮通过湿法制粒法制粒。将所述颗粒在流化床干燥器中干燥，研磨并且与外部赋形剂如硬脂酸镁混合。接着，将最终的混合物填充到硬明胶胶囊中。 
显示硬明胶胶囊制备的示意图示于图4中。 

Claims (8)

1.单位剂型的组合物，其包含
a)约50mg至400mg的N-(2-氯-6-甲基苯甲酰基)-4-[(2，6-二氯苯甲酰基)氨基]-L-苯丙氨酸-2-(二乙基氨基)乙酯盐酸盐，和基于a重量％的b)约5至40％的泊洛沙姆188、c)约0至20％的ProSolv SMCC50
Figure FDA0000082285620000011
和d)约0％至60％的无水乳糖。
2.权利要求1的组合物，其还包含
a)300至400mg的N-(2-氯-6-甲基苯甲酰基)-4-[(2，6-二氯苯甲酰基)氨基]-L-苯丙氨酸-2-(二乙基氨基)乙酯盐酸盐，
b)约10至25％的泊洛沙姆188，
c)约2至4％的ProSolv SMCC50
Figure FDA0000082285620000012
和
d)约30至50％的无水乳糖。
3.权利要求1的组合物，其中所述组合物通过热熔制粒法或热熔挤出法制备。
4.薄膜包衣片剂，其具有组合物，包含
Figure FDA0000082285620000013
5.薄膜包衣片剂，其具有组合物，包含
Figure FDA0000082285620000021
6.一种组合物，其包含
Figure FDA0000082285620000022
Figure FDA0000082285620000031
7.一种组合物，其包含
Figure FDA0000082285620000032
8.一种组合物，其包含
Figure FDA0000082285620000033
Figure FDA0000082285620000041
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CA2637240A1 (en) 2007-07-26
US20150209294A1 (en) 2015-07-30
EP1978928B1 (en) 2010-03-31
US20070184113A1 (en) 2007-08-09
JP5123207B2 (ja) 2013-01-23
JP2009523754A (ja) 2009-06-25
TW200735858A (en) 2007-10-01
WO2007082809A1 (en) 2007-07-26
DE602007005601D1 (de) 2010-05-12
ES2340544T3 (es) 2010-06-04

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