CN102596953A - 丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺组合物及其用途 - Google Patents

丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺组合物及其用途 Download PDF

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CN102596953A
CN102596953A CN2010800506244A CN201080050624A CN102596953A CN 102596953 A CN102596953 A CN 102596953A CN 2010800506244 A CN2010800506244 A CN 2010800506244A CN 201080050624 A CN201080050624 A CN 201080050624A CN 102596953 A CN102596953 A CN 102596953A
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hpmcas
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R·迪奥多尼
S·劳珀
H-J·梅尔
J·普德韦尔
F·威尔谢姆
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F Hoffmann La Roche AG
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Abstract

本发明涉及用于制备含有活性药物成分丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺和乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)的微量沉淀的整装粉剂(MBP)的改善的方法。本发明还涉及含有所述MBP的药物组合物，以及其在制备用于治疗癌症的药物中的用途。式(I)如下。

Description

丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺组合物及其用途
技术领域
本发明涉及用于制备含有化合物丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺(式1)和乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)的固体分散体、特别是微量沉淀的整装粉剂(Micro-precipitated Bulk Powder，MBP)的改善的方法。
Figure BDA00001618182800011
式1
式1的化合物、合成其的方法以及含有所述化合物的常规药物制剂已经在WO 2007002433和WO 2007002325中披露。式1的化合物显示了作为用于抑制癌症增殖特别是实体瘤生长的潜在药物的有价值的药物性质。
背景技术
具有低的水中溶解度的化合物(例如结晶形式的某些化合物)具有低的溶出度且因此可显示不良的生物利用度。不良生物利用度的化合物可存在对患者的治疗给药的问题，这通常是由于患者对化合物的不稳定吸收引起的给药/治疗作用的不可预知性。例如摄食可影响患者吸收所述不良生物利用度的化合物的能力，由此可能需要考虑到食物影响的给药方案。此外，当给药时，作为不可预知的给药作用的结果，剂量可能需要大的安全范围。此外，由于不良的生物利用度，可能需要大剂量的化合物来实现理想的治疗作用，由此这可能导致不期望的副作用。
相比于结晶形式，无定形形式的化合物1具有改善的水中溶解度，但由于其具有结晶趋势因此是不稳定的。由此理想的是配制化合物I使得其可主要以无定形形式来稳定存在。
HPMCAS为已经用于制备药物的固体分散体(SD)的聚合物(参见例如H.Konno,L.S.Taylor,Journal of Pharmaceutical Sciences,Vol.95,No.12,2006,2692-2705)。
EP 0 901 786 B1披露了包含不良水溶性药物和HPMCAS的喷雾干燥的固体分散体的组合物。WO 96/39385和WO 95/05360中分别披露的药物为糖原磷酸化酶抑制剂和5-脂肪氧化酶抑制剂。
EP 1 368 001 B1披露了包含药物比卡鲁胺和肠溶聚合物如HPMCAS的药物制剂。披露了用于蒸发溶剂的方法包括旋转蒸发、喷雾干燥、冷冻干燥和薄膜蒸发。还披露了可使用其它技术诸如溶剂控制沉淀、pH控制沉淀、喷雾冷凝和超临界流体技术(例如超临界流体增强分散溶液(SolutionEnhanced Dispersion by Supercritical Fluid,SEDS)技术)。
EP 0 344 603 B1披露了用命名为NZ-105的药物配制HPMCAS。该专利披露了通过如下制备制剂：将NZ-105和HPMCAS在有机溶剂中溶解并通过真空干燥、喷雾干燥、冷冻干燥等的方法除去溶剂。更具体地，HPMCAS和NZ-105的分散体通过如下形成：(1)通过包衣磷酸氢钙颗粒或者乳糖结晶进行流化床制粒；或者2)用乳糖真空干燥以形成固体滤饼，然后将其雾化以形成粉状物质。粒度描述为在100至400目筛(0.037mm至0.149mm)的范围内。
EP 0 580 860披露了用于制备在聚合物中溶解的药物的固体分散体的方法，所述聚合物具体的是HPMCAS。要求保护的方法的特征在于使用配备有桨状装置的双螺杆挤出机。
F.Tanno等披露了使用HPMCAS作为在固体分散体中的载体。在研究中用作模型物质的具体药物为硝苯地平。固体分散体通过如下获得：将HPMCAS和药物的混合物在有机溶剂中在TeflonTM板上喷雾、蒸发溶剂并移去并且研磨所得的薄膜(Drug Development and Industrial Pharmacy,Vol.30,No.1,2004,9-17)。Molecular Pharmaceutics,Vol.5,No.6，2008,1003-1019也披露了使用若干不良水溶性药物的HPMCAS喷雾干燥的分散体。
Bruno C.Hancock,George Zografi,Journal of Pharmaceutical Sciences,Vol 86，No.1,1997,1-12披露了在制备固体分散体时除去溶剂的方法，其使用所谓的溶剂方法，包括例如喷雾干燥、真空干燥、冷冻干燥或者沉淀。
发明内容
在某些方面和实施方案中，本发明提供了制备包含HPMCAS和式1的化合物的固体分散体的方法。在许多实施方案中，与其它方法相比，所述方法可使用较少量的有机溶剂且由此可为更加环境友善的；在工业规模使用时是安全的；和/或显示改善的性质诸如针对重结晶的稳定性。在许多方面和实施方案中，所述方法包括使用本申请所述的条件和操作参数进行HPMCAS和式1的化合物的混合物在水相中的微量沉淀。
在一个实施方案中，本发明提供了用于制备含有无定形形式的式1的化合物和HPMCAS的固体分散体的方法，其中所述固体分散体通过如下获得：在相同的有机溶剂中在水相中引入式1的化合物和HPMCAS的溶液，并且随后进行所述固体分散体由所述水相的沉淀和分离。
在某些更具体的实施方案中，上述方法包括下述步骤：
(a)将式1的化合物和HPMCAS在相同的有机溶剂中溶解以得到一个单一的有机相；
(b)将由(a)得到的有机相连续加入至存在于混合室的水相中，所述混合室配备有高剪切混合单元和将所述混合室与封闭回路(closed loop)连接的两个另外的开口，其中所述水相循环并通过所述混合室；
(c)将由无定形形式的式1的化合物和HPMCAS组成的混合物由(b)中提及的水相沉淀析出，同时操作所述高剪切混合器并使所述水相通过封闭回路内的混合室，这导致形成沉淀物的含水混悬液；
(d)在操作所述高剪切混合单元的同时且在由(a)制备的有机溶液已经完全加入至所述水相中之后使所述含水混悬液连续循环通过所述混合室，直到获得确定的粒度和/或粒度分布；
(e)将固相由所述混悬液分离；
(f)将所述分离的固相用0.01N HCl和/或水洗涤；以及
(g)使所述固相不结块(delump)并干燥。
在更具体的实施方案中，本方法包括以下步骤，其中
-上面步骤(a)中的所述有机相为化合物1和HPMCAS在DMA中的浓度为10至40%的溶液，化合物1与HPMCAS的比例为约10至90%(w/w)至约60至40%(w/w)；且
-上面步骤(b)中的连续加入经注射器喷嘴来完成，所述注射器喷嘴以与高剪切混合器的纵轴成40至50°之间的角度定向并且与所述高剪切混合器的转子具有约1至约10mm的距离，所述转子以约15至约25m/秒的桨尖速度操作。
在更具体的实施方案中，本方法包括以下步骤，其中
-上面步骤(b)中的连续加入经注射器喷嘴来完成，所述注射器喷嘴以与高剪切混合器的纵轴成约45°的角度定向并且与所述高剪切混合器的转子具有约2至约4mm的距离，所述转子以约25m/秒的桨尖速度操作。
在其它实施方案中，本方法包括以下步骤，其中
-上面步骤(g)中的干燥经流化床干燥来实现。
在另外的特别优选的实施方案中，(a)中的所述有机相包含DMA、式1的化合物和HPMCAS-L，且步骤(b)包括将所述有机相以约80/1至200/1(水相/有机相)范围内的质量流量比(mass flow ratio)加入至HCl水溶液(0.01N)中，同时将所述HCl水溶液保持在约2-8°C的温度。
在另外的实施方案中，本发明提供了通过上面提及的方法得到的固体分散体。
干燥的沉淀物可进一步加工为任意类型的固体药物制剂或者剂型，其对于本领域技术人员来说是已知的。特别优选的是口服剂型诸如片剂、胶囊剂、丸剂、粉末剂、混悬剂、糊剂等。用于制备所述药物制剂的适当的赋形剂以及方法的详述可出现在例如Raymond C.Rowe et al,Handbook ofPharmaceutical Excipients,6th edition,2009,Pharmaceutical Press(Publ.);ISBN-10:0853697922中。
因此，由此得到的药物制剂构成本申请提供的另外的实施方案。
附图说明
图1显示了用于制备本发明的固体分散体(MBP)的装置的示意图。该装置提供了具有温度控制工具的两个贮器(容器)，一个用于提供在控制的温度的水相(1)，另一个用于提供在控制的温度的有机相(2)。两个容器均进一步配备有自动搅拌器(3)。使用泵(5)使水相在封闭回路(4)中循环，同时通过高剪切混合单元(6)。在定量泵(dosing pump)(7)的辅助下且经在图2中更加详细显示的注射器喷嘴将有机相加入至高剪切混合单元内的水相中。
图2显示高剪切混合单元(图1的(6))的更加详细的示意图。喷嘴(8)置于高剪切混合单元之内的水相内。喷嘴可定向为相对于高剪切混合单元的转子(9)的不同角度(α)以及与转子尖端的确定距离(d)内。
图3显示了由通过本发明的高剪切混合器沉淀(3a)和常规喷雾沉淀(3b)制备的两批固体分散体(MBP)得到的X射线衍射图的比较。在该图中显示的结果表明相比于高剪切沉淀的MBP，喷雾沉淀的MBP对于重结晶来说是较不稳定的，这通过如下证实：(b)的衍射图中的尖的信号峰的早期出现，其可指定为式(1)的化合物的结晶形式。在每个图中的底部线表示初始样品，由此向上的各条线分别表示在气候室(50°C，90%RH)中在14小时、41小时、96小时、6天以及13天储存后采集的样品。
具体实施方式
将作为活性药物成分(API)的式1的化合物和赋形剂乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)在有机水可混溶性溶剂中在进料斗中溶解。在第二容器中，将确定温度的水相泵入容器外的圈内，同时通过高剪切混合器(HSM，转子/定子单元)。该操作的示意图可参见图1。在完成制备方法的过程中控制两种溶液的温度。将具有API和赋形剂的溶液(有机相)以确定的流速投料至包括转子/定子工具的混合室中，同时操作高剪切单元(分散单元)。在混合两种液体(水相和有机相)的过程中，形成了作为具有确定比例的无定形API和HPMCAS的混合物的几乎水不溶的沉淀物，这导致形成微量沉淀的整装粉剂(MBP)在外相(水和有机溶剂的混合物)中的混悬液。在加入有机相完成后，促使所述混悬液通过许多通道经过分散单元以调整粒度。随后将混悬液离心并用水相洗涤几次以除去有机溶剂并最终另外用纯水洗涤。使得到的湿的MBP不结块并干燥以使水含量低于按重量计2%(w/w)。得到MBP，其为白色、自由流动的粉末。
式1的化合物可硅胶在WO 2007002433或者WO 2007002325中披露的方法合成。
术语“HPMCAS”是指乙酸羟丙基甲基纤维素琥珀酸酯(商品名：AQOAT，购自Shin-Etsu Chemical Industry Co.,Ltd.,Japan或者指定销售者)，其以下述级别获得：AS-LF、AS-MF、AS-HF、AS-LG、AS-MG和AS-HG。不同HPMCAS级别的溶解度以及它们的药物释放性能取决于环境的pH值。因此，通过选择适当的HPMCAS级别(参见AQOAT的产品信息手册)，药物的释放性能可在约pH5.2至约pH6.5的范围内调整。因此，在一个实施方案中，所述式1的化合物在具有选自HPMCAS级别AS-L、AS-M、AS-H的至少一种聚合物的固体分散体中。然而，认为两种或者多种不同HPMCAS级别的混合物也可根据本发明使用。
本申请使用的术语“固体分散体”是指由高分子量化合物诸如聚合物优选为HPMCAS形成的固态物质，其中低分子量化合物诸如式1的化合物进行分子级分散。优选地，固体分散体作为单相系统存在。本发明特别优选的固体分散体为基本上由HPMCAS和主要以其无定形形式存在的式1的化合物组成的微量沉淀的整装粉剂(MBP)。
步骤(a)提及的“有机溶剂”是指其中式1的化合物和HPMCAS可混溶的任何有机溶剂。优选的有机溶剂为N-甲基吡咯烷酮、二甲基甲酰胺、二甲基亚砜、二甲基乙酰胺(DMA)，其中DMA是最优选的。一起存在于有机相的式1的化合物和HPMCAS的组合量可在约10至40wt%的范围内，优选地约15至40wt%的范围内，更优选地约25至40wt%的范围内，最优选地约35wt%。有机溶剂中的式1的化合物/HPMCAS的重量比为约10/90至约60/40wt%，更优选地约30/70至约60/40wt%，且最优选地约30/70wt%。优选地，有机溶剂的温度调节为50和110°C之间，优选地60和90°C之间，最优选地约70°C，之后将其加入至步骤(b)提及的混合室。在有机溶剂中的式1的化合物和HPMCAS的混合物在本申请中也称为“有机相”或者“DMA相”。
步骤(b)提及的“水相”优选地由酸性水(pH<7)组成，最优选地0.01N盐酸(HCl)。水相保持在约2和约60°C的温度，优选在约5和约20°C的温度，最优选地约5°C的温度。由于经高剪切混合器或者辅助泵优选为凸轮泵(rotary lobe pump)产生的流，水相由其贮器的末端阀循环出来(图1的(1))，然后通过高剪切混合器，返回至所述贮器。优选地，圈的出口置于在贮器中保持的流体水平之下以防止发泡。
上面步骤(b)提及的有机相加入至混合室经直接指向水相的注射器喷嘴来实现。可使用本领域技术人员已知的任何常规的喷嘴。显示中心或者无中心几何学的优选的注射器喷嘴被分离且具有约1至10mm的直径。无中心(无中心的)几何学和5mm的直径为特别优选的。所述注射器喷嘴可指向于高剪切混合单元的转子，其成0和90°之间的角度，优选地40和50°之间的角度，最优选地45°的角度(α，图2)。在本发明的方法过程中，注射器喷嘴的指向点和高剪切混合单元的转子的尖端之间的距离为约1至10mm，优选地约2至4mm，且最优选地约2.6mm。有机相的加入优选地以约60/1至约300/1、优选地约70/1至约120/1且最优选地约100/1的投料速率(即沉淀过程中的水相/有机相的质量流量比)来进行。沉淀后的水相/有机相的最终比例在约5/1-12/1、优选地7/1-10/1且最优选地8.5/1的范围内。
当有机相加入(注射)至混合室的水相中时，操作高剪切混合单元。可应用本领域技术人员已知的任何常规的高剪切混合单元(转子/定子单元)。特别优选的是齿状盘分散单元。本发明优选的转子几何学使用具有放射状单一齿列(teeth row)或者双重齿列或者它们的组合的转子/定子单元。也可应用具有圆锥状齿列的转子。转子的桨尖速度为约15至约25m/秒，优选地25m/秒。
在完成将有机相加入至水相之后，所得的混悬液(由此沉淀物由水相中的无定形的式1的化合物和HPMCAS组成)进一步在包括高剪切混合单元的封闭回路中循环。在高剪切混合单元之外，所述循环必须在辅助泵优选为凸轮泵的辅助下进行。所述混悬液通过所述高剪切混合单元若干次，直到获得理想的粒度和/或粒度分布。通常所述混悬液通过所述高剪切混合单元达约1至60次，最优选地6次。粒度和/或粒度分布可通过本领域技术人员熟知的标准技术控制，例如动态光散射。本发明优选的粒度在D50=80–230μm的范围内，优选地D50=80-160μm的范围内。
上面步骤(e)的固体分散体(MBP)的分离可通过使用常规过滤技术或者离心机来进行。在分离之前，将所述混悬液优选地调节至约5至10°C。随后，将分离的固体分散体用酸性水、优选为0.01N HCl洗涤；接着进一步用纯水洗涤以基本上除去有机溶剂(步骤(f))。所述分离的(湿的)固体分散体(MBP)通常显示60和70%(w/w)之间的水含量，其在任何进一步加工之前需要干燥。所述干燥可通过使用本领域技术人员已知的任何标准技术来进行，例如在30和50°C之间、优选在约40°C的温度在减压、优选低于20毫巴使用干燥箱。可组合或者连续使用若干干燥操作，其中流化床干燥的使用特别优选作为本发明的最终干燥步骤。
将本发明的固体分散体(MBP)的稳定性与经常规喷雾沉淀得到的MBP的稳定性进行比较。“常规喷雾沉淀”是指将有机相经喷嘴喷雾至水相上，所述喷嘴置于水相之外、其表面之上，正如其在许多常规喷雾沉淀技术的情况下那样。所有另外的操作参数对于两种方法来说是相同的。稳定性(由此对式1的化合物的重结晶的抑制)通过X射线衍射测量使用本领域技术人员熟知的常规广角X射线散射装置来确定。样品制备对于两种MBP来说是相同的。在X射线测量之前，将样品在气候室(50°C和90%湿度(RH))处理若干小时以及若干天(0小时、14小时、41小时、4天、6天、13天)。针对本发明得到的MBP的结果在图3(a)中显示，且针对常规方法得到的MBP的结果在图3(b)中显示。对于两种MBP的最早出现的X射线曲线显示广角区域的宽的卤素峰且不存在尖的信号峰，由此清楚地证实两种物质为无定形形态。在若干天之内，尖的信号峰出现在由常规方法制备的MBP得到的X射线曲线中(图3(b))，但不出现在由本申请披露的方法制备的MBP得到的X射线曲线中(图3(a))。
本申请提供的新的方法可优选地使用在附图1中显示的装置来进行。
根据本申请提供的方法得到的固体分散体具体的是MBP可按照对于给予药物(诸如式1的化合物包括具有不良水溶性的药物)且特别是对于口服剂型的多种形式来使用。示例性剂型包括粉末剂或者颗粒剂，其可无水进行口服或者通过加入水以形成糊剂、淤浆、混悬剂或者溶液剂来复溶(reconstitute)进行口服；片剂、胶囊剂或者丸剂。可将各种添加剂与本申请所述的固体分散体混合、研磨或者制粒以形成适于上述剂型的物质。可能的有益添加剂通常可落入下述类别的范围内：其它基质材料或者稀释剂、表面活性剂、药物络合剂或者增溶剂、填充剂、崩解剂、粘合剂、润滑剂和pH调节剂(例如酸、碱或者缓冲剂)。其它基质材料、填充剂或者稀释剂的实例包括乳糖、甘露醇、木糖醇、微晶纤维素、焦磷酸钙和淀粉。表面活性剂的实例包括月桂硫酸钠和聚山梨酯80。药物络合剂或者增溶剂的实例包括聚乙二醇、咖啡因、呫吨、龙胆酸和环糊精。崩解剂的实例包括羧甲基淀粉钠、海藻酸、羧甲基纤维素钠、甲基纤维素和交联羧甲基纤维素钠。粘合剂的实例包括甲基纤维素、微晶纤维素、淀粉以及树胶诸如瓜尔胶和西黄蓍胶。润滑剂的实例包括硬脂酸镁和硬脂酸钙。pH调节剂的实例包括酸诸如枸橼酸、乙酸、抗坏血酸、乳酸、门冬氨酸、琥珀酸、磷酸等；碱诸如乙酸钠、乙酸钾、氧化钙、氧化镁、磷酸三钠、氢氧化钠、氢氧化钙、氢氧化铝等；以及通常包含酸和所述酸的盐的混合物的缓冲剂。所述pH调节剂的包含物的至少一种功能是控制药物、基质聚合物或者两者的溶出度，由此控制溶出过程中的局部药物浓度。
如早前所述，添加剂可在形成固体无定形分散体的过程中或者之后掺入其中。除了上述添加剂或者赋形剂之外，针对使用本领域技术人员已知的本申请披露的组合物配制和制备口服剂型的任何常规物质和方法的使用是可能有效的。
因此，另外的实施方案包括含有通过本申请所述的方法得到的固体分散体的药物制剂。
在一个实施方案中，所述固体分散体可加工为含有至多92%的由本申请披露的方法得到的MBP的薄膜包衣的片剂，且其中所述MBP由约30%的式(1)的化合物和约70%的HPMCAS组成。片剂的剩余部分由以下物质的混合物组成：常规崩解剂，例如交联羧甲基纤维素钠；助流剂，例如无水胶状二氧化硅；粘合剂，例如羟丙纤维素；润滑剂，例如硬脂酸镁；以及薄膜包衣。可应用本领域技术人员已知的任何常规的薄膜包衣混合物，例如Opadry II pink 85F14411。对于薄膜包衣的片剂的代表性混合物在实施例6中给出。
在另外的实施方案中，本申请提供了用作药物的根据本发明方法得到的固体分散体。
在另外的实施方案中，本申请提供了通过本发明方法得到的固体分散体在制备用于治疗癌症特别是实体瘤且更具体的是恶性黑色素瘤的药物中的用途。
在另外的实施方案中，本申请提供了根据本发明方法得到的固体分散体，其用作治疗癌症特别是实体瘤且更具体的是恶性(转移性)黑色素瘤的药物。
实施例
通过以示例说明本发明而不是限制其意在范围而给出的下述实施例，本发明将变得显而易见。
实施例1:制备DMA相：
式1的化合物和HPMCAS在有机溶剂中的浓度为35%(w/w)，而式1的化合物和HPMCAS的比例为30:70。溶液的温度调节为70°C。
在250ml双套层玻璃烧瓶反应器中，在20-25°C将21g式1的化合物在130g二甲基乙酰胺(DMA)中溶解。在搅拌的同时，将48.9g HPMC-AS加入至溶液中。将混合物加热以达到70°C。得到澄清溶液。
实施例2:制备水相
在双套层2.0升反应器中，将1210g 0.01N HCl温热至5°C。在反应器的末端阀的外部，通过高剪切混合器或者辅助泵优选为凸轮泵使水相循环，然后通过高剪切混合器，返至反应器的顶部。再循环至反应器的入口位于流体水平之下以防止发泡(参见图1)。
实施例3:沉淀
高剪切混合器
高剪切混合器中的转子的桨尖速度设置为25m/秒。使用具有一个齿列的转子/定子组合，每个齿列用于转子和定子。
投料DMA溶液
在70°C温热的DMA溶液使用齿轮泵经注射器喷嘴投料，所述注射器喷嘴指向在循环水相中的高剪切混合器的混合室。
DMA溶液的投料速率
DMA溶液投料至水相，这导致在高剪切混合器的混合室中的HCl/DMA的比例为100/1。
实施例4:在HSM中的另外的分散(沉淀后)、分离和洗涤
在加入DMA溶液之后，再一次分散得到的MBP混悬液，其相应于通过高剪切混合器的等量的批次。时间相应于按照6次的该批次的计算的再循环次数的翻转时间(turnover)。
保持在5-10°C的得到的混悬液由固体MBP分离。通过使用抽滤器完成该操作。将分离的MBP用0.01N HCl(15kg，0.01N HCl/gMBP)洗涤，接着用水(5kg水/kg MBP)洗涤以除去DMA。分离的(湿的)MBP具有60和70%之间的水含量。
实施例5:去结块和干燥
在干燥之前，通过使用筛磨机使(湿的)MBP不结块。将(湿的)MBP在干燥箱中干燥。在MBP的干燥操作过程中，使产物的温度低于40°C以避免API的重结晶。干燥箱内部的压力低于20毫巴。干燥后的MBP的水含量低于2.0%且在XRPD图谱中表示无定形形式。
实施例6:薄膜包衣的片剂
  组分   质量(mg/片剂)
  MBP(30%化合物(1),70%HPMCAS)   800.00
  交联羧甲基纤维素钠   29.40
  胶状无定形硅胶   10.40
  羟丙纤维素   4.25
  硬脂酸镁   5.95
将上面提及的成分混合通过常规方法压制为片剂。该薄膜包衣由聚乙烯醇(8.00mg)、二氧化钛(4.98mg)、聚乙二醇3350(Macrogol 3350)(4.04mg)、滑石(2.96mg)和氧化铁(0.02mg)组成。也可使用任何其它常规的薄膜包衣混合物，例如Opadry II pink 85F14411。

Claims (10)

1.用于制备含有无定形形式的式1的化合物和HPMCAS的固体分散体的方法：
Figure FDA00001618182700011
包括以下步骤：
(a)将式1的化合物和HPMCAS在相同的有机溶剂中溶解以得到一个单一的有机相；
(b)将由(a)得到的有机相连续加入至存在于混合室的水相中，所述混合室配备有高剪切混合单元和将所述混合室与封闭回路连接的两个另外的开口，其中所述水相循环并通过所述混合室；
(c)使由无定形形式的式1的化合物和HPMCAS组成的混合物由(b)中提及的水相沉淀，同时操作所述高剪切混合器并使所述水相通过封闭回路内的混合室，这导致形成沉淀物的含水混悬液；
(d)在操作所述高剪切混合单元的同时且在由(a)制备的有机溶液已经完全加入至所述水相中之后，使所述含水混悬液连续循环通过所述混合室，直到获得确定的粒度和/或粒度分布；
(e)将固相由所述混悬液分离；
(f)将所述分离的固相用0.01N HCl和/或水洗涤；以及
(g)使所述固相不结块并干燥。
2.权利要求1的方法，其中
-(a)中的所述有机相为化合物1和HPMCAS在DMA中的浓度为10至40%的溶液，化合物1与HPMCAS的比例为约10至90%(w/w)至约60至40%(w/w)；且
-步骤(b)中的连续加入经注射器喷嘴来完成，所述注射器喷嘴以与高剪切混合器的纵轴成40至50°之间的角度定向并且与所述高剪切混合器的转子具有约1至约10mm的距离，所述转子以约15至约25m/秒的桨尖速度操作。
3.权利要求2的方法，其中(a)中的所述有机相为化合物1和HPMCAS在DMA中的浓度为35%的溶液，化合物1与HPMCAS的比例为30%至70%(w/w)。
4.权利要求1至3中任一项的方法，其中(a)中的所述有机相包含DMA、式1的化合物和HPMCAS-L，且步骤(b)包括将所述有机相以约80/1至200/1(水相/有机相)范围内的质量流量比加入至HCl水溶液(0.01N)中，同时将所述HCl水溶液保持在约2-8°C的温度。
5.通过权利要求1至4中任一项的方法得到的固体分散体。
6.权利要求5的固体分散体，特征在于其为微量沉淀的整装粉剂(MBP)，其中所述式1的化合物主要以其无定形形式存在。
7.药物制剂，含有权利要求1至4中任一项的方法得到的固体分散体，任选同时含有另外的药用辅料。
8.权利要求1至4中任一项的方法得到的固体分散体，用作药物。
9.权利要求1至4中任一项的方法得到的固体分散体，用作用于治疗癌症特别是实体瘤、更具体的是恶性黑色素瘤的药物。
10.基本上如本申请所述的新的组合物、方法和用途。
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