CN101693029A - 具有改善生物利用度的口服制剂 - Google Patents
具有改善生物利用度的口服制剂 Download PDFInfo
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- CN101693029A CN101693029A CN200910166667A CN200910166667A CN101693029A CN 101693029 A CN101693029 A CN 101693029A CN 200910166667 A CN200910166667 A CN 200910166667A CN 200910166667 A CN200910166667 A CN 200910166667A CN 101693029 A CN101693029 A CN 101693029A
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- carbonate
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Abstract
本发明涉及具有改善的生物利用度的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒的口服制剂。更具体而言,本发明涉及一种口服制剂,所述口服制剂包含:N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药物上可接受的盐;和一种或多种选自由碱金属碳酸盐、碱金属碳酸氢盐和碱土金属碳酸盐组成的组的碳酸盐,和/或一种或多种选自由淀粉甘醇酸钠、羧甲基纤维素钙和交联羧甲基纤维素钠组成的组的崩解剂。根据本发明的口服制剂抑制N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药物上可接受的盐在释放的初始阶段的胶凝作用,其增加溶解速率并显著增加生物利用度。
Description
技术领域
本发明涉及具有改善的生物利用度的N-羟基-4-5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒的口服制剂。
更具体而言,本发明涉及口服制剂包含:化学式1的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药学上可接受的盐;和选自由碱金属碳酸盐、碱金属碳酸氢盐和碱土金属碳酸盐组成的组的一种或多种碳酸盐和/或选自由淀粉甘醇酸钠(sodium starch glycolate)、羧甲基纤维素钙(carmellose calcium)和交联羧甲基纤维素钠(croscarmellose sodium)组成的组的一种或多种崩解剂。
化学式1
背景技术
本发明人已经在韩国专利公开公布号10-2003-0008654中公开了化学式1的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒及其盐通过抑制破骨细胞的功能抑制过多的骨吸收,从而在骨质疏松症上具有优异的预防和治疗效果。
化学式1的化合物是水溶性差的、高度亲脂性的并且是弱的碱,在低pH条件诸如胃液中大部分电离。因此,当溶液pH从强酸性条件改变成弱酸性或弱碱性条件(pH3~pH7.5)时,化学式1的化合物的水溶性显著地降低。特别是,化学式1的化合物在水条件中实际上是不可溶的,其中pH约为pH5或更大并且当与水接触时自身胶凝。
关于制药方面,为了化学式1的化合物可以显示作为活性成分的适当药物功效,其药物制剂应当迅速在胃中崩解,并且应当将所述活性成分释放成吸收到体内。另外,化学式1的化合物取决于水条件的pH。尽管所述化合物可溶于非常强的酸性水条件诸如胃液,其中所述化合物大部分电离,但是它在弱酸性或中性水条件中实际上是不溶的。而且,因为当与水接触时它自身胶凝,所以不能预期迅速释放并有效吸收到体内。
一般地,为了改善水溶性差的活性成分的溶解速率,已经提出了制药方法诸如活性成分粒子大小的减少,同质多晶,无定形,喷雾干燥,混合压碎,进入水溶性聚合物中的固体分散物,溶剂合物化合物,与添加剂相互作用,等。在它们之中,固体分散,其中将不溶的活性成分分散到药物无活性的水溶性聚合物中,作为增加不溶活性成分溶解速率方法是众所周知的。(Albert等,International Journal of Pharmaceutics,Vol.104,p169~174,1994;J.M.Gines等,International Journal of Pharmaceutics,Vol.143,p247~253,1996)。
在这点上,本发明人进行研究以利用诸如进入水溶性聚合物的固体分散物、喷雾干燥、混合压碎和无定形的上述方法增加化学式1的化合物的溶解。然而,没有改善溶解却相反抑制了溶解,所以没有获得满意结果。因此,本发明人进行了深入细致的研究以分析所述化合物的缓慢溶解速率的原因并解决所述问题。
所述研究导致发现,当化学式1的化合物与诸如淀粉衍生物或纤维素衍生物的特定崩解剂(disintegrant)、碳酸盐或上述特定崩解剂和碳酸盐的混合物配制时,可以显著增加溶解速率和生物利用度。
发明内容
技术问题
本发明的目的是提供具有改善的生物利用度的口服制剂,包含氮-羟基4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药学上可接受的盐,和碳酸盐和/或特定的崩解剂。
技术解决方案
为了实现以上目的,本发明提供一种口服制剂,所述口服制剂包含:化学式1的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药学上可接受的盐;和一种碳酸盐。
在另一方面,本发明提供一种口服制剂,所述口服制剂包含:化学式1的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药学上可接受的盐;和选自由淀粉甘醇酸钠、羧甲基纤维素钙和交联羧甲基纤维素钠组成的组的一种或多种崩解剂。
在另外的方面,本发明提供一种口服制剂,所述口服制剂包含:化学式1的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药学上可接受的盐;一种碳酸盐;和选自由淀粉甘醇酸钠、羧甲基纤维素钙和交联羧甲基纤维素钠组成的组的一种或多种崩解剂。
<化学式1>
有益效果
根据本发明的口服制剂通过在释放的开始阶段与水接触时抑制它的胶凝作用,增加化学式1的化合物的溶解速率并显著增强化学式1的化合物的生物利用度。N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒的口服制剂或其药学上可接受盐,其具有与水接触时独自胶凝的特征,将其与碳酸盐和/或与特定的崩解剂配制以防止所述胶凝作用。
除上述成分之外,根据本发明的口服制剂还可以包括一种或多种药学上可接受的无机赋形剂诸如磷酸二氢钙、磷酸钙或沉淀碳酸钙。所述无机赋形剂不仅改善化学式1的化合物的溶解速率,而且作为用于防止和治疗骨质疏松症的钙供应者。
附图说明
图1显示根据本发明的口服制剂(胶囊)的溶出试验的结果;
图2显示根据本发明的口服制剂(片剂)的溶出试验的结果;
图3显示根据本发明的口服制剂的溶出试验结果,所述口服制剂含有无机或有机赋形剂;和
图4显示根据本发明的口服制剂的生物利用度研究结果。
最佳方式
以下,将详细地描述本发明。
本发明涉及由化学式1表示的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或,其具有pH-依赖的溶解度、强静电引力、由水溶液中疏水性和胶凝性质所引起的低润湿性的特性。因此,当施用未配制的普通口服制剂诸如用活性成分装满的胶囊时,在释放的初始阶段,所述制剂表面被水缓慢渗透,转化成凝胶并最终用粘性的栓塞涂层。该粘性的栓塞防止水进一步并迅速渗透到所述制剂中,其导致形成一块保持所述制剂原形状的凝胶。因此,从所述制剂凝胶层的活性成分释放速率是非常缓慢的,其导致低的生物利用度。另外,因为化学式1的化合物具有低表观密度和强的静电引力,所以发生所述化合物粒子的附聚。在制备过程期间不仅化学式1的化合物与多种赋形剂的可混合性而且所述混合物的流动性都是不良的。因此,存在实现所述制剂均质性和再现性的困难。
尽管通过利用多种制药方法进行许多试验以增加化学式1的化合物的生物利用度,但是还没有获得满意效果,原因在于释放的初始阶段的硬质形式自身的化合物形式的凝胶。例如,因为固体分散方法广泛地用于增加不溶活性成分的溶解速率,所以存在将化学式1的化合物分散到水溶性聚合物中的试验,所述水溶性聚合物诸如聚乙烯吡咯烷酮或羟基丙基甲基纤维素。然而所述试验导致抑制而不是改善从所述固体分散物释放化学式1的化合物。这些结果的原因可能在于,用作药物无活性载体的通常的水溶性聚合物诸如聚乙烯吡咯烷酮或羟基丙基甲基纤维素加速而不是防止化学式1的化合物在释放初始阶段的胶凝作用。
另外,存在其它试验,将化学式1的化合物与作为超崩解剂的聚乙烯聚吡咯烷酮和/或作为普通崩解剂的多种赋形剂配制到所述口服固体制剂中,所述口服固体制剂举例来说是片剂或胶囊,所述普通崩解剂例如淀粉、低取代的羟基丙基纤维素、微晶纤维素等。然而上述试验也不能实现在化学式1的化合物溶解上的满意改善。
作为化学式1化合物的药物制剂的进一步研究的结果,包括上述试验,本发明人已经发现,在化学式1的化合物释放或快速分散所述制剂期间,上述碳酸盐和/或特定的崩解剂在与水接触的扩散层中区域性形成中性pH或弱碱性环境,其有效防止在释放初始阶段由水合所引起的胶凝作用。
在根据本发明的口服制剂中,可以将化学式1的化合物用作它的药学上可接受的盐形式。可以将盐酸、溴酸、硫酸或磷酸用于制备化学式1化合物的无机酸盐。可以将柠檬酸、乙酸、乳酸、酒石酸、富马酸、甲酸、丙酸、草酸、三氟乙酸、甲磺酸、马来酸、苯甲酸、葡糖酸、甘醇酸、琥珀酸、4-吗啉乙烷磺酸、樟脑磺酸、4-硝基苯磺酸、羟基-邻-磺酸、4-甲苯磺酸、半乳糖醛酸、双羟萘酸、谷氨酸或天冬氨酸用于制备化学式1化合物的有机酸盐。可以优选将盐酸和甲磺酸分别用于制备化学式1的化合物的无机酸和有机酸盐。特别是,当利用甲磺酸制备所述盐时,化学式1化合物的2甲磺酸盐是优选的。
虽然化学式1化合物的2甲磺酸盐具有改善的水溶性,但是取决于水溶液的pH环境和胶凝性质,它还显示不溶活性成分的特征。原因是,当所述盐溶解在诸如例如水、唾液的水液体和胃肠道中时,在口服以后,将N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒离解而形成化学式1的化合物的2甲磺酸盐。因此,当将上述化学式1化合物的药学上可接受盐配制到本发明中描述的口服制剂中时,在释放早期胶凝作用进行以前所述活性成分容易释放,从而显著改善它的生物利用度。取决于显示所述化合物治疗效果需要的剂量,不特别限制化学式1化合物的量,但是优选1~60重量%的范围。在含有化学式1化合物的口服制剂中使用的碳酸盐选自由下列盐组成的组:碱金属碳酸盐,诸如碳酸钠、碳酸钾、等;碱金属碳酸氢盐,诸如碳酸氢钠、碳酸氢钾、等;和碱土金属碳酸盐诸如碳酸钙、碳酸镁、等。优选碳酸氢钠或碳酸钙。
在不考虑任何活性成分的物理化学性质的情况下,试图单独利用由简单的酸-碱中和反应引起泡腾反应增加活性成分的溶解速率。例如,在日本专利公开公布号90-704(对应于美国专利号5091191)中公开了一种溶解曲线取决于水溶液pH的化合物,当将它配制成含有甘露糖醇、碳酸氢钠和大量水溶性聚合物的粒剂时,所述化合物显示pH独立的稀释曲线。然而,描述了对于pH依赖溶解的这样一种改善效果不仅是由利用碳酸氢钠所引起,而且是由于一起使用的多种添加剂的组合相互作用。
不像那些常规的尝试,本发明在下列方面不同于它们,不仅通过简单泡腾反应而且通过多种和复杂的胶凝作用上的抑制效果显著地改善溶解速率,即使将化学式1的化合物和碳酸盐配制成没有任何其它添加剂诸如水溶性聚合物的口服制剂。所以,显然本发明与传统技术不同。
也就是说,根据本发明的化学式1化合物显示pH依赖的溶解度和pH依赖的胶凝作用的性质。因为pH环境从强酸性改变成弱酸性或弱碱性(pH3~pH7.5),化学式1化合物的溶解度和胶凝作用显著减少。
此外,在根据本发明的化学式1化合物的口服制剂中,抑制胶凝作用的碳酸盐与胃液反应而在释放的初始阶段产生二氧化碳。因而,该产生的气体引起口服制剂泡腾崩解,其导致抑制胶凝作用。另外,在释放的初始阶段期间,所述碳酸盐区域性将与水接触的扩散层的pH环境改变成中性或弱碱性条件,其有效抑制化学式1化合物的胶凝作用。
基于化学式1化合物或其药学上可接受盐的一个重量份,以约0.4至6.0重量份,优选0.5至2.0重量份的量含有根据本发明的碳酸盐。当以小于0.4重量份的量使用所述碳酸盐时,不增强所述化合物的释放速率。在胃肠道中大于6.0重量份的碳酸盐产生气体并因而可以引起腹胀。
根据本发明的化学式1化合物的口服制剂包含选自由淀粉甘醇酸钠、羧甲基纤维素钙和交联羧甲基纤维素钠组成的组的一种或多种崩解剂。在它们之中,优选淀粉甘醇酸钠或交联羧甲基纤维素钠。上述崩解剂快速吸水并广泛膨胀以在释放的初始阶段中分散化学式1化合物的活性成分粒子。所以有效抑制所述制剂表面上的胶凝作用并因而增加了来自所述制剂的释放。
基于一重量份的化学式1化合物或其药学上可接受的盐,以约0.5~5.0重量份的量含有抑制胶凝作用的特定崩解剂。当以小于0.5重量份含有所述崩解剂时,可能减少对于溶解速率的改善效果,因为活性成分不均匀分散并且在释放的初始阶段中借助于载体在胶凝作用上的抑制效果低。大于5.0重量份的崩解剂在所述化合物的释放速率上不再显示增强的效果,并且增大了所述制剂的体积,从而引起所述口服制剂摄取上的不便,其降低患者顺从性。
为了改善化学式1的化合物的溶解速率,可以将所述化合物与特定的崩解剂和碳酸盐配制。在组合使用的情况下,与崩解剂或碳酸盐单独使用相比较,更加改善所述溶解速率。同样,即使当较少量的崩解剂和碳酸盐一起使用时,可以获得相同或更优异的溶解曲线。因此,可以减少口服制剂的体积,因为可以减少所述口服制剂的总量并且可以将每一剂量单位的大量活性成分包含在其中。因而,可以实现满意的患者顺从性。
当所述崩解剂和碳酸盐一起使用时,基于一重量份的化学式1的化合物或其药学上可接受的盐,根据本发明的口服制剂优选含有约0.5至5.0重量份的量的崩解剂和约0.1至6.0重量份的量的碳酸盐。当所述崩解剂和碳酸盐分别以小于0.5和0.1重量份的量使用时,它们不在凝胶形成上显示适合的抑制效果。当所述崩解剂和碳酸盐的量分别超过5.0和6.0重量份时,不能实现满意的患者顺从性。
另外,化学式1的化合物的口服制剂还可以包括赋形剂。为了有效抑制凝胶形成并快速分散所述活性成分而增加所述活性成分的释放速率,所述赋形剂优选是无机赋形剂,诸如二价的磷酸钙、磷酸钙、重质氧化镁、沉淀碳酸钙、或碳酸镁。更优选的是二价的磷酸钙、磷酸钙、或重质氧化镁(heavy magnesium oxide)。相反,有机赋形剂,诸如微晶纤维素、甘露糖醇、玉米淀粉和乳糖,对于所述活性成分的释放速率没有增强效果。
当所述无机赋形剂,诸如磷酸二氢钙、磷酸钙或沉淀碳酸钙,用于根据本发明的化学式1化合物的口服制剂时,它增强溶解速率和生物利用度,并且充当钙供应者。因此,由此观点,可以预期含有化学式1化合物和上述无机赋形剂的口服制剂对于骨质疏松症的预防和治疗显示协同效果。
除上述成分之外,本制剂可以包括药学上可接受的普通赋形剂或辅药,并且可以经由普通的制药学方法配制成用于口服的固体剂型,诸如片剂、胶囊、粒剂、或微粒剂。
也就是说,根据本发明,可以将本组合物配制为粒剂,并且可以用润滑剂及其它药学上可接受的添加剂补充并且以粉末或颗粒剂形式直接填充到硬质胶囊中。另外,可以将所述组合物用制药的片剂用添加剂补充并且根据已知的方法挤压而产生片剂。
根据本发明的口服制剂还可以包括药物上可接受的普通添加剂。所述添加剂的实例包括粘合剂、润滑剂、助流剂、表面活性剂、着色剂和味道/气味掩蔽剂。药物上可接受的普通粘合剂和助流剂是可利用的。通过麦芽糖、阿拉伯树胶和羟丙基纤维素举例说明所述粘合剂。通过巴西棕榈蜡、轻无水硅酸(silic acid)、合成硅酸铝、硬脂酸、硬脂酸镁和滑石举例说明所述润滑剂。
普遍已知的湿式造粒方法可以用于根据本发明的口服制剂的造粒。将化学式1的化合物或其药物上可接受的盐与碳酸盐和/或特定的崩解剂混合,所述崩解剂抑制胶凝作用,并且,如有必要,与药物上可接受的普通赋形剂或添加剂混合。将由此获得的混合物与溶液湿式造粒,通过将粘合剂溶解在诸如乙醇或异丙醇等的溶剂或其混合溶剂中制备所述溶液。然后,通过搅拌颗粒机或高速搅拌颗粒机进行造粒。
作为用于根据本发明的口服制剂的另一个造粒方法,将上述混合物与粘合剂溶液通过挤出颗粒机湿法聚集、捏制、造粒并筛选。
作为用于根据本发明的口服制剂的另一个造粒方法,在流化床颗粒机下,将上述混合物用喷雾粘合剂溶液而造粒。
根据本发明的口服制剂的剂型可以取决于患者的重量、年龄、性别、健康状态、饮食、给药周期、给药途径、排泄速率、疾病严重性等。例如,可以以1至1,000mg/kg,优选10至500mg/kg的每天剂量施用化学式1的化合物的2甲磺酸盐。可以将每天剂量分成一至数个剂量。
发明方式
以下,将更充分地描述本发明的优选实例实施方案,促进本发明的理解。然而,本发明可以在许多不同形式中实施并且不应该解释为受限于这里陈述的实例实施方案。
<参考实施例1>所述化合物的2甲磺酸盐的制备
通过下列方法制备根据本发明的化学式1的化合物的2甲磺酸盐。将150g(0.33mol)的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒溶解在1.1L的乙醇中,用47mL(2.2当量)的甲磺酸滴加混合,并随后在室温下搅拌1小时。然后将由此获得的溶液与3L的丙酮1.1L的正已烷混合,并随后另外搅拌1小时。将由此产生的固体通过过滤回收,用丙酮洗涤,并在真空下干燥。结果,获得了作为白色固体的188g(收率:88%)的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒2甲磺酸盐。
熔点:156.4℃。
<参考实施例2>胶凝作用实验
进行下列测试以评价胶凝度,所述胶凝度取决于根据本发明的化学式1的化合物的2甲磺酸盐的浓度。
将200mg的化学式1的化合物的2甲磺酸盐溶解在10mL的水中(20mg/mL)。将所述溶液用水稀释而产生20、10、5、和2.5mg/mL。根据描述在表1中的下列测试条件测量这些稀溶液的粘度,并且所述测试的结果也显示在表1中。
表1
如表1中所示,已经观察到,化学式1的化合物的2甲磺酸盐在水溶液中显示高度胶凝作用性质。结果表示,当所述化合物浓度增加时,所述溶液的粘度显著增加。化学式1的化合物及其其它的盐显示类似的胶凝作用性质。
<实施例1至24>胶囊的制备
将化学式1的化合物的2甲磺酸盐、盐酸盐或游离碱与碳酸盐或特定的崩解剂或它们二者混合。同样,如有必要,将其它赋形剂加入到所述混合物。将所述混合物用粘合剂溶液弄湿,所述粘合剂溶液已经通过将聚乙烯吡咯烷酮溶解在乙醇、异丙醇等或其混合物中制备。将湿法聚集物捏制,经过16筛目,在50℃干燥并通过25网状筛筛选。利用胶囊灌药器(capsulefiller)将由此获得的粒剂作为有效成分以200mg的量填充到胶囊中。
实施例1至6的组合物的含量比例表示在表2中,其中包含化学式1的化合物的2甲磺酸盐和碳酸盐。实施例13至18的组合物的含量比例表示在表4中,其中包含化学式1的化合物的2甲磺酸盐、碳酸盐和崩解剂。
实施例19至24的组合物的含量比例表示在表5中,其中化学式1的化合物的盐酸盐或游离碱与碳酸盐或崩解剂或它们二者混合。
表2
表3
表4
表5
<实施例25至30>片剂的制备
将化学式1的化合物的2甲磺酸盐、盐酸盐或游离碱与碳酸盐或特定的崩解剂或它们二者混合。同样,如有必要,可以将其它赋形剂加入到所述混合物。将所述混合物用粘合剂溶液弄湿,通过将聚乙烯吡咯烷酮溶解在乙醇异丙醇等或其混合物中制备所述粘合剂溶液。将湿法聚集物捏制,经过16网筛,在50℃干燥并通过25网状筛筛选。将由此获得的粒剂与硬脂酸镁混合,并通过利用常规压片机挤压成片剂,所述片剂包含100mg的化学式1的化合物的2甲磺酸盐。所述片剂的硬度在4~5KP范围内。
实施例25至30的组合物的含量比例表示在表6中,其中化学式1的化合物的2甲磺酸盐、盐酸盐或游离碱与碳酸盐或崩解剂或它们二者混合。实施例31至36的组合物的含量比例表示在表7中,其中化学式1的化合物的2甲磺酸盐与特定的崩解剂混合;并且在有机赋形剂上,诸如微晶纤维素、玉米淀粉或乳糖;或在无机赋形剂上,诸如重质氧化镁、磷酸二氢钙、或磷酸钙。
表6
表7
<比较例1~18>胶囊或片剂的制备
将根据本发明的化学式1的化合物的2甲磺酸盐、盐酸盐或游离碱的原料通过45网状筛单独筛分,并将其以200mg有效成分的量填充到明胶胶囊中(比较例1、10和13)。
将化学式1的化合物的2甲磺酸盐、盐酸盐或游离碱与少量碳酸盐或其它赋形剂混合。在根据应用于实施例的相同方法制备粒剂以后,各自通过利用胶囊灌药器和常规压片机制备胶囊(比较例2至9、11、12、14和15)和片剂(比较例16至18)。所述组合物的含量比例表示在表8、9和10中。
表8
表9
表10
<实验实施例1>溶解研究
在实施例1至36和比较例1至18中制备的胶囊和片剂上进行体外溶解研究。所述介质是37℃在装置2(USP 27,<711>Dissolution,pp2303~2304)(平桨,50rpm)中900ml的0.1N HCl
在预定时间间隔(5、10、15、30、60和120分钟)抽出3mL的试验介质并且重新补充预热至37℃的新介质。立即在抽出后,将所述样品离心并通过孔径大小为0.45μm的膜式过滤器过滤。通过用UV分光计在254nm测量它的吸光度测定溶解在试验介质中的所述有效成分的量(%释放)。所述结果表示在表11、12和图1至3中。
表11
表12
如表11和12所示,已经观察到,本发明的胶囊和片剂与比较例中制备的胶囊和片剂相比较,显示显著更高的溶解速率。可以将其解释为,根据本发明的特定崩解剂迅速吸收水,巨大溶胀,有效分散有效成分并随后抑制释放的初始阶段的胶凝作用,因此导致增强所述释放速率。
相反,在比较例1、10、和13的情况(无胶凝抑制剂)下,用有效成分装满的胶囊缓慢吸收水而形成凝胶,其最终与明胶胶囊附聚。即使当20分钟过去时,有效成分的释放量也是非常低的并且没有完全除去所述明胶胶囊。在保持剂型的情况下,所述有效成分从凝胶层缓慢释放。
当与聚乙烯聚吡咯烷酮或其它赋形剂配制时溶解速率没有显著改善,所述聚乙烯聚吡咯烷酮通常用作口服制剂制剂中的超崩解剂,所述其它赋形剂通常用作常规崩解剂并例举为低取代的羟基丙基纤维素、微晶纤维素、玉米淀粉、或乳糖(比较例2至6)。
当包含所述碳酸盐时(实施例1至6),通过泡腾反应突然崩解片剂,并迅速释放有效成分。这应当理解,所述糖类有效预防释放的初始阶段中的胶凝作用,其导致增强释放速率,因为通过碳酸盐的突然泡腾反应迅速分散粒剂颗粒,破裂明胶胶囊并且从其释放有效成分而区域性改变扩散层的pH环境至弱酸性的或弱碱性条件。
当所述口服制剂另外包括药物上可接受的赋形剂时,已经观察到,在化学式1的化合物的2甲磺酸盐的溶解上,无机赋形剂(实施例34至36)诸如磷酸二氢钙比有机赋形剂(实施例31至33)诸如乳糖更有效。可以解释为,通过有效抑制溶解期间的胶凝作用,均匀存在于化学式1的化合物的2甲磺酸盐分子之间的无机赋形剂有助于有效成分的迅速分散。换言之,可以说,在根据本发明的化学式1的化合物的经口固体剂型中,所述无机赋形剂在释放的初始阶段辅助碳酸盐和特定崩解剂的作用。
与化学式1的化合物的盐酸盐(比较例10)相比较,当化学式1的化合物的盐酸盐与碳酸盐、特定崩解剂或它们二者造粒时(实施例19至21),显著地增加溶解速率。
与化学式1的化合物的游离碱(比较例13)相比较,当化学式1的化合物的游离碱与碳酸盐、特定崩解剂或它们二者造粒时(实施例22至24),显著地增加溶解速率。
另外,当碳酸盐和特定崩解剂同时一起使用时,然而即使少量,相比于单一施用的情况,也实现相等或更优异的溶解曲线。
总之,当化学式1的化合物与碳酸盐和/或崩解剂配制时可以实现迅速溶解,所述崩解剂在释放的初始阶段中所述化合物附聚以前有效抑制胶凝作用。
<实验实施例2>药动学研究
进行下列实验以评价实施例16和比较例1中所制备胶囊的生物利用度。
1)实验动物
从Jung Ang Lab Animal Inc.供给雄性毕尔格猎犬(beagle dogs).用于药动学研究的动物重量在7.6~10.5kg的范围内。在给药以前,将所述狗在实验室中至少适应1周。
2)给药
在实验以前,将动物过夜禁食8小时。将实施例16和比较例1的胶囊经口施用。化学式1的化合物的施用量是50mg/1kg动物。
3)血收集和分析
在每一胶囊的口服以后,通过下列方法测量血浆中有效成分的浓度。对于药动学研究,在预定时间间隔(剂量给药后0、0.5、1、1.5、2、3、5、8和24小时)从毕尔格猎犬的头静脉收集血液并且在血收集后将血浆立即分离并储存在-20℃直到测定。对于化学式1的化合物的HPLC分析,将融化至室温并与相等体积的内标溶液(在乙腈中含有30μg/ml的倍他米松)混合。通过振荡器将所述混合物搅拌1分钟并在12,000rpm离心。将上清液的等分部分注入到HPLC中用于定量(Waters Module 1)。
在口服以后血浆中化学式1的化合物的浓度表示在表13和图4中。全部药动学参数表示在表14中。
表13
表14
Cmax:血浆中的最大浓度
Tmax:在血浆中达到最大浓度所需时间
AUC0-t:血浆中浓度对时间0至t在曲线下的面积
总AUC:血浆中浓度对时间0至∞在曲线下的面积
如表14和图4中所示,在化学式1的化合物的2甲磺酸盐的原料情况下(比较例1),随着时间经过在血浆浓度中没有明显的改变。
如表14中所示,当根据本发明制备的胶囊(实施例16)经口施用至毕尔格猎犬时,与化学式1的化合物的2甲磺酸盐的原料(比较例1)相比较,Cmax和AUC0-t分别增加至3.6倍和4.7倍。
工业适用性
根据本发明的口服制剂改善N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苯甲脒或其药物上可接受的盐的溶解速率和生物利用度,通过抑制在释放的初始阶段与水接触时那些胶凝作用。因此,根据本发明的口服制剂可以非常有用地用于制药工业。
Claims (6)
2.权利要求1的口服制剂,其中所述药物上可接受的盐是二甲磺酸盐或盐酸盐。
3.权利要求1的口服制剂,其中基于一重量份的化学式1的化合物或其药物上可接受的盐,以约0.5至5.0重量份的量含有所述崩解剂。
4.权利要求3的口服制剂,其中所述崩解剂是淀粉甘醇酸钠或交联羧甲基纤维素钠。
5.权利要求1的口服制剂,其中所述口服制剂是选自由片剂、胶囊、粒剂、和微粒剂组成的组的制剂。
6.权利要求1的口服制剂,其中所述口服制剂包括磷酸二氢钙、磷酸钙、沉淀碳酸钙或重质氧化镁作为改善溶解速率的无机赋形剂。
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