CN1347315A - 生产水不溶性的无定形或部分无定形可控释放的基质的方法 - Google Patents

生产水不溶性的无定形或部分无定形可控释放的基质的方法 Download PDF

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CN1347315A
CN1347315A CN00806419A CN00806419A CN1347315A CN 1347315 A CN1347315 A CN 1347315A CN 00806419 A CN00806419 A CN 00806419A CN 00806419 A CN00806419 A CN 00806419A CN 1347315 A CN1347315 A CN 1347315A
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休伯特·赖因
克劳斯-于尔根·斯蒂芬斯
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Abstract

本发明涉及通过挤压成形制备药物剂型及其前体。药物剂型具有基本上含活性物质的基质,并其基本特征由挤压工艺所决定,并含有多糖和/或其衍生物和/或其配合物和/或上述物质与其它物质的混合物和/或糖类和/或其衍生物作为主要成分,并至少含有一种药物活性物质。本发明也涉及一种药物剂型,它具有基本上含活性物质的基质,并且其主要性质由挤压工艺决定,它含有多糖和/或其衍生物和/或其配位物和/或上述物质和其它物质的混合物和/或糖类和/或其衍生物作为主要成分,并至少一种药物活性物质。最后本发明也涉及所述药物剂型的用途,用于制备片剂或充填胶囊用的颗粒,用于使用注模技术的进一步加工以及用于直接压片和/或制备整体药物制剂中的助剂。

Description

生产水不溶性的无定形或部分无定形 可控释放的基质的方法
本发明涉及使用挤压成型法生产药物剂型或其前体的方法。
本发明进一步涉及通过挤压成型法生产的药物剂型。
挤压成型法是一种很普遍的方法,尤其是在粘合剂工业中或塑料加工中以改性多糖,特另是淀粉。在食品工业中用于生产含淀粉的组合物,如面条,通常所说的花生条(flips)或各种糖果,其挤压成型技术是已知的。然而,所有这些产品的生产条件都要这样选择,以致获得泡沫体,通常所说的膨化产品。
在药物生产技术中,挤压成型法用于加工蜡、脂肪醇、脂肪和各种热塑性塑料和硬塑料。例如,EP-A2 0 240 904、EP-A2 0 240 906和EP-A2 0 358 105中描述了由各种聚合化合物挤出的基质。EP-B2 0 118 240描述了采用注模技术把含淀粉的混合物加工成为药物产品(胶囊)。在这方面,并不十分了解使用的多糖在挤压成型过程中的变化。
由EP-A 0 580 860可以了解制备在聚合载体中的活性剂固体分散体的挤压成型法。所使用的原料通常是如上指出的淀粉和淀粉衍生物。然而,该专利所描述的方法对于以淀粉作主成分的制剂是不合适的。
在医药生产技术中,口服给药的剂型如片剂、糖衣丸或胶囊是特别重要的。这些剂型还包括所谓的延缓释放的剂型,这类剂型包含较高剂量的活性剂,且以可控方式在很长的时间内释放这种活性剂。对于病人来说,这就意味着施用药品的频率显著地降低。从医药-药理的观点考虑,延迟释放剂型的优点在于活性剂在血液中的浓度非常均匀,因而保持长效作用并低副作用。当配置延迟释放剂型时,所谓基质的形态是非常重要的。基质指成形体,如由惰性助剂制成的片剂或糖衣丸,由其把活性剂以可控方式释放到胃肠道中。通常活性剂的释放一部分是由扩散发生的,一部分是由基质的结构缓慢降解发生的。
在药物生产技术中,这样的基质是由合成的聚合物,如聚丙烯酸酯或聚乙烯生产的。从这种意义来说,由合成原料生产延迟释放剂型的挤压成型方法是已知的。
至今通过挤压成型法生产剂型的的一个最重要的缺点是使用的活性物质载体如塑料、蜡乃至脂肪醇。这些助剂,生物学上不能降解,而且部分对环境有害,如所用聚合物中的残留单体,但至今,为了由挤压成型法生产剂型且能控制和缓慢释放活性剂,所述助剂仍然是必须的。况且,就生产快速释放活性剂的剂型来说,目前也不存在已知的挤压成型法。
因此对能生产可控的,即通过选择延缓或更迅速释放活性剂的剂型的挤压成型方法是极为需要的,这种方法应能克服现有技术的缺点,特别是能避免使用生物学上不能降解的且在某种意义上对环境有害的载体材料。另外的一些目的可以从本发明的下面说明得到了解。
有关方法的目的的解决方案在于权利要求1的特征。
本发明方法的有益实施方案限于从属权利要求。
本发明提出一种由挤压成型法生产剂型或其前体的方法,其特征在于,剂型是主要含有活性剂量的基质,其基本特征由挤压成型法形成,并且作为基质的成分含有生物学上可降解的多糖和/或其衍生物和/或其络合物和/或上述物质与其它物质的任意混合物和/或糖和/或其衍生物以及至少一种药物有效的物质。
按照优选的实施方案,剂型中活性剂的释放可通过添加助剂和/或通过变化挤压成型过程的工艺参数,如温度、模具的几何形状和/或挤压速度等加以调节。
在另一优选实施方案中,按照本发明制成的剂型的基质是无定形的或部分为无定形的。
此外,在优选实施方案中,本发明涉及一种方法,其中本发明制造的剂型在基质中包含作为多糖的淀粉或其衍生物,尤其是无定形或部分无定形淀粉或其衍生物。
在另外的优选实施方案中,本发明涉及一种生产方法,其中剂型包含水不溶性且最好是可膨胀的基质。
按照特别优选的实施方案,本发明的剂型是延迟释放的基质。
另一优选实施方案包括一种本发明的剂型,基本上按照lapidus功能的活性剂释放且最佳情况是显示调节活性剂在24小时或更长的时间内释放。
本发明的另一重要的目的在于剂型基本上能起作用而没有生物降解成分。
按照本发明目的的解决是通过一种剂型,它是主要含有活性剂的基质,其基本性质由挤压成型法构成,并且作为基质的基本成分含有多糖和/或其衍生物和/或其络合物和/或上述物质与其它物质的任何混合物和/或糖和/或其衍生物,以及至少一种药物有效物质。
此外,本发明涉及本发明剂型在直接压片中作为助剂的用途,用于生产压片和填充胶囊的颗粒,用于使用注模技术时的进一步加工和/或用于生产整体式药物剂型。
在挤压成型过程中,即当使用或施加热、剪切力和压力时,由结晶或部分结晶的多糖,尤其是由淀粉或其衍生物,或这些组分的混合物可以产生无定形的或部分无定形的基质。对于基于挤压成型多糖及其衍生物的剂型再现性生产来说,挤压条件,如温度、模具的几何形状和挤压速度是非常重要的。例如,在合适的挤压条件下,天然淀粉可被完全塑化或玻璃化,以致可以获得均匀的塑性状的成形体。
当挤压淀粉时,仅在工艺开始时需要加热。在工艺的进一步过程中,由强剪切力或摩擦产生的热量最好通过冷却加以消除,以保持恒定的温度。用于本发明方法中的制剂是由下列物质组成,即多糖和/或其衍生物的混合物,优选淀粉和/或淀粉衍生物的混合物,其中各种淀粉是合适的。此外,混合物含有至少一种药物有效的物质,其量基于制剂总重量最高为50%,优选最高30%,另外还可以含有其它物质。添加的水浓度高达15%,以便彻底地混合干燥制剂。当使用压力输送挤压机时,少于15%的水分是足够的。
为了保证经过螺旋进料器进行输送,在彻底混合并添加水后,优选使所获得的预混合物过筛,以便使其无块状物。启动和清洁挤压器可以使用例如玉米渣进行。当按本发明方法产生基质时,在正常的压力下,挤压器孔板上的温度不应超过100℃,因为温度在100℃以上时,不可能形成无孔的基质。以剪切力、温度、热量或压力的形式引入工艺过程中的总能量,应尽可能恒定,并且应足以实现玻璃化转变。对于含有本发明载体和水的混合物,要调整螺杆旋转速度和模具的几何形状至最佳程度。当挤压温度低于100℃和螺杆旋转速度合适时,在大多数的情况下都可以获得透明而完全无定形的产品。活性剂/多糖混合物,优选活性剂/淀粉混合物的塑化程度与螺杆的旋转速度紧密相关。当挤压成型不再可能低于最低速度时,过高的螺杆旋转速度会引起剂型“突发爆开(pop open)”。
由于变换挤压成型过程的工艺参数,使本发明方法生产的剂型能呈显可控释放活性剂。在本发明的含义中“可控”一词意指通过本发明挤压成型法可以生产出快速剂型和缓释剂型,释放周期高达24小时或更长的所谓缓释剂型。除了早已提到的工艺参数外,还有加工温度对于控制活性剂的释放也是极为重要的。例如通过在低于所用多糖的胶凝化温度的所有情况下进行挤压成型,都可以获得快速释放的剂型。因为,除了其它以外,其中基质的密度影响所掺入活性剂的释放,通过部分到完全玻璃化,即通过含多糖的混合物在合适的挤压成型条件下转化成无定形状态,可以产生可控释放的相应剂型。与上述的系统相反,按照本发明方法的这种无定形或部分无定形基质,优选由无定形或部分无定形淀粉或其衍生物或这些成分的混合物制成,基本上是水不溶性的,而优选的是可膨胀和水不溶性的。药物有效的一种物质或多种物质可以以溶解、固体或液体的形式存在于基质中。
能用于本发明生产方法中的淀粉实例是木薯淀粉、小麦淀粉、马铃薯淀粉、淀粉1500(部分预胶凝化的玉米淀粉,可由Colorcon获得)、Waxylis(由Roquette买到的蜡玉米淀粉)、Eurylon7(由Roquette买到的直链玉米淀粉)、玉米淀粉、乙酰化淀粉。
另外,按本发明挤压成型方法可以获得的剂型,由于添加了助剂,所以可控活性剂的释放。为了加速活性剂的释放,可以借助于基质中形成孔隙,可以添加下列的物质,例如:
亲水或两亲性的固体,水溶性的物质,如氯化钠、乳糖、表面活性剂,如十二烷基硫酸钠、二氧化硅(胶体分散的和/或干凝胶),
亲水或两亲性的液体,聚乙二醇类,如甘醇、聚乙二醇,表面活性剂,如聚山梨酸酯,
气体,如氮、二氧化碳。
通过抑制扩散而减低活性剂的释放,例如可通过添加下列助剂来进行:
亲油或两亲性的天然、合成和/或部分合成源的助剂,如固体或液体状态的脂肪、脂肪酸、蜡,
饱和或不饱和的烃,
金属皂,如硬脂酸镁。
此外,活性剂释放的减少可以通过形成化学计量或非化学计量的络合物实现,如碘-淀粉络合物、miltefosin-直链淀粉络合物。
此外,所加活性剂的释放受所用合适的基质组分混合物的影响,优选受所用不同的淀粉和/或其衍生物的混合物的影响。影响活性剂释放的其他因素是剂型成形体的外表面及其粒度,或者活性剂在颗粒中的分布。
检验活性剂释放的过程证实活性剂的释放优先受控于扩散而且还遵循所谓的lapidus规则,正如下文所说明的实验显示的。释放的过程没有变化,即使在剂型存放数月之后。
使用本发明方法所产生的剂型,可以用于生产适于压片和填充胶囊的颗粒并作为助剂用于直接压片,用于通过挤压成型技术的进一步加工和/或作为整体的剂型,在类似于皂类的生产情况下,通过合适装置的挤压模具使挤压物成型。本发明方法可生产和使用整体成型,在该工艺中挤压物只在表面上玻璃化并且包括在其内部以未发生变化的状态存在的活性物质/载体混合物。为了获得所要求的生物-药物性质的剂型,可以使用适于生产固体形式的已知的所有助剂。
剂型的干燥仅可通过所产生的摩擦热来进行,致使没有必要进行最终的干燥步骤。所用的生产挤压机中,优选是双螺杆挤压机,特别是优选压力输送双螺杆挤压机,所有的工艺步骤,如计量、增湿、混合、挤压和成形可以连续进行。本发明方法还可以把混合、造粒和干燥步骤组合在一个装置中,对此无须消耗另外的能量。
按照本发明,还有可能减少许多不兼容的数目,因为例如剂型仅包含一种载体材料,优选淀粉或其衍生物,以及一种药物有效物质。按本发明方法制成的基质还可进一步阻止可能的不希望有的反混合。
下列实施例表明活性剂延缓的程度是通过工艺过程或工艺过程参数,多糖的类型或另外助剂的添加,而得到最好的控制。实施例仅用来说明本发明并不表示对某些实施方案或应用作任何的限制。更确切说,在所附 书所限定范围内有另外一些实施方案是可理解的。
实施例
下列的实施例,是按本发明方法进行的,它使用添加咖啡因的各种多糖作典型活性剂。采用Brabender的811201型单螺杆挤压机进行挤压实验。这台装置具有三个部分,即加料区、螺杆旋转区和模具,彼此可以独立地进行调节。使用不加压的螺旋输送机,其螺杆长度为22cm,螺杆直径为19mm,中心部分直径为16mm以及间距为15mm。使用介于2.5到7mm不同直径的模具。
一次实验的批料量介于350-600克。使活性剂和淀粉在Stephan混合器中彻底混合,增湿水分为15%,该预混合物过筛直到无块状物。
挤压机加料区的温度约65℃,螺杆旋转区约80℃而模具的温度约98℃,证明对于完成本发明方法的温度是最合适的选择。
检验多糖的结晶或部分结晶结构转化成无定形或部分无定形结构可借助于不同的技术完成。
通过差示热分析法(DSC)可以检测结晶或部分结晶淀粉转化成无定形的状态。在合适的挤压条件下,淀粉完全玻璃化,即变成无定形的状态。作为实施例,用木薯淀粉作多糖和咖啡因作活性剂进行实验。图1a表示预混和物的差示热分析图,所述预混和物是由90%的木薯淀粉和10%的咖啡因与加入的水所组成,在大约65℃的范围内显示典型的吸热峰。
在按本发明完成挤压成型后,在决定性温度范围内检测不到峰。由此得出,即淀粉已完全玻璃化,这意味着它已转化成无定形的状态(见图1b)。
由结晶或部分结晶转化成无定形或部分无定形状态可以借助于X-射线衍射法进行鉴定。对于下面的典型实验,使用由80%马铃薯淀粉和20%咖啡因组成的样品。图2示出马铃薯淀粉-咖啡因预混和物的X-射线衍射图,在大约20°范围内出现淀粉晶体部分的一些信号。在使用本发明方法后,相应挤出物的X-射线衍射图未显示淀粉晶体部分的任何信号。
在这方面值得再次指出的是对于活性剂的释放动力学来说,成为玻璃态的变构作用程度起决定作用。按USP在0.1N的盐酸(pH值为1的人造胃液)和在pH值为7.2的磷酸盐缓冲液(人造肠液)的液体中,采用桨式搅动器检验活性剂的释放。在这里必须再次指出,挤出物在实验中是不溶解的,观察到的仅仅是挤出物的膨胀。在下面测定活性剂的定量释放的典型实验中,使用由市场上买到的淀粉Eurylon7(由Roquette买到的直链玉米淀粉)和30%咖啡因组成的样品。图3中的曲线表明活性剂释放的定量过程。为了比较起见,引入纯咖啡因,释放未延缓并装入胶囊中。
人们可以看出将咖啡因埋置于多糖基质中会导致释放显著延迟,在本例中,对于25毫克的总剂量来说,从约15分钟延迟到约8-10小时。
按照lapidus规则,释放量对时间的平方根的曲线图表明曲线几乎是一条直线的过程,这表示活性剂的释放是由扩散控制的(见图4)。
正如早已说明的,活性剂的释放速度还受多糖或多糖混合物种类的控制。在下面的实施例中,把由马铃薯淀粉和10%咖啡因组成的预混和物用于定量研究活性剂的释放。改变淀粉的类型,与更低的活性剂的剂量一起,会导致活性剂释放的显著下降。图5所示曲线表明按本发明方法制备的挤出物提供的活性剂释放时间超过24小时。
按照lapidus规则,图6所示的曲线表明活性剂的释放是由扩散控制。
正如上面早已说明的,可以调节活性剂总释放的时间和过程。在上面提到的实施例中,很长的活性剂释放时间,如24小时,是从发展新的延缓原理的观点出发,是作为优点,因为以这样一种方式可以获得对于特别好的水溶性活性剂的“储备”。通过多糖或相应的衍生物及其混合物,通过添加相应的助剂和/或通过挤压成型工艺参数,可以选择性地影响活性剂的释放,正如早已多次指出的。
按照本发明方法,也可以达到活性剂较快的释放时间。下面列出的表显示通过改变工艺参数的实施例,可以导致例如不完全的玻璃化,结果有可能控制活性剂的释放时间在很宽的范围内。
                    表
  多糖 活性剂 活性剂浓度 50%活性剂的释放时间[分] 活性剂的理论释放时间[小时]
木薯淀粉 咖啡因 10%(50mg )     240     16
木薯淀粉 咖啡因 10%(50mg)     120     8
玉米淀粉 咖啡因 30%(50mg)     195     13
玉米淀粉 咖啡因 30%(50mg)     55     3.7
正如从表中所见,对于同样类型的淀粉而言,通过改变工艺过程的参数,可以获得活性剂的较短的释放时间和落入可延缓释放剂型范围的活性剂释放时间。

Claims (19)

1.使用挤压成型法生产药物剂型或其前体的方法,其特征在于,剂型是基本含有活性剂的基质,其中,其基本性能由挤压成型法确定,并且含有作为基质的主成分的多糖和/或其衍生物和/或其络合物和/或上述物质与其它物质的任意混合物和/或糖和/或其衍生物,以及至少一种药物有效的物质。
2.按权利要求1所述的方法,其特征在于,通过添加助剂和/或改变挤压成型工艺过程的参数,如温度、模具的几何形状和/或挤压成型速度,可以控制剂型活性剂的的释放。
3.按权利要求1或2所述的方法,其特征在于,基质是无定形的或部分无定形的。
4.按前述任何一项权利要求所述的方法,其特征在于,多糖是淀粉或其衍生物。
5.按前述任何一项权利要求所述的方法,其特征在于,基质是水不溶性的。
6.按前述任何一项权利要求所述的方法,其特征在于,基质是延缓释放的基质。
7.按前述任何一项权利要求所述的方法,其特征在于,剂型中的活性剂释放基本上采纳lapidus功能。
8.按前述任何一项权利要求所述的方法,其特征在于,可以调节剂型中的活性剂在24小时或更长的时间内释放。
9.按前述任何一项权利要求所述的方法,其特征在于,至少一种药物活性物质以溶解的、固体或液体形式存在于基质中。
10.药物剂型,包含其中主要含有活性剂的基质且其主要性能可由挤压工艺过程确定,基质含有多糖和/或其衍生物和/或其络合物和/或上述物质与其它物质的任意混合物和/或糖和/或其衍生物作为基质的主要成分,以及至少一种药物有效的物质。
11.按权利要求10所述的剂型,其特征在于,通过添加助剂和/或通过改变挤压成型工艺过程参数,如温度、模具的几何形状和/或挤压成型速度可以控制活性物质的释放。
12.按权利要求10或11所述的剂型,其特征在于,基质是无定形或部分无定形的。
13.按权利要求10-12中任何一项所述的剂型,其特征在于,多糖是淀粉或其衍生物。
14.按权利要求10-13中任何一项所述的剂型,其特征在于,基质是水不溶性的。
15.按权利要求10-14中任何一项所述的剂型,其特征在于,基质是延缓释放的基质。
16.按权利要求10-15中任何一项所述的剂型,其特征在于,活性剂的释放基本上按lapidus功能。
17.按权利要求10-16中任何一项所述的剂型,其特征在于,调节活性剂在24小时或更长的时间内释放。
18.按权利要求10-17中任何一项所述的剂型,其特征在于,至少一种药物活性物质以溶解、固体或液体形式存在于基质中。
19.按权利要求10-18所述剂型的用途,它用于生产供压片和填充胶囊用的颗粒,用于使用注模技术进一步加工,作为助剂以进行直接压片和/或生产整体药物剂型。
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