CN107205945A - 可分散组合物 - Google Patents
可分散组合物 Download PDFInfo
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- CN107205945A CN107205945A CN201680007314.1A CN201680007314A CN107205945A CN 107205945 A CN107205945 A CN 107205945A CN 201680007314 A CN201680007314 A CN 201680007314A CN 107205945 A CN107205945 A CN 107205945A
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Abstract
本发明涉及含有富马酸贝达喹啉作为活性成分的可分散组合物。这些组合物可用于治疗结核病,并且其固有的分散性特性使得其特别适用于小儿或老年群体。
Description
本发明关注含有某种抗细菌产品(富马酸贝达喹啉作为活性成分)的药物组合物。更具体地讲,本发明涉及可分散或可崩解的片剂、其制备方法以及其用于治疗抗细菌疾病如结核病的用途。这种新型组合物特别适于小儿群体。它也适于老年群体。
在这种情况下,活性成分是富马酸盐形式的贝达喹啉:(αS,βR)-6-溴-α-[2-(二甲基氨基)乙基]-2-甲氧基-α-1-萘基-β-苯基-3-喹啉乙醇,特别是(αS,βR)-6-溴-α-[2-(二甲基氨基)乙基]-2-甲氧基-α-1-萘基-β-苯基-3-喹啉乙醇(2E)-2-丁烯二酸盐(1∶1),并且可由以下化学式表示:
本发明的富马酸盐可以在合适的溶剂(例如异丙醇)的存在下,通过使相应的游离碱与富马酸发生反应来制备。
含有活性成分的这种SirturoTM产品已经在包括美国、俄罗斯、欧盟、南非和韩国在内的一些地区获得营销许可。
本发明的效用源自活性成分及其盐,已知该活性成分及其盐显示抗分枝杆菌活性,该分枝杆菌包括耐药菌株,特别是结核分枝杆菌、牛分枝杆菌、鸟分枝杆菌、麻风分枝杆菌和海分枝杆菌,尤其是抗包括耐药结核分枝杆菌菌株在内的结核分枝杆菌。该活性成分,包括其盐,显示出抗活跃的、敏感的、易感的分枝杆菌菌株以及潜伏的、休眠的、持久的分枝杆菌菌株的活性。
国际专利申请WO 2004/011436首次披露了贝达喹啉游离碱的抗分枝杆菌的活性。后来的文件,例如国际专利申请WO 2005/117875和WO 2006/067048披露了在治疗(尤其是在对耐药结核病和潜伏性结核病的治疗)中的其他用途。国际专利申请WO 2008/068231首次描述了富马酸盐作为药物产品的适用性,表明其可接受的生物利用度。贝达喹啉的富马酸盐被描述为非吸湿的和稳定的。本文件还披露了含有富马酸贝达喹啉的某些配制品和片剂的制备。
特别是,WO 2008/068231披露了包含贝达喹啉富马酸盐的药物配制品的制备方法,在该方法中可获得粉末混合物并将其压制成片剂。这样的配制品不具有足够的分散性/崩解性。
结核分枝杆菌每年导致超过200万人的死亡,并且是感染HIV的人死亡的主要原因。不管数十年的结核病(TB)防治规划如何,但是仍有约20亿人无症状地被结核分枝杆菌感染。这些个体中约10%在其寿命期间处于发展为活动性TB的风险中。因此,药物治疗活动性TB的需求很大。
TB的全球流行被HIV患者由TB的感染以及多药耐受TB菌株(MDR-TB)的出现所激化。潜伏性TB的再活化对于疾病发展而言是一个高风险因素并且导致32%的HIV感染个体死亡。为了控制TB流行,需要发现可以杀死休眠的或潜伏的杆菌的新药。该休眠的TB可以被再活化以通过若干因素引起疾病,这些因素像如通过使用免疫抑制剂来抑制宿主免疫力,这些免疫抑制剂是像针对肿瘤坏死因子α或干扰素的抗体γ。在HIV阳性患者的情况下,可用于潜伏性TB的唯一预防性治疗是两个月-三个月的利福平、吡嗪酰胺方案。该治疗方案的疗效仍不清楚并且此外,治疗的长度在资源受限的环境中是一种重要约束。因此,对于鉴定可以充当带有潜伏性TB杆菌的个体的化学预防剂的新药存在强烈需要。
结核杆菌通过吸入进入健康个体;它们被肺的肺泡巨噬细胞吞噬。这导致有效的免疫应答以及肉芽肿的形成,肉芽肿由被T细胞包围的结核分枝杆菌感染的巨噬细胞组成。在6-8周的一段时间后,宿主免疫应答通过以下方式导致被感染细胞死亡:被巨噬细胞包围的某些细胞外杆菌、上皮样细胞和周围淋巴组织层坏死和干酪样物质累积。在健康个体的情况下,大部分分枝杆菌在这些环境中被杀死,但小部分杆菌仍存活,并且认为其以非复制、低代谢状态存在且耐受抗-TB药物(像异烟肼)的杀伤。这些杆菌可以在改变的生理环境中维持甚至持续个体的一生,而不显示疾病的任何临床症状。然而,在10%的这些病例中,这些潜伏性杆菌可以再活化而引起疾病。关于这些顽固性细菌发展的假说之一是人类损害中的病理生理环境,也就是降低的氧张力、营养限制以及酸性pH。已经假定这些因素使得这些细菌对主要的抗分枝杆菌药物显型地有耐药力。
尽管已经为成人群体开发了富马酸贝达喹啉的药物配制品,但迄今为止还没有开发和寻求小儿配制品。开发药物配制品有许多方法,包括直接压制、干法制粒和湿法制粒。每种方法仍然存在各自的挑战,并且还依赖于要配制的药物。此外,对于小儿群体可能需要有可分散片剂,并且这也可能提供了额外的挑战。从设计具有适当快速分散时间的片剂的观点出发,特别如此。
在用于制备片剂的技术中,直接压缩是最简单的,仅涉及混合和压缩。这具有生产速度方面的优点,因为它需要更少的单元操作、更少的机械,因此更有效率。
直接压缩之后是其他制造程序,例如干法或湿法制粒。
现在提供一种包含富马酸贝达喹啉作为活性成分的可分散组合物(例如片剂)。这在此处可以称为“本发明的(可分散的)片剂”。
通过“可分散的”,我们是指在合适的介质中崩解的组合物(例如片剂),这些合适的介质例如水性介质(水)或其他适用于给药的介质或载体(例如牛奶、果汁甚至半固体样载体,如酸奶、苹果酱)。更具体地,我们是指该片剂在少量的水中崩解,从而通过温和的旋转使其分散(例如均匀地和/或快速地)。例如,100mg片剂组合物可在90秒内均匀地分散在约50ml水中。因此,1mg片剂组合物的重量当量可在90秒内均匀分散在0.5ml水中。更优选地,1mg片剂组合物的重量当量可在60秒内均匀分散在0.5ml水中,更优选在45秒内。特别是它可以在30秒左右(例如在30秒内)分散。如以下实例所示,这种分散时间/比例特别适用于在20mg至400mg之间(特别是在约50mg至约200mg之间)的组合物重量。因此,具体而言,100mg的片剂组合物可以在30秒左右(或在30秒内)均匀地分散在50ml水中。这种分散体可以穿过具有710μm的标称网孔孔径的筛网。
然而,尽管1mg组合物(例如片剂组合物)的重量当量于0.5ml水中是在分散的背景下提及的,该片剂配制品的固有性质是关键。例如,分散可以在非常小量的流体中发生,如100mg组合物也可以分散在非常少量的水中,如低至1ml至5ml(即1mg的片剂组合物当量/0.01ml至0.005ml水)。在这种情况下,所得到的混合物可描述为分散体,但也可描述为软质(soft mass)。对于这样的软质,它可能不能穿过上述筛网(考虑到少量水与其混合),但是仍适用于给药,即软质可以适当地通过勺子进行给药。同样地,组合物可以通过与另一种合适的给药媒介或载体(如上所述)混合来给予,该媒介或载体可以是分散体、软质(例如:如果该组合物仅与相对少量的水混合)或另一种混合物(例如:如果该组合物与半固态物质混合)。
相比之下,WO 2008/068231中的实例中披露的配制品不具有可比较的分散性/崩解性。特别是,这样先前的配制品可能不具有可比较的分散性,并且更特别的是它们(例如,在50ml水中的100mg组合物或与按重量和体积的比计相当的组合物)可能在超过90秒的时间分散,例如超过120秒(并且可能在超过180秒的时间分散,例如在240秒左右或者甚至更长)。这种相对长的分散时间可能是不利的,并且可能不令人满意。
通过“均匀分散”,我们是指该组合物(例如片剂组合物)在水中迅速崩解成物理上较小的颗粒,这些颗粒在整个水中散开(或分散)。这导致在水的任意等同部分都含有大致等量的组合物(例如片剂组合物)颗粒(以重量计),这里我们是指在±25%的偏差以内,优选±15%,并且特别是±10%(或更少,例如在±5%以内)。因此,如果将100mg片剂组合物分散在50ml水中,则每部分25ml的水(分开时)应含有约50mg的片剂组合物重量,但可能偏差为±25%(即±12.5mg),优选±15%(即±7.5mg),特别是±10%(即±5mg)-最优选偏差将为±5%(即±2.5mg)。因此,该片剂组合物物理上均匀或同一的处于其放置的整个水介质中(经过必要的分散时间后;见上文)。应当理解,每毫克片剂组合物的水体积越大,在分散方面的偏差就越小。
在此表明该水可分散组合物(例如片剂组合物)可以穿过710μm筛,这是为了使该可分散组合物(例如片剂)满足某些质量阈值/要求,例如当前(或未来)版本的英国药典和欧洲药典中的那些阈值/要求。这就是为什么分散质量(穿过筛网)以及分散时间很重要(最优选在30秒内分散)。尽管这些性质对于水性介质中的实际分散体很重要,但是应当理解,分散体(例如在水中)不需要进行制备,但是可分散片剂可以通过替代性方式进行给药。例如,该可分散片剂可以与某些食品混合(原样或如上所述,通过将片剂组合物与少量/小体积的水混合而形成软质)。这在下面详细阐述。
现在将更详细地描述本发明的可分散组合物(例如片剂)。显然,它具有保留了分散性(或崩解)特性的固有性质。
因此,在本发明的一个方面,提供了一种包含富马酸贝达喹啉作为活性成分的可分散组合物(例如片剂),并且其中片剂包含颗粒内和颗粒外层,其中在颗粒内层中包含不溶性赋形剂/稀释剂,且其特征在于颗粒内层不含为淀粉的可溶性赋形剂/稀释剂(并且在最优选的实施例中,颗粒内层不含任何可溶性赋形剂/稀释剂)。例如,颗粒内层可以包含作为赋形剂/稀释剂的甘露醇(其被划分为可溶性赋形剂/稀释剂),但不包含淀粉。在优选的实施例中,颗粒内层不含甘露醇和淀粉(并且也不含任何其他可溶性赋形剂/稀释剂)。
在本发明的替代性方面,颗粒内层包含为微晶纤维素的不溶性赋形剂/稀释剂,但该层不是必定不含可溶性赋形剂/稀释剂。
在一个实施例中,当使用可溶性赋形剂/稀释剂时,则优选其不是淀粉。这是因为淀粉可能在37℃的水中(例如约5%-10%)膨胀(在温度高于糊化温度下,它可能变得溶于热水)。
优选颗粒内层包含为微晶纤维素的不溶性赋形剂/稀释剂,并且该层也不含任何可溶性赋形剂/稀释剂。
当涉及微晶纤维素时,其旨在包括硅化微晶纤维素。本发明片剂的颗粒内部中的这种不溶性赋形剂/稀释剂是其固有的分散性/崩解性的关键。
在可溶性赋形剂/稀释剂的背景下,“不存在”意指组合物(例如片剂组合物)含有不显著量的这种成分(例如,在这种情况下为可溶性赋形剂/稀释剂),借此我们意指少于基于组合物总重的5%(以重量计),更优选小于2.5%(以重量计),例如少于1%。最优选这意指成分完全不存在,即含该成分的0%或接近0%(以重量计)-这是其可忽略的量。
通常,可分散片剂是用可溶性赋形剂/稀释剂制造的,例如糖基赋形剂,如木糖醇、果糖、乳糖等。然而在这种情况下,发现可溶性赋形剂对于分散性/崩解性(如下文参考实例所示)是不利的,例如,由于它们可以吸收水并形成饱和层阻止溶质从饱和滞留层进一步扩散(根据Noyes Whitney的扩散层理论)-这种现象可能是对所需分散时间造成不利影响的原因。也可能是可溶性赋形剂更容易吸收环境水分。如果可溶性赋形剂与部分可溶或不溶性赋形剂组合使用,也可能发生这种情况。无论如何,显而易见的是,使用非可溶性赋形剂特别是微晶纤维素,尤其是在片剂配制品的颗粒内部内,是获得具有所需性质的可分散片剂的关键。
因此,在本发明的一个方面,提供了可分散组合物(例如片剂组合物),以重量计,基于该组合物的总重量,其包含(例如由......组成):
5%至50%(例如10%至30%)的活性成分
35%至90%(例如50%至70%)的不溶性赋形剂/稀释剂
2%至10%(例如4%至8%)的崩解剂
0.1%至5%(例如1.5%至3.5%)的助流剂
0.01%至5%(例如0.1%至1%)的润湿剂或表面活性剂
0至10%(例如2%至5%)的粘合剂或聚合物
0至5%(例如1%至3%)的润滑剂
溶剂(qs),例如水
该可分散组合物也可以称为本发明的组合物。
在上述组合物的情况下,其中不溶性赋形剂是微晶纤维素(例如硅化微晶纤维素),则以重量计的量可以在20%至90%之间,与本文所定义的组合物的剩余量相同。
此处提及的本发明的这些组合物的特征在于它们不含可溶性赋形剂/稀释剂。
例如,以重量计,基于组合物的总重量,组合物(例如片剂组合物)最优选由以下几项组成:
24.18%(或约25%)的活性成分
62.12%(或约60%)不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
6%(或约6%)崩解剂(例如交聚维酮,如交联聚维酮XL(Polyplasdone XL))
2.5%(或约2.5%)助流剂(如胶态二氧化硅,气相二氧化硅200(Aerosil 200))
0.2%(或约0.2%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
3%(或约3%)粘合剂或聚合物(例如羟丙甲纤维素5cps(hypromellose 5cps),即甲基纤维素E 5LV(Methocel E 5LV))
2%(或约2%)润滑剂(例如硬脂酰富马酸钠(Pruv))
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
另一方面提供了一种组合物(例如片剂组合物),其中该组合物的不同部分,特别是颗粒内和颗粒外级分以及粘合剂部分,以重量计,基于该组合物的总重量,包含(例如由......组成)以下成分:
颗粒内级分
5%至50%(例如10%至30%)的活性成分
10%至50%(例如20%至40%)的不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
1%至5%(例如2%至4%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0.1%至5%(例如0.5%至4%,如1%至3%)助流剂(例如胶态二氧化硅,气相二氧化硅200)
粘合剂
1%至10%(例如2%至5%)3%粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
0.01%至5%(例如0.1%至1%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
颗粒外级分
10%至50%(例如20%至40%)的赋形剂/稀释剂(优选不溶性赋形剂/稀释剂,例如微晶纤维素,如硅化微晶纤维素)
1%至5%(例如2%至4%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0至3%(例如0.1%至1%)助流剂(如胶态二氧化硅,气相二氧化硅200)
0至5%(例如1%至3%)润滑剂(例如硬脂酰富马酸钠(Pruv))。
本发明此处提及的组合物(例如片剂组合物)特征在于,特别地,颗粒内层不含任何可溶性赋形剂/稀释剂。因此,颗粒外级分不必不含任何可溶性赋形剂/稀释剂,尽管情况优选是颗粒外级分也不含任何可溶性赋形剂/稀释剂。
例如,最优选的组合物由颗粒内级分、粘合剂和颗粒外级分的以下组成成分组成(以重量计,基于该组合物的总重量):
颗粒内级分
24.18%(或约25%)的活性成分
29.82%(或约30%)的不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
3%(或约3%)崩解剂(例如交聚维酮,如交联聚维酮XL)
2%(或约2%)助流剂(如胶态二氧化硅,气相二氧化硅200)
粘合剂
3%(或约3%)粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
0.2%(或约0.2%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
颗粒外级分
32.3%(或约30%)的赋形剂/稀释剂(优选不溶性赋形剂/稀释剂,例如微晶纤维素,如硅化微晶纤维素)
3%(或约3%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0.5%(或约0.5%)助流剂(如胶态二氧化硅,气相二氧化硅200)
2%(或约2%)润滑剂(例如硬脂酰富马酸钠(Pruv))
颗粒内级分(或部分)可以构成该组合物(例如片剂)总重量的以重量计多达75%,并且优选构成该组合物(或片剂)的以重量计在40%和70%之间(例如在50%和65%之间)。最优选地,组合物(例如片剂组合物)的颗粒内级分(或部分)构成该组合物总重量的约60%。粘合剂级分(或部分,或元素)可以构成该组合物(例如片剂)总重量的以重量计多达20%,例如以重量计从0.5%至10%,并且优选以重量计在1%和8%之间(例如约3%,以重量计)。颗粒外层可以构成该组合物(例如片剂)总重量的以重量计多达60%,并且优选构成该组合物(或片剂)的以重量计20%至50%(例如在30%至45%之间)。最优选地,该组合物(例如片剂组合物)的颗粒外级分(或部分)构成该组合物总重量的约37.5%。
在本文所描述的组合物(例如片剂组合物)背景下,可以将该组合物的特质描述为包括颗粒内和颗粒外级分和粘合剂部分(或级分)。组合物的这些级分或部分最终彼此混合。然而,应当理解(例如,参见用于制备此类组合物的方法)这些级分(或部分)的区别导致所得组合物的不同性质。
本文所描述的本发明的组合物可以是颗粒内和颗粒外级分(或部分)以及粘合剂部分的混合物或掺合物,并且在经受适当的压缩技术之后,也可以呈现(单位)剂型,如片剂。
在本文所述的发明方面,特别是上述的可分散组合物,总片剂的重量可以为约100mg(并且因此,存在的活性成分可以在5mg至50mg之间,例如在约10mg和30mg之间,如约20mg)。以这种方式,可以提供其中存在约20mg活性成分的小儿(或老年)配制品。在其他方面,特别是下面描述的那些,总片剂重量可以更高(但仍可递送相同量的活性成分),例如,可以提供200mg的可分散配制品,目的也是递送约20mg的活性成分,例如以可于下文描述的方面和百分比。
在本发明的另一方面,还可以提供具有以下特征的可分散组合物,其特别适用于本发明的组合物,其中总片剂重量相对较高(例如大于100mg,如200mg的总片剂重量):
-提供了可分散组合物(例如片剂组合物),以重量计,基于该组合物的总重量,包含(例如由......组成):
5%至50%(例如5%至20%或10%至15%)的活性成分
35%至90%(例如60%至80%或70%至75%)的不溶性赋形剂/稀释剂
2%至10%(例如4%至8%)的崩解剂
0.1%至5%(例如1.5%至3.5%)的助流剂
0.01%至5%(例如0.1%至1%)的润湿剂或表面活性剂
0至10%(例如2%至5%)的粘合剂或聚合物
0至5%(例如1%至3%)的润滑剂
溶剂(qs),例如水
-提供了可分散组合物(例如片剂组合物),以重量计,基于该组合物的总重量,包含(例如由......组成):
12.09%(或约12%)的活性成分
73.71%(或约70%)不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
6%(或约6%)崩解剂(例如交聚维酮,如交联聚维酮XL)
2.5%(或约2.5%)助流剂(如胶态二氧化硅,气相二氧化硅200)
0.2%(或约0.2%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
3%(或约3%)粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
2%(或约2%)润滑剂(例如硬脂酰富马酸钠(Pruv))
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
在另一方面,特别是在本发明的总片剂重量相对较高(例如200mg)的那些组合物中:
-提供一种组合物(例如片剂组合物),其中该组合物的不同部分,特别是颗粒内和颗粒外级分以及粘合剂部份,以重量计,基于该组合物总重量,包含(例如由......组成)以下成分:
颗粒内级分
5%至50%(例如5%至20%或10%至15%)的活性成分
10%至50%(例如30%至50%或35%至45%)的不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
1%至5%(例如2%至4%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0.1%至5%(例如0.5%至4%,如1%至3%)助流剂(例如胶态二氧化硅,气相二氧化硅200)
粘合剂
1%至10%(例如2%至5%)3%粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
0.01%至5%(例如0.1%至1%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
颗粒外级分
10%至50%(例如20%至40%)的赋形剂/稀释剂(优选不溶性赋形剂/稀释剂,例如微晶纤维素,如硅化微晶纤维素)
1%至5%(例如2%至4%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0至3%(例如0.1%至1%)助流剂(如胶态二氧化硅,气相二氧化硅200)
0至5%(例如1%至3%)润滑剂(例如硬脂酰富马酸钠(Pruv))
-提供一种组合物(例如片剂组合物),其中该组合物的不同部分,特别是颗粒内和颗粒外级分以及粘合剂部份,以重量计,基于该组合物总重量,包含(例如由......组成)以下成分:
颗粒内级分
12.09%(或约12%)的活性成分
41.41%(或约40%)的不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
3%(或约3%)崩解剂(例如交聚维酮,如交联聚维酮XL)
2%(或约2%)助流剂(如胶态二氧化硅,气相二氧化硅200)
粘合剂
3%(或约3%)粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
0.2%(或约0.2%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
颗粒外级分
32.3%(或约30%)的赋形剂/稀释剂(优选不溶性赋形剂/稀释剂,例如微晶纤维素,如硅化微晶纤维素)
3%(或约3%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0.5%(或约0.5%)助流剂(如胶态二氧化硅,气相二氧化硅200)
2%(或约2%)润滑剂(例如硬脂酰富马酸钠(Pruv))
本发明的组合物被描述为具有某些组分或成分,以下详细阐述这些组分或成分。
“活性成分”是指富马酸贝达喹啉,即贝达喹啉的富马酸盐形式。该形式是在某些地区获得监管部门批准的成人用组合物的一部分。
这里指出本发明的组合物(例如片剂组合物)含有不溶性赋形剂/稀释剂。除非已经规定了赋形剂,否则这种赋形剂/稀释剂可以是淀粉、粉末状纤维素、微晶纤维素(如硅化微晶纤维素)、磷酸钙(例如磷酸氢钙、二水合磷酸氢钙、磷酸三钙)、碳酸钙、硫酸钙等(或其组合,即共同处理的不可溶性赋形剂;其他可以考虑的赋形剂包括蜡状氢化油等)。可以理解的是,最优选的不可溶性赋形剂/稀释剂是微晶纤维素(例如硅化微晶纤维素),因为这样所得的组合物具有有利的固有性质。在提到赋形剂/稀释剂不必是不可溶的情况下,则也可以考虑糖和多元醇,例如也可以考虑以下赋形剂/稀释剂:葡萄糖结合剂、糊精、右旋糖赋形剂、果糖、高岭土、乳糖醇、无水乳糖、乳糖一水合物、甘露醇、山梨糖醇、氯化钠、蔗糖、可压缩糖、糖果糖、乳糖一水合物和微晶纤维素(75∶25)的喷雾干燥混合物、可商购的共同处理的微晶纤维素和胶态二氧化硅(98∶2)的喷雾干燥混合物、可商购的(其可能包括糖和其他可溶性赋形剂/稀释剂)。
这里指出本发明的组合物(例如片剂组合物)含有崩解剂。可能的崩解剂包括药学上可接受的崩解剂,其包括淀粉、离子交换树脂(例如安伯来特(Amberlite))、交联聚乙烯吡咯烷酮、改性纤维素胶(例如交联羧甲基纤维素钠(例如))、淀粉乙醇酸钠、羧甲基纤维素钠、十二烷基硫酸钠、改性玉米淀粉、微晶纤维素、硅酸镁铝、藻酸、藻酸盐、粉末状纤维素、交聚维酮(例如交联聚维酮XL)。可考虑的其他崩解剂包括L-HPC、黄原胶、结冷胶(Gellan gum)、大豆多糖等。最优选的崩解剂是交聚维酮,优选粗级交聚维酮(例如交联聚维酮XL)。
这里指出本发明的组合物(例如片剂组合物)含有助流剂。可能的助流剂包括药学上可接受的助流剂,其包含滑石、胶态二氧化硅、淀粉、硬脂酸镁。优选胶态二氧化硅(气相二氧化硅200)
这里指出本发明的组合物(例如片剂组合物)含有润湿剂或表面活性剂。这种润湿剂(或表面活性剂)可以是适用于药物组合物的任何生理上可耐受的润湿剂。
本领域熟知润湿剂为两亲性化合物;它含有极性亲水性部分以及非极性疏水性部分。
术语“亲水性”或“疏水性”为相对术语。
润湿剂的相对亲水性或疏水性可由其亲水-亲油平衡值(“HLB值”)表示。具有较低HLB值的润湿剂被归为“疏水性”润湿剂,而具有较高HLB值的润湿剂被归为“亲水性”润湿剂。根据经验,一般认为HLB值大于约10的润湿剂是亲水性润湿剂;一般认为HLB值小于约10的润湿剂是疏水性润湿剂。
本发明组合物优选包含亲水性润湿剂。
应理解润湿剂的HLB值仅大概指示润湿剂的亲水性/疏水性。具体润湿剂的HLB值可根据测定HLB值所用的方法而不同;可根据其商业来源而变化;批次与批次间也有变化。本领域技术人员可以容易地鉴定适用于本发明的药物组合物的亲水润湿剂。
本发明的润湿剂可以是阴离子、阳离子、两性离子或非离子润湿剂,优选后者。本发明的润湿剂也可以是两种或多种润湿剂的混合物。
适用于本发明组合物的润湿剂列于下文。应该强调的是,所述润湿剂列表仅为举例说明、代表性的,并非详尽的。因此,本发明不限于以下列出的润湿剂。在本发明的组合物中也可使用湿润剂的混合物。
可用于本发明的合适润湿剂包含:
a)聚乙二醇脂肪酸单酯,包括月桂酸、油酸、硬脂酸、蓖麻油酸等与PEG 6、7、8、9、10、12、15、20、25、30、32、40、45、50、55、100、200、300、400、600等的酯,例如PEG-6月桂酸酯或硬脂酸酯、PEG-7油酸酯或月桂酸酯、PEG-8月桂酸酯或油酸酯或硬脂酸酯、PEG-9油酸酯或硬脂酸酯、PEG-10月桂酸酯或油酸酯或硬脂酸酯、PEG-12月桂酸酯或油酸酯或硬脂酸酯或蓖麻油酸酯、PEG-15硬脂酸酯或油酸酯、PEG-20月桂酸酯或油酸酯或硬脂酸酯、PEG-25硬脂酸酯、PEG-32月桂酸酯或油酸酯或硬脂酸酯、PEG-30硬脂酸酯、PEG-40月桂酸酯或油酸酯或硬脂酸酯、PEG-45硬脂酸酯、PEG-50硬脂酸酯、PEG-55硬脂酸酯、PEG-100油酸酯或硬脂酸酯、PEG-200油酸酯、PEG-400油酸酯、PEG-600油酸酯;(属于该组的润湿剂是,如被称为Cithrol、Algon、Kessco、Lauridac、Mapeg、Cremophor,Emulgante,NikkoU、Myrj、Crodet、Albunol、Lactomul)
b)聚乙二醇脂肪酸二酯,包括月桂酸、硬脂酸、棕榈酸、油酸等与PEG-8、10、12、20、32、400等的二酯,例如PEG-8二月桂酸酯或二硬脂酸酯、PEG-10二棕榈酸酯、PEG-12二月桂酸酯或二硬脂酸酯或二油酸酯、PEG-20二月桂酸酯或二硬脂酸酯或二油酸酯、PEG-32二月桂酸酯或二硬脂酸酯或二油酸酯、PEG-400二油酸酯或二硬脂酸酯;(属于该组的润湿剂是,如被称为Mapeg、Polyalso、Kessco、Cithrol)
c)聚乙二醇脂肪酸单酯和二酯混合物,例如PEG4-150单月桂酸酯和二月桂酸酯、PEG4-150单油酸酯和二油酸酯、PEG4-150单硬脂酸醋和二硬脂酸酯等;(属于该组的润湿剂是,如被称为Kessco)
d)聚乙二醇甘油脂肪酸酯,例如PEG-20甘油月桂酸酯或甘油硬脂酸酯或甘油油酸酯、PEG-30甘油月桂酸酯或甘油油酸酯、PEG-15甘油月桂酸酯、PEG-40甘油月桂酸酯等;(属于该组的润湿剂是,如被称为Tagat、Glycerox L、Capmul),
e)醇-油酯交换产物,包含醇或多元醇(如甘油、丙二醇、乙二醇、聚乙二醇、山梨醇、季戊四醇等)与天然油和/或氢化油或者油可溶性维生素(如蓖麻油、氢化蓖麻油、维生素A、维生素D、维生素E、维生素K)、食用植物油(如玉米油、橄榄油、花生油、棕榈仁油、杏仁油、扁桃仁油等)的酯,例如PEG-20蓖麻油或氢化蓖麻油或玉米油甘油酯或者扁桃仁油甘油酯,PEG-23蓖麻油、PEG-25氢化蓖麻油或三油酸酯,PEG-35蓖麻油、PEG-30蓖麻油或氢化蓖麻油、PEG-38蓖麻油、PEG-40蓖麻油或氢化蓖麻油或棕榈仁油、PEG-45氢化蓖麻油、PEG-50蓖麻油或氢化蓖麻油、PEG-56蓖麻油、PEG-60蓖麻油或氢化蓖麻油或玉米油甘油酯或扁桃仁油甘油酯,PEG-80氢化蓖麻油、PEG-100蓖麻油或氢化蓖麻油、PEG-200蓖麻油、PEG-8辛酸/癸酸甘油酯,PEG-6辛酸/癸酸甘油酯,月桂酰聚乙二醇-32甘油酯,硬脂酰聚乙二醇甘油酯,生育酚PEG-1000琥珀酸酯(TPGS);(属于该组的润湿剂是,如被称为Emalex、Cremophor、Emulgante、Eumulgin、Nikkol、Thornley、Simulsol、Cerex、Crovol、Labrasol、Softigen、Gelucire、Vitamin E TPGS),
f)聚甘油化的脂肪酸包含聚甘油脂肪酸酯,例如,如聚甘油-10月桂酸酯或油酸酯或硬脂酸酯、聚甘油-10单油酸酯和二油酸酯、聚甘油多聚蓖酸酯等;(属于该组的润湿剂是,如被称为Nikkol Decaglyn、Caprol或Polymuls)
g)甾醇衍生物,包含甾醇的聚乙二醇衍生物,如PEG-24胆固醇醚、PEG-30胆甾烷醇、PEG-25植物甾醇、PEG-30大豆甾醇等;(属于该组的润湿剂是,如被称为SolulanTM或Nikkol BPSH)
h)聚乙二醇脱水山梨醇脂肪酸酯,例如,如PEG-10脱水山梨醇月桂酸酯、PEG-20脱水山梨醇单月桂酸酯或脱水山梨醇三硬脂酸酯或脱水山梨醇单油酸酯或脱水山梨醇三油酸酯或脱水山梨醇单异硬脂酸酯或脱水山梨醇单棕榈酸酯或脱水山梨醇单硬脂酸酯、PEG-4脱水山梨醇单月桂酸酯、PEG-5脱水山梨醇单油酸酯、PEG-6脱水山梨醇单油酸酯或脱水山梨醇单月桂酸酯或脱水山梨醇单硬脂酸酯、PEG-8脱水山梨醇单硬脂酸酯、PEG-30脱水山梨醇四油酸酯、PEG-40脱水山梨醇油酸酯或脱水山梨醇四油酸酯、PEG-60脱水山梨醇四硬脂酸酯、PEG-80脱水山梨醇单月桂酸酯、PEG山梨醇六油酸酯(Atlas G-1086)等;(属于该组的润湿剂是,如被称为Liposorb、Tween、Dacol MSS、Nikkol、Emalex、Atlas)
i)聚乙二醇烷基醚,例如,如PEG-10油基醚或十六烷基醚或硬脂基醚、PEG-20油基醚或十六烷基醚或硬脂基醚、PEG-9月桂基醚、PEG-23月桂基醚(月桂醇聚醚-23)、PEG-100硬脂基醚等;(属于该组的润湿剂是,如被称为Volpo、Brij)
j)糖酯,例如,如蔗糖二硬脂酸酯/单硬脂酸酯、蔗糖单硬脂酸酯或单棕榈酸酯或单月桂酸酯等;(属于该组的润湿剂是,如被称为Sucro ester、Crodesta、Saccharosemonoaurate)
k)聚乙二醇烷基苯酚,例如,如PEG-10-100壬基苯酚(Triton X系列)、PEG-15-100辛基苯酚醚(Triton N系列)等;
1)聚氧乙烯-聚氧丙烯嵌段共聚物(泊洛沙姆),例如,如泊洛沙姆108、泊洛沙姆188、泊洛沙姆237、泊洛沙姆288等;(属于该组的润湿剂是,如被称为Synperonic PE、Pluronic、Emkalyx、LutrolTM、Supronic、Monolan、Pluracare、Plurodac)
m)离子润湿剂,包括阳离子、阴离子和两性离子表面活性剂,例如脂肪酸盐,如油酸钠、十二烷基硫酸钠、十二烷基肌氨酸钠、二辛基磺基琥珀酸钠、肉豆蔻酸钠、棕榈酸钠、钠态(sodium state)、蓖麻油酸钠等;例如胆汁盐,如胆酸钠、牛磺胆酸钠、甘氨胆酸钠等;例如磷脂,如蛋黄卵磷脂/大豆卵磷脂、羟化卵磷脂、溶血磷脂酰胆碱、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸等;例如磷酸酯,如二乙醇铵聚氧乙烯-10油基醚磷酸酯、脂肪醇或乙氧化脂肪醇与磷酸或酸酐的酯化产物;例如羧酸酯(盐),如琥珀酰单酸甘油酯、硬脂酰富马酸钠、硬脂酰丙二醇琥珀酸氢酯、单甘酯和双甘酯的单/二乙酰酒石酸酯、单甘酯和双甘酯的柠檬酸酯、脂肪酸的甘油-乳酯、脂肪酸的乳酯、硬脂酰基-2-乳酸钙/钠、硬脂酰乳酸钙/钠、藻酸盐、丙二醇藻酸酯、醚羧酸盐等;例如硫酸盐和磺酸盐,如乙氧基化烷基硫酸盐、烷基苯硫酸盐、α-烯烃磺酸盐、酰基羟乙基磺酸盐、酰基牛磺酸盐、烷基甘油醚磺酸盐、辛基磺基琥珀酸二钠、十一碳烯酰胺基-MEA-磺基琥珀酸二钠等;例如阳离子润湿剂,如十六烷基溴化三铵、癸基三甲基溴化铵、十六烷基三甲基溴化铵、十二烷基氯化铵、烷基苄基二甲基铵盐、二异丁基苯氧乙氧二甲基苄基铵盐、烷基吡啶盐、甜菜碱(十二烷基甜菜碱)、乙氧基化胺(聚氧乙烯-15椰油胺)等。
在上述合适的润湿剂名单中列出了不同的可能性,例如,如PEG-20油基醚或十六烷基醚或硬脂基醚,这意指包含PEG-20油基醚和PEG-20十六烷基醚以及PEG-20硬脂基醚。因此,例如PEG-20蓖麻油或氢化蓖麻油或玉米油甘油酯或扁桃仁油甘油酯必须被解读成PEG-20蓖麻油和PEG-20氢化蓖麻油和PEG-20玉米油甘油酯和PEG-20扁桃仁油甘油酯。
本组合物中优选的润湿剂是属于聚乙二醇脱水山梨醇脂肪酸酯类的那些试剂,例如称为吐温的润湿剂,如吐温20、60、80。润湿剂最优选是吐温20(聚山梨醇酯20)。
润湿剂(或表面活性剂)的优选量在本文中有描述,但是应当理解,当用于本组合物时,其可以取决于组合物中存在的活性成分的量或活性成分的粒度。量越多或粒度越小,可能需要越多润湿剂。
这里指出本发明的组合物(例如片剂组合物)含有粘合剂或聚合物(例如用于本发明组合物的粘合剂级分)。这种粘合剂或聚合物可以是有机聚合物。
本发明组合物(例如片剂)中使用的有机聚合物可以是任何生理上可耐受的水溶性合成、半合成或非合成的有机聚合物。
因此,例如聚合物可以为天然聚合物如多糖或多肽或其衍生物,或为合成聚合物如聚亚烷基氧化物(如PEG)、聚丙烯酸酯、聚乙烯吡咯烷酮等。当然也可使用混合的聚合物,如嵌段共聚物和糖肽。
聚合物适宜的分子量在500D-2MD之间,并且当在20℃的2%水溶液中时,其适宜地具有1至15,000mPa.s的表观粘度。例如水溶性聚合物可选自下组,该组包含
-烷基纤维素,如甲基纤维素,
-羟烷基纤维素,如羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丁基纤维素,
-羟烷基烷基纤维素,如羟乙基甲基纤维素和羟丙基甲基纤维素,
-羧烷基纤维素,如羧甲基纤维素,
-羧烷基纤维素的碱金属盐,如羧甲基纤维素钠,
-羧烷基烷基纤维素,如羧甲基乙基纤维素,
-羧烷基纤维素酯,
-淀粉,
-果胶,如羧甲基支链淀粉钠,
-几丁质衍生物,如脱乙酰几丁质,
-肝素和类肝素,
-多糖,如藻酸、其碱金属和铵盐、角叉菜聚糖、半乳甘露聚糖、黄芪胶、琼脂、阿拉伯胶、瓜尔胶和黄原胶,
-聚丙烯酸及其盐,
-聚甲基丙烯酸及其盐,甲基丙烯酸酯共聚物,
-聚乙烯醇,
-聚乙烯吡咯烷酮,聚乙烯吡咯烷酮与乙酸乙烯酯的共聚物,
-聚亚烷基氧化物,如聚环氧乙烷和聚环氧丙烷以及环氧乙烷与环氧丙烷的共聚物,例如泊洛沙姆和泊洛沙胺。
药学上可接受的并具有如前文定义的恰当物理化学性质的未列举聚合物同样适合用于制备本发明组合物。
有机聚合物优选为淀粉、聚乙烯吡咯烷酮或纤维素醚,如PVP K29-32、PVP K90、甲基纤维素、羟丙基纤维素、羟乙基甲基纤维素或羟丙基甲基纤维素(HPMC)。
所述HPMC含足够的羟丙基和甲氧基,以使其具有水溶性。具有约0.8至约2.5的甲氧基取代度和约0.05至约3.0的羟丙基摩尔取代度的HPMC通常是水溶性的。甲氧基取代度是指纤维素分子的每个葡糖酐单元所存在的甲醚基团的平均数。羟丙基摩尔取代是指已经与纤维素分子的每个葡糖酐单元反应的环氧丙烷的摩尔平均数。优选的HPMC是羟丙甲纤维素2910 15mPa.s或羟丙甲纤维素2910 5mPa.s,尤其优选羟丙甲纤维素2910 15mPa.s。羟丙基甲基纤维素是羟丙甲纤维素在美国收录名称(United States Adopted Name)(见Martindale,The Extra Pharmacopoeia,第29版,第1435页)中的名称。在四位数字“2910”中,前两位数字表示甲氧基的近似百分比,且第三和第四位表示羟丙氧基的近似百分比组成;15mPa.s或5mPa.s是表示2%水溶液在20℃的表观粘度值。
最优选本发明组合物的粘合剂或聚合物是羟丙甲纤维素5cps(即甲基纤维素E5LV)。
这里指出本发明的组合物(例如片剂组合物)含有润滑剂。这种润滑剂可以是药学上可接受的润滑剂,例如硬脂酸镁、硬脂酸钙、硬脂酸、滑石、聚乙二醇、十二烷基硫酸钠、十二烷基硫酸镁。最优选地,润滑剂是硬脂基富马酸钠(Pruv)。
本发明的组合物可以使用的活性成分具有粒度为:
-小于50μm(优选小于25μm,例如小于15μm,如约9μm(甚至更少)的d10
-小于100μm(优选小于50μm,例如小于25μm,如约22μm(甚至更少)的d50
-小于200μm(优选小于100μm,例如小于50μm,如约48μm(甚至更少)的d90
如在此使用的,术语d50具有其如本领域普通技术人员已知的常规含义,并且可以通过本领域已知的粒度测量技术,例如像沉降场流份化、光子相关谱、激光衍射或圆盘离心对其进行测量。在此提到的d50可涉及这些颗粒的体积分布。在此情况下,“22μm的d50”指至少50%的颗粒的体积粒度小于22μm。所提到的其他粒度也同样适用,并且d10和d90具有类似的含义。对于平均粒度,通常体积和重量分布导致相同或大致相同的值。
粒度可以是决定压片速度,特别是可流动性并且因此对具体剂型或配制品的大规模可制造性以及最终产物的质量的一个重要因素。例如,对于胶囊,粒度范围可优选为从约5至约300μm(d50);对于片剂,粒度优选小于250μm,更优选小于100μm(例如小于50μm)(d50)。颗粒太小会引起粘附在片剂冲头上以及可制造性问题。粒度对本发明组合物的固有性质具有影响。
此处所描述的组合物可进一步包含一种或多种药学上可接受的赋形剂,例如增塑剂、调味剂、甜味剂、着色剂、防腐剂等(前提是这些附加的赋形剂不含可溶性赋形剂/稀释剂,其中已经规定该组合物或组合物的级分适当地不包含这种可溶性组分)。在本发明的一个方面,本发明的组合物不含增塑剂或其他这种此处提到的可选赋形剂。尤其在通过热熔融挤出制备的情况下,所述赋形剂不应是热敏感的,换言之,它们在熔融挤出机的工作温度下不应显示任何可感知的降解或分解。
本发明的当前组合的优点(且特别是分散性/崩解性)可能源于不可溶性赋形剂(例如微晶纤维素,如硅化微晶纤维素)的存在,其可能具有快速吸收存在于分散介质中水的能力,即它可能具有芯吸作用,有助于引起分散性/崩解性的改善。鉴于此,本发明的组合物有利地实现了良好的分散或崩解作用,例如与先前已知的组合物相比或与此处所描述的其他组合物相比。如所指出的,芯吸作用可能导致更快的分散,并且可能绕过增溶过程(例如,液体可以通过毛细作用被拉伸或“芯吸”到这些途径中并使颗粒间的键破裂,导致片剂/组合物断裂分开),这可能是有利的。此外,不溶性赋形剂/稀释剂即使经过长时间(例如6小时)也可以容易地重新悬浮-这可以具有以下优点:本发明的组合物不需要悬浮剂来重新分散颗粒/微粒。
本发明也涉及制备本发明组合物(例如片剂组合物)的方法,并且因此提供:
-用于制备本发明的组合物(例如片剂)的方法(例如,如下文所描述)
-通过本发明(例如,如下文所描述)的方法获得的产品(例如本发明的组合物,例如此处所描述的可分散片剂)
如上所述,本发明的组合物优选包含不同的级分/部分:颗粒内级分、粘合剂部分和颗粒外级分。
因此,提供了制备本发明组合物的方法,该方法包括:
(a)使用本文提及的颗粒内级分的组分获得颗粒内级分;
(b)使用本文提及的粘合剂级分的组分制备粘合剂级分;
(c)使用本文提及的颗粒外级分的组分获得颗粒外级分,
并使用那些级分来制备本发明的组合物。
更具体地讲,可以通过混合或掺合相关组分来制备颗粒内级分(如本文所定义)。
可以采用直接压片法,但是这可能具有掺合物所具有的流动性差和/或可能粘附在冲头表面上的缺点。因此,直接压片之后是制粒。干法制粒在流动(或压缩)性方面可能有不足,并且上述的粘附/拾取现象也可能仍然存在。所以,对于本发明组合物优选采用湿法制粒法。
因此,更具体地说,粘合剂级分/部分可以通过使相关成分(即粘合剂或聚合物、以及润湿剂以及(如果必要)水性或非水性的载体或者组合;该载体优选水(qs),优选纯化水(qs))接触或混合来制备,并且粘合剂级分/部分可以与颗粒内级分一起经受湿法制粒。这种湿法制粒法优选是低剪切制粒的方法(或顶部喷雾流化床制粒),并且在粘合剂级分中采用低粘度可溶性聚合物(优选粘度为5cps或更低)。然后将获得的颗粒干燥并按大小分类(或筛分),之后将其与颗粒外级分(如本文所定义)的组分混合或掺合。如果颗粒外层还包括润滑剂,这种掺合也固有地涉及润滑。
一旦本发明的组合物得以制备(例如如上所述,包括颗粒内、颗粒外和粘合剂级分的混合),这种组合物可以任选地并且优选地转化为片剂形式。在本发明方法的优选方面,如此制备的组合物优选被压制成片剂形式,从而允许制备本发明的可分散片剂。这样的片剂可以是以任何合适的剂量,但是每个单位可以含有的活性成分在5mg与200mg之间(在这种情况下,意指不考虑富马酸盐组分的活性物质贝达喹啉)。该单位可能含有100mg贝达喹啉(加上富马酸盐部分的相应重量),或者如果该单位形式针对小儿群体,则其优选包含20mg的贝达喹啉(对应于24.18mg的富马酸贝达喹啉)。
压片方法本身是另外标准的并且通过从所需成分的共混物或混合物使用常规压片机形成适当形状的片剂而易于实施。
本发明的片剂可进一步被薄膜包衣以改良味道,提供吞咽的容易性和极好的外观。许多适合的聚合薄膜包衣材料在本领域中是已知的。优选的薄膜包衣材料是羟丙基甲基纤维素HPMC,尤其是HPMC 29105mPa.s。也可以在此使用其他合适的成膜聚合物,包括羟丙基纤维素和丙烯酸酯-甲基丙烯酸酯共聚物。除成膜聚合物外,薄膜包衣可以进一步包括增塑剂(例如丙二醇)和任选地色素(例如二氧化钛)。薄膜包衣悬浮液也可以包含作为抗粘着剂的滑石。在根据本发明的速释片剂中,薄膜包衣很小且以重量计占总片剂重量的小于约3%(w/w)。在本发明的一个实施例中(例如在优选的实施例中),本发明的片剂未进行薄膜包衣。
如上所述,本发明的效用源自活性成分及其盐,已知该活性成分及其盐显示抗分枝杆菌活性,该分枝杆菌包括耐药菌株,特别是结核分枝杆菌、牛分枝杆菌、鸟分枝杆菌、麻风分枝杆菌和海分枝杆菌,尤其是抗包括耐药结核分枝杆菌菌株在内的结核分枝杆菌。该活性成分,包括其盐,显示出抗活跃的、敏感的、易感的分枝杆菌菌株以及潜伏的、休眠的、持久的分枝杆菌菌株的活性。
因此,在本发明的一个方面,提供了根据本发明的组合物(例如片剂),其适用于治疗包括分枝杆菌感染在内的细菌感染,特别是那些由致病性分枝杆菌引起的疾病,例如结核分枝杆菌(包括其潜伏和耐药形式)、牛分枝杆菌、麻风分枝杆菌、鸟分枝杆菌、麻风分枝杆菌和海分枝杆菌。
此外,如下文中描述,本发明还涉及本发明的组合物、其药学上可接受的盐、其溶剂化物或其N-氧化物形式,连同任何其药物组合物的用途,用于制造用于治疗细菌感染(包括分枝杆菌感染)的药剂。
因此在另一方面,本发明提供了一种治疗受细菌感染(包括分枝杆菌感染)或处于此风险的患者的方法,其包括向该患者给予治疗有效量的根据本发明的药物组合物(例如片剂)。
本发明的组合物可以与已知可用于治疗如本文所定义的细菌感染(并且特别是用于治疗如本文所定义的分枝杆菌感染、结核病)的其他治疗剂组合。这些其他的抗菌剂包括β-内酰胺类抗生素,例如天然青霉素、半合成青霉素、天然头孢菌素、半合成头孢菌素、头霉素类、1-氧头孢烯类、克拉维酸、青霉烯类、碳青霉烯类、诺卡菌素类、单环β-内酰胺类;四环素类、脱水四环素、蒽环类;氨基糖苷类;核苷如N-核苷、C-核苷、碳环核苷、杀稻瘟菌素S;大环内酯类如十二元环大环内酯类、十四元环大环内酯类、十六元环大环内酯类;安沙霉素类;肽,如博来霉素类、短杆菌肽类、多粘菌素类、杆菌肽类、含有内酯键的大环肽类抗生素、放线菌素类、安福霉素、卷曲霉素、偏端霉素、持久杀菌素类、米卡霉素、新制癌菌素、涂链霉素、紫霉素、维吉尼霉素;放线酮;环丝氨酸;变曲霉素;肉瘤霉素A;新生霉素;灰黄霉素;氯霉素;丝裂霉素类;烟曲霉素;莫能霉素类;硝吡咯菌素;磷霉素;夫西地酸;D-(p-羟基苯基)甘氨酸;D-苯基甘氨酸;烯二炔类。
可以与本发明的组合物组合的具体抗生素是例如苄基青霉素(钾、普鲁卡因、苄星青霉素)、苯氧基甲基青霉素(钾)、苯氧乙基青霉素钾、丙匹西林、羧苄青霉素(二钠、苯基钠、茚满基钠)、磺苄西林、替卡西林二钠、甲氧西林钠、苯唑西林钠、氯唑西林钠、双氯西林、氟氯西林、氨苄西林、美洛西林、哌拉西林钠、阿莫西林、环己西林、海他西林(hectacillin)、舒巴坦钠、盐酸酞氨西林、盐酸巴氨西林、匹美西林、头孢氨苄、头孢克洛、头孢来星、头孢羟氨苄、头孢拉定、头孢沙定、头孢匹林钠、头孢噻吩钠、头孢乙腈钠、头孢磺啶钠、头孢噻啶、头孢曲秦、头孢哌酮钠、头孢孟多、盐酸头孢替安、头孢唑啉钠、头孢唑肟钠、头孢噻肟钠、盐酸头孢甲肟、头孢呋辛、头孢曲松钠、头孢他啶、头孢西丁、头孢美唑、头孢替坦、拉氧头孢、克拉维酸、亚胺培南、氨曲南、四环素、盐酸金霉素、地美环素、土霉素、美他环素、多西环素、罗利环素、米诺环素、盐酸柔红霉素、多柔比星、阿柔比星、硫酸卡那霉素、卡那霉素、妥布霉素、硫酸庆大霉素、地贝卡星、阿米卡星、小诺米星、核糖霉素、硫酸新霉素、硫酸巴龙霉素、硫酸链霉素、二氢链霉素、越霉素A、潮霉素B、安普霉素、西索米星、硫酸奈替米星、盐酸大观霉素、盐酸阿司米星、有效霉素、春雷霉素、多氧菌素、杀稻瘟菌素S、红霉素、依托红霉素、磷酸竹桃霉素、醋竹桃霉素(tracetyloleandomycin)、吉他霉素、交沙霉素、螺旋霉素、泰洛星、伊维菌素、麦迪霉素、硫酸博来霉素、硫酸培洛霉素、短杆菌肽S、多粘菌素B、杆菌肽、硫酸粘杆菌素、粘杆菌素甲磺酸钠、恩拉毒素、米卡霉素、维吉尼霉素、硫酸卷曲霉素、紫霉素、恩维霉素、万古霉素、放线菌素D、新制癌菌素、贝他定、胃酶抑素、莫能菌素、拉沙洛西、沙利霉素、两性霉素B、制霉菌素、那他霉素、曲古霉素、普卡霉素、林可霉素、克林霉素、棕榈酸盐酸克林霉素、黄霉素、环丝氨酸、培西洛星、灰黄霉素、氯霉素、棕榈酸氯霉素、丝裂霉素C、吡咯尼群、磷霉素、夫西地酸、二环霉素、泰妙菌素、西卡宁。
可与本发明组合物组合的其他分枝杆菌剂例如是利福平利福平(=利肺宁(rifampin));异烟肼;吡嗪酰胺;阿米卡星;乙硫异烟胺;乙胺丁醇;链霉素;对氨基水杨酸;环丝氨酸;卷曲霉素;卡那霉素;氨硫脲;PA-824;喹诺酮类/氟喹诺酮类,如莫西沙星、加替沙星、氧氟沙星、环丙沙星、司帕沙星;大环内酯,例如,如克拉霉素、氯法齐明、与克拉维酸组合的阿莫西林;利福霉素;利福布汀;利福喷汀。
如在此所使用的与数值相连的术语“大约”是指具有在数值的上下文中它的通常含义。必要时,词语“大约”可以被±10%、或±5%、或±2%、或±1%的数值替代。
所有在此引用的文件都通过引用以其全文结合。
以下实例旨在说明本发明。
实验部分
该活性成分富马酸贝达喹啉可以(例如)根据国际专利申请WO 2008/068231中描述的程序制备。从下表1可知,TMC207是指富马酸贝达喹啉。
实例
1)颗粒内填充剂的影响
颗粒内部的可溶性赋形剂在分散时间上没有显示任何改善增加。观察到片剂分散所需的时间受到颗粒内加入可溶性赋形剂的不利影响。因此,决定继续使用“硅胶MCC”。
2)颗粒外填充剂的影响
颗粒外部的可溶性赋形剂没有显示任何改善增加。观察到可溶性赋形剂的加入不利地影响片剂分散所需的时间。因此,决定继续使用“硅胶MCC”。
3)交聚维酮等级的影响
交聚维酮(交联聚维酮XL)较粗级与细颗粒交聚维酮(交联聚维酮XL 10)相比,显示出更好的分散模式和行为,因此决定在颗粒内以及颗粒外继续使用交联聚维酮XL级。
其他实例
根据本文所述的技术制备本发明的以下组合物:
表1:TMC207可分散片剂的当前组成
(1)这种材料是加工助剂并且在加工过程中被除去
稳定性数据:
外观、测定和色谱纯度
备注:光ICH:CIE85-ID65700W/m2(对包装于容器中的片剂进行光学研究)
如果指“任何指定的降解产物”,这可能是API中的杂质(例如来自方法的杂质)。
发现本发明的组合物在ICH条件下是稳定的。
使用稳定性:
考虑分散体的制备与剂量给予之间的滞后时间来评估片剂在水中的分散稳定性。
方法:-
由于本发明的组合物(即上述分散性片剂)稳定长达6hr,所以其制备后可以施用高达6hr。
在环境条件下在透明玻璃烧瓶中,将5颗片剂(等同于100mg的剂量)分散于50ml水中,并在0hr、2hr、4hr和6hr后进一步分析测定相关物质。
发现产物以水分散体形式稳定6小时。此外,其在透明的玻璃容器中也是稳定的,表明它不是光敏感性的。
通过两种不同的方法比较成人配制品与小儿配制品的溶解特性概况:
配制品 | 成人 | 成人 | 小儿 | 小儿 |
批号 | 136695 | 136695 | HG-121019 | HG-121019 |
强度 | 100mg | 100mg | 5x 20mg | 5x 20mg |
结果集ID | 81938 | 82584 | 83398 | 83598 |
溶解介质 | 0.01N HCL | 0.01N HCL | 0.01N HCL | 0.01N HCL |
单位数量 | 6 | 6 | 6 | 6 |
条件 | RT_6M | RT_6M | RT_1.5Yrs | RT_1.5Yrs |
体积 | 900mL | 900mL | 900mL | 900mL |
装置 | 篮 | 桨 | 篮 | 桨 |
RPM | 150 | 75 | 150 | 75 |
5 | 55.97 | 32.61 | 63.37 | 73.43 |
10 | 77.26 | 59.06 | 72.46 | 93.39 |
15 | 85.95 | 68.12 | 81.56 | 97.96 |
20 | 90.02 | 71.97 | 89.10 | 100.07 |
30 | 93.49 | 77.76 | 95.91 | 101.27 |
45 | 95.60 | 85.76 | 98.36 | 102.15 |
60 | 96.45 | 92.63 | 98.38 | 101.93 |
90 | 97.43 | 97.24 | 100.14 | 102.03 |
F2 | 66.6** | 27.7* |
*wrt成人片剂;桨75rpm
**wrt成人片剂;篮150rpm
RT=室温;6M=6个月
F2:FDA和EMEA将相似性因子定义为“1的对数互逆平方根变换加上测试和参比产品之间溶解药物百分比的均方(平方和的平均值)差”。如果F2>50,产物是相似的,如果小于50,则不相似。
在两种溶解方法中,与成人配制品相比,小儿配制品的溶解特性概况更快。
对生物利用度的影响:
1)与成人片剂相比,食物对于生物利用度的影响是降低了的
常规早餐 | 酸奶 | |
成人片剂 | 91% | 32% |
水可分散片剂 | 82% | 17% |
2)用常规早餐和酸奶测试的成人配制品和小儿配制品均显示,两种配制品都是生物等效的,尽管可分散片剂在体外显示更快的溶解特性概况。
组1(标准早餐)
水可分散片剂 | 比率(%) | 90%CI |
Cmax | 106.58 | 96.11-118.18 |
AUC72h | 98.43 | 91.85-105.47 |
组2(酸奶)
水可分散片剂 | 比率(%) | 90%CI |
Cmax | 111.93 | 104.26-120.16 |
AUC72h | 112.95 | 105.94-120.42 |
因此,当以禁食、喂食以及用酸奶对成年群体进行测试时,发现本发明的组合物与成年普通片剂配制品具有生物等效性。与成人片剂配制品相比,当使用酸奶进行按量给予时,本产品(发明)将食物效果降低了9%和15%。
附加实例
配制品的进一步发展旨在满足10mg剂量增量的临床需求。这是通过开发具有断裂线的20mg配制品来实现的,以在需要时以10mg剂量增量给药。
为了实现这一点,对生物等效性研究中测试的先前的配制品进行了以下改变。
另外的配制品的组成:
研究配制品中的不同因素的配制品试验
1)颗粒内填充剂与颗粒外填充剂的影响
结论:当颗粒内填充剂(硅化MCC)在41%至58%之间变化时,其对产品的关键质量属性(CQA)不显示任何影响。这种变化直接影响颗粒外填充剂的浓度,当颗粒外填充剂浓度在32%至16%之间变化时不影响CQA。
交聚维酮量的影响
结论:-研究了在配制品中占3%至6%的崩解剂(交聚维酮)浓度。这不影响CQA,但具有6%交聚维酮的分散时间略好于3%的
2)粘合剂的增加的量的影响
结论:-研究了在3.5%至5.25%之间的粘合剂(HPMC)浓度。较高浓度的粘合剂显示较高的分散时间。
另外的可分散片剂配制品的初始和稳定性数据:
RT:报告阈值
配制品在HDPE瓶中直到6个月表现出令人满意的稳定性。
溶解特性概况(0.01N HCl)-比较100mg可分散片剂配制品与200mg可分散片剂配制品
100mg和200mg片剂配制品的溶解特性概况是相当的。
分裂片剂数据:
1-分裂片剂的重量损失
分裂片剂(100转)的易碎性:0.06%
分裂片剂(400转)的易碎性:0.16%
Claims (18)
1.一种可分散组合物(例如片剂),其包含富马酸贝达喹啉作为活性成分,并且其中这种组合物(例如片剂)包含颗粒内和颗粒外层,其中该颗粒内层包含不溶性赋形剂/稀释剂并且特征在于该颗粒内层不含可溶性赋形剂/稀释剂,即淀粉。
2.如权利要求1所述的可分散组合物,其中该颗粒内层不含任何可溶性赋形剂/稀释剂。
3.如权利要求1或权利要求2所述的可分散组合物,其中该颗粒内层中的不溶性赋形剂/稀释剂是微晶纤维素。
4.一种可分散组合物(例如片剂),其包含富马酸贝达喹啉作为活性成分,并且其中这种组合物(例如片剂)包含颗粒内和颗粒外层,其中该颗粒内层包含不溶性赋形剂/稀释剂,即微晶纤维素。
5.如权利要求3所述的可分散组合物,其中该颗粒内层不含可溶性赋形剂/稀释剂。
6.一种可分散组合物(例如片剂组合物),以重量计,基于该组合物的总重量,其包含(例如由...组成):
5%至50%(例如10%至30%)的活性成分(即富马酸贝达喹啉)
35%至90%(例如50%至70%)的不溶性赋形剂/稀释剂
2%至10%(例如4%至8%)的崩解剂
0.1%至5%(例如1.5%至3.5%)的助流剂
0.01%至5%(例如0.1%至1%)的润湿剂或表面活性剂
0至10%(例如2%至5%)的粘合剂或聚合物
0至5%(例如1%至3%)的润滑剂
溶剂(qs),例如水。
7.一种可分散组合物(例如片剂组合物),以重量计,基于该组合物的总重量,其包含(例如由...组成):
5%至50%(例如10%至30%)的活性成分
20%至90%(例如50%至70%)的不可溶性赋形剂/稀释剂,即微晶纤维素(例如硅化微晶纤维素)
2%至10%(例如4%至8%)的崩解剂
0.1%至5%(例如1.5%至3.5%)的助流剂
0.01%至5%(例如0.1%至1%)的润湿剂或表面活性剂
0至10%(例如2%至5%)的粘合剂或聚合物
0至5%(例如1%至3%)的润滑剂
溶剂(qs),例如水。
8.如权利要求6或权利要求7所述的组合物,其中它们的其他特征进一步在于它们不含可溶性赋形剂/稀释剂。
9.如前述权利要求中任一项所述的组合物(例如片剂组合物),以重量计,基于该组合物的总重量,该组合物由以下各项组成:
24.18%(或约25%)的活性成分
62.12%(或约60%)不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
6%(或约6%)崩解剂(例如交聚维酮,如交联聚维酮XL)
2.5%(或约2.5%)助流剂(如胶态二氧化硅,气相二氧化硅200)
0.2%(或约0.2%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
3%(或约3%)粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
2%(或约2%)润滑剂(例如硬脂酰富马酸钠(Pruv))
溶剂(qs),如水-必要时(即如果有的话,仅所需量)。
10.一种组合物(例如片剂组合物),其中这种组合物的不同部分,特别是颗粒内和颗粒外级分以及粘合剂部分,以重量计,基于该组合物的总重量,包含(例如由......组成)以下成分:
颗粒内级分
5%至50%(例如10%至30%)的活性成分
10%至50%(例如20%至40%)的不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
1%至5%(例如2%至4%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0.1%至5%(例如0.5%至4%,如1%至3%)助流剂(例如胶态二氧化硅,气相二氧化硅200)
粘合剂
1%至10%(例如2%至5%)3%粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
0.01%至5%(例如0.1%至1%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
颗粒外级分
10%至50%(例如20%至40%)的赋形剂/稀释剂(优选不溶性赋形剂/稀释剂,例如微晶纤维素,如硅化微晶纤维素)
1%至5%(例如2%至4%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0至3%(例如0.1%至1%)助流剂(如胶态二氧化硅,气相二氧化硅200)
0至5%(例如1%至3%)润滑剂(例如硬脂酰富马酸钠(Pruv))。
11.如权利要求10所述的组合物,其中该颗粒内层不含任何可溶性赋形剂/稀释剂;和/或,任选地,该颗粒外级分也不含任何可溶性赋形剂/稀释剂。
12.如权利要求10或权利要求11所述的组合物,以重量计,基于该组合物的总重量,其由颗粒内级分、粘合剂和颗粒外级分的以下组成成分组成:
颗粒内级分
24.18%(或约25%)的活性成分
29.82%(或约30%)的不溶性赋形剂/稀释剂(例如微晶纤维素,如硅化微晶纤维素)
3%(或约3%)崩解剂(例如交聚维酮,如交联聚维酮XL)
2%(或约2%)助流剂(如胶态二氧化硅,气相二氧化硅200)
粘合剂
3%(或约3%)粘合剂或聚合物(例如羟丙甲纤维素5cps,即甲基纤维素E 5LV)
0.2%(或约0.2%)润湿剂或表面活性剂(如聚山梨醇酯20,即吐温20)
溶剂(qs),如水-必要时(即如果有的话,仅所需量)
颗粒外级分
32.3%(或约30%)的赋形剂/稀释剂(优选不溶性赋形剂/稀释剂,例如微晶纤维素,如硅化微晶纤维素)
3%(或约3%)崩解剂(例如交聚维酮,如交联聚维酮XL)
0.5%(或约0.5%)助流剂(如胶态二氧化硅,气相二氧化硅200)
2%(或约2%)润滑剂(例如硬脂酰富马酸钠(Pruv))。
13.如前述权利要求中任一项所述的组合物,其用于治疗结核病(例如,MDR结核病)。
14.如权利要求13所述的组合物,其用于小儿和/或老年群体。
15.如前述权利要求中任一项所述的组合物,其与用于治疗结核病的一种或多种其他治疗剂组合使用。
16.一种组合,其包含如权利要求1至14中任一项所述的组合物与一种或多种用于治疗结核病的其他治疗剂。
17.一种方法,用于制备如权利要求1至12中任一项所述的组合物(例如片剂组合物),其包括:
(a)使用如在权利要求10至12中任一项所提及的颗粒内级分的组分获得颗粒内级分;
(b)使用如在权利要求10至12中任一项所提及的粘合剂级分的组分制备粘合剂级分;
(c)使用如在权利要求10至12中任一项所提及的颗粒外级分的组分获得颗粒外级分,
并使用那些级分来制备组合物。
18.一种组合物,其可通过如权利要求17所述的方法获得。
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EE05394B1 (et) | 2004-12-24 | 2011-04-15 | Janssen Pharmaceutica N.V. | Kinoliinihendid kasutamiseks latentse tuberkuloosi ravis |
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WO2014075692A1 (en) * | 2012-11-19 | 2014-05-22 | Azanta A/S | Dispersible tablet |
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