CN110191704A - 可分散组合物 - Google Patents
可分散组合物 Download PDFInfo
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- CN110191704A CN110191704A CN201780065671.8A CN201780065671A CN110191704A CN 110191704 A CN110191704 A CN 110191704A CN 201780065671 A CN201780065671 A CN 201780065671A CN 110191704 A CN110191704 A CN 110191704A
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Abstract
本发明涉及包含利匹韦林或其药学上可接受的酸加成盐作为活性成分的可分散组合物。此类组合物可用于治疗HIV感染,并且其分散性特性使得其特别适用于小儿或老年群体。
Description
本发明涉及药物组合物,该药物组合物含有某种HIV(人类免疫缺陷病毒)试剂,特别是E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐作为活性成分。更具体地讲,本发明涉及可分散或可崩解的片剂、其制备方法以及其在治疗HIV感染中的用途。此类新颖组合物特别适于小儿群体。它也适于老年群体。
活性成分是E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈(利匹韦林)或其药学上可接受的酸加成盐,特别是处于由以下化学式表示的盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈:
含有这种活性成分的产品EDURANTTM已经在例如美国和欧盟获得营销许可。
本发明的实用性来自对HIV感染(包括耐药和多重耐药HIV菌株,特别是耐药和多重耐药HIV-1菌株)显示出活性的活性成分,更具体地说,来自对HIV菌株(特别是HIV-1菌株,该类菌株已获得对一种或多种本领域已知的非核苷逆转录酶抑制剂的抗性)显示出活性的活性成分。本领域已知的非核苷逆转录酶抑制剂是除本发明活性成分以外的那些非核苷逆转录酶抑制剂,并且特别是商业的非核苷逆转录酶抑制剂。
在WO 03/16306中描述了4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苯甲腈的HIV复制抑制活性,将其通过引用结合在此。WO 2006/024668(将其通过引用结合在此)披露了包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苯甲腈盐酸的药物配制品。
本发明披露了E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苯甲腈或其药学上可接受的酸加成盐,特别是其盐酸盐的小儿或老年配制品的开发。对于小儿或老年群体,可能难以吞咽固体组合物(像片剂),并且可能希望具有可分散组合物,特别是可分散片剂,并且这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。
现提供了一种可分散组合物(例如,片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苯甲腈或其药学上可接受的酸加成盐,特别是其盐酸盐作为活性成分。这在此处可以称为“本发明的(可分散的)片剂”。
通过“可分散的”,我们意指在适当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(例如水)或其他适用于给药的介质或媒介物(例如牛奶、果汁(例如橙汁)、或甚至半固体样媒介物(如酸奶、苹果酱))。更具体地,该组合物(例如片剂)可在短时段内(特别是在几分钟(特别是1.5分钟或更少、或1分钟或更少、或少于1分钟(例如在55秒或50秒或45秒或40秒或35秒或30秒或更少之内))的时间范围内)、在小体积的介质(例如,50ml或更少的分散介质,例如水)中崩解,这样使得其通过温和的旋转而分散(特别是均匀地和/或快速地)。优选地,在合适的崩解介质中的崩解导致可饮用的液体,例如可饮用的悬浮液或可饮用/可食用的半固体。在一个实施例中,这种分散体可以穿过具有710μm的标称网孔孔径的筛网。
当在小体积的液体中发生分散(例如100mg组合物可以分散在少量(例如低至1ml至5ml)的水中)时,所得混合物可以描述为分散体,也可以描述为软质。对于这样的软质,它可能不能穿过以上提及的筛网(考虑到与其混合的小体积的水),但是仍适用于给予,即软质可以适当地通过勺子进行给予。
通过“分散的”,意指该组合物(例如片剂组合物)在分散介质(例如水)中迅速崩解成物理上较小的颗粒,这些颗粒在介质(例如水)中散开(或分散)。当该组合物被均匀地分散时,会导致在介质(例如水)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),这里我们意指在±25%的偏差以内(%w/v),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(当散开时)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),并且特别是±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分散或散开的处于其放置的分散介质(例如水)中(经过必要的分散时间后;参见上文)。应当理解的是,可以施加一些温和或轻柔的搅拌或温和或轻柔的旋转以获得在分散介质(例如水)中的可分散组合物(例如可分散片剂)的均匀分散体。
在此表明该分散组合物(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。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予。例如,该可分散片剂可以与某些食品混合(原样或如上描述的,通过将片剂组合物与少量/小体积的水混合而形成软质)。
为了治疗用途,利匹韦林的盐是其中的平衡离子是药学上可接受的那些。
如在此所提及的药学上可接受的加成盐意指包含利匹韦林所能形成的治疗活性的无毒酸加成盐形式。后者可以方便地通过用此类适当的酸来处理碱形式来获得,如无机酸,例如氢卤酸(例如盐酸、氢溴酸等),硫酸,硝酸,磷酸等;或者有机酸,例如乙酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、2-羟基-1,2,3-丙三羧酸、甲磺酸、乙磺酸、苯磺酸、4-甲基苯磺酸、环己烷氨基磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等,只要化学上可能即可。相反地,可以通过用碱处理将盐形式转化为游离碱形式。优选的盐是利匹韦林的盐酸盐。
现在将更详细地描述本发明的可分散组合物(例如片剂)。它具有保留了分散性(或崩解)特性的性质。
因此,在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈(利匹韦林)或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂(颗粒级分)。
因此,本发明的可分散组合物包含颗粒级分(颗粒),该颗粒级分包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈(利匹韦林)或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且进一步包含药学上可接受的赋形剂和颗粒外级分(紧邻颗粒级分(颗粒)/在颗粒级分(颗粒)旁边的组合物的级分)。
通过将活性成分以颗粒的形式并入本发明组合物中,改进了组合物的可制造性。在一个方面中,最终组合物共混物的可压缩性和/或流动性得到改进,因为与包含活性成分本身的混合物相比,所述混合物的粘性较小,因此不是颗粒形式。颗粒包含活性成分和药学上可接受的赋形剂。颗粒可以通过干法或湿法制粒法来制备。优选使用湿法制粒法。优选使用粘合剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的粘合剂。
这种粘合剂可以是聚合物,例如有机聚合物。
本发明的组合物(例如片剂)中使用的有机聚合物可以是任何生理上可接受的优选水溶性合成、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(例如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。
当聚合物在20℃的2%水溶液中时,该聚合物适宜地具有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适合本发明组合物的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,例如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含有足够的羟丙基和甲氧基基团,以使其具有水溶性。具有从约0.8至约2.5的甲氧基取代度和从约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291015mPa.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 AdoptedName)(参见Martindale,The Extra Pharmacopoeia[药学大全],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基团的近似百分比,且第三和第四位数字表示羟丙氧基基团的近似百分比组成;15mPa.s或5mPa.s是表示20℃的2%水溶液的表观粘度值。
优选用于本发明的组合物中的聚合物是PVP K30(聚维酮K30)。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的润湿剂。
润湿剂可以增加活性成分的生物利用度。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的粘合剂和润湿剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的崩解剂。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的润湿剂和崩解剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的粘合剂和崩解剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的粘合剂、润湿剂和崩解剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的稀释剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的粘合剂和稀释剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的润湿剂和稀释剂。
在本发明的一个方面中,可分散组合物的颗粒(颗粒级分)包含作为药学上可接受的赋形剂的崩解剂和稀释剂。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的润湿剂、崩解剂和稀释剂。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的润湿剂、崩解剂和粘合剂。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的润湿剂、稀释剂和粘合剂。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的稀释剂、崩解剂和粘合剂。
在本发明的一个方面中,可分散组合物的颗粒包含作为药学上可接受的赋形剂的润湿剂、崩解剂、稀释剂和粘合剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的稀释剂,特别是不溶性稀释剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的崩解剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的稀释剂(特别是不溶性稀释剂)和崩解剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的润湿剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的稀释剂(特别是不溶性稀释剂)和润湿剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的润湿剂和崩解剂。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的稀释剂(特别是不溶性稀释剂)、崩解剂和润湿剂。
颗粒外级分中的润湿剂可以确保组合物的均匀润湿并且可以加速崩解/分散。
在本发明的一个方面中,颗粒外级分中的稀释剂(因此不存在于包含活性成分的颗粒中)优选不溶性稀释剂。不溶性稀释剂(例如微晶纤维素,如硅化微晶纤维素)的存在通过提供快速吸收分散介质中水的能力(即它可以提供芯吸作用,其有利地导致改进的分散性/崩解性)对于本发明组合物的分散性/分解性能是有利的。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”到途径中并使颗粒间的键破裂,引起片剂/组合物断裂分开),这可能是有利的。此外,不溶性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。
关于本发明的组合物中的润湿剂,可以使用任何适用于药物组合物的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值可根据确定HLB值所用的方法而变化;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。
以下列出了适用于本发明组合物的润湿剂。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润湿剂的混合物。
可用于本发明的合适润湿剂包含:
a)聚乙二醇脂肪酸单酯,包含月桂酸、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,例如被称为Cithrol、Algon、Kessco、Lauridac、Mapeg、Cremophor、Emulgante、Nikkol、Myrj、Crodet、Albunol、Lactomul)
b)聚乙二醇脂肪酸二酯,包含月桂酸、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,例如被称为Mapeg、Polyalso、Kessco、Cithrol)
c)聚乙二醇脂肪酸单酯和二酯混合物,像例如PEG 4-150单月桂酸酯和二月桂酸酯、PEG 4-150单油酸酯和二油酸酯、PEG 4-150单硬脂酸醋和二硬脂酸酯等;(属于该组的润湿剂是,例如被称为Kessco)
d)聚乙二醇甘油脂肪酸酯,像例如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,例如被称为Tagat、GlyceroxL、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,例如被称为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,像例如聚甘油-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,例如被称为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,例如被称为SolulanTM或Nikkol BPSH)
h)聚乙二醇脱水山梨醇脂肪酸酯,像例如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,例如被称为Liposorb、Tween、Dacol MSS、Nikkol、Emalex、Atlas)
i)聚乙二醇烷基醚,像例如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,例如被称为Volpo、Brij)
j)糖酯,像例如蔗糖二硬脂酸酯/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,例如被称为Sucro ester、Crodesta、Saccharosemonoaurate)
k)聚乙二醇烷基苯酚,像例如PEG-10-100壬基苯酚(Triton X系列)、PEG-15-100辛基苯酚醚(Triton N系列)等;
l)聚氧乙烯-聚氧丙烯嵌段共聚物(泊洛沙姆),像例如泊洛沙姆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,例如被称为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,如脂肪酸盐,例如油酸钠、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;如胆汁盐,例如胆酸钠、牛磺胆酸钠、甘氨胆酸钠等;如磷脂,例如蛋黄卵磷脂/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;如磷酸酯,例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;如羧酸酯(盐),例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;如硫酸盐和磺酸盐,例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;如阳离子润湿剂,例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,像例如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。
本发明组合物中优选的润湿剂是十二烷基硫酸钠、二辛基磺基琥珀酸钠、或属于聚乙二醇脱水山梨醇脂肪酸酯类的那些润湿剂,如称为的润湿剂,例如20、60、80。优选颗粒中包含活性成分的润湿剂是例如20。优选颗粒外级分中的润湿剂是十二烷基硫酸钠。
在此描述了润湿剂(或表面活性剂)的优选量,但是应当理解,当用于本发明组合物时,其可以取决于例如组合物中存在的活性成分的量。量越多可能需要越多润湿剂。
在此指出本发明的组合物(例如片剂组合物)可以含有崩解剂。可能的崩解剂包括药学上可接受的崩解剂,其包含淀粉、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(例如交联羧甲基纤维素钠(例如Ac-di-))、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。最优选的针对包含活性成分的颗粒的崩解剂是交联羧甲基纤维素钠(例如Ac-di-)。
最优选的针对颗粒外级分的崩解剂是交联羧甲基纤维素钠(例如Ac-di-)。
在此指出本发明的组合物(例如片剂组合物)可以含有稀释剂。除非已经规定了稀释剂,否则这种稀释剂可以是淀粉、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(参见上文),最优选的颗粒外级分的稀释剂是不溶性稀释剂,如微晶纤维素(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。优选的微晶纤维素是微晶纤维素PH112( PH 112)。颗粒外级分可以进一步包含更可溶的第二稀释剂。可以考虑糖和多元醇,例如可以考虑以下稀释剂: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、可商购的优选颗粒外级分含有第二稀释剂。优选所述第二稀释剂是甘露醇,特别是甘露醇SD 200。这增加了本发明组合物的口感。
优选颗粒包含稀释剂。优选所述稀释剂是糖。优选所述糖为乳糖,即乳糖一水合物。
在本发明的一个方面中,提供了可分散组合物(例如片剂),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈或其药学上可接受的酸加成盐,特别是盐酸盐形式的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈作为活性成分,并且其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂,并且所述组合物进一步包含紧邻颗粒的颗粒外级分中的第一稀释剂(特别是不溶性稀释剂)、和第二稀释剂(特别是糖或多元醇)。在一个方面中,第一稀释剂是微晶纤维素。在一个方面中,第二稀释剂是糖。在一个方面中,第一稀释剂是微晶纤维素,并且第二稀释剂是甘露醇。在一个方面中,第一稀释剂和第二稀释剂的重量比为1:1。在一个方面中,微晶纤维素和甘露醇的重量比为1:1。发现颗粒外级分中第一稀释剂和第二稀释剂的组合,特别是第一不溶性稀释剂和第二更可溶性稀释剂,特别是微晶纤维素和糖,特别是微晶纤维素和甘露醇,特别是以1:1的重量比的组合改进了含量均一性。含量均一性是药典中规定的剂型(特别是片剂)的测试,其中活性成分的剂量和比例<25mg或<25%。
在此指出本发明的组合物(例如片剂组合物)可以含有润滑剂。这种润滑剂可以是药学上可接受的润滑剂,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、硬脂酰富马酸钠、十二烷基硫酸镁。最优选地,润滑剂是硬脂酰富马酸钠。
在此指出本发明的组合物(例如片剂组合物)可以含有助流剂。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。在一个方面中,本发明的组合物不含有助流剂。
如在此描述的组合物可以进一步包含一种或多种药学上可接受的赋形剂,像例如增塑剂、调味剂、甜味剂、着色剂、防腐剂等。在本发明的一个方面中,本发明的组合物不含有增塑剂或其他这种此处提到的可选赋形剂。
本发明的组合物的特征在于口感良好和崩解良好(快速)。
在本发明的一个方面中,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,该可分散组合物包含从1%至50%、从1%至30%、从1%至20%、从1%至15%、从1%至10%、从1%至5%、从2%至5%、从2%至3%的活性成分。
在本发明的一个方面中,提供了可分散组合物(例如片剂组合物),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈的2.5mg碱当量,对应于2.75mg的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈HCl。
在本发明的一个方面中,提供了可分散组合物(例如片剂组合物),该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈的5mg碱当量,对应于5.5mg的E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈HCl。
在本发明的一个方面中,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,该可分散组合物包含(例如由……组成):
1%至50%(例如1%至10%或2%至5%)的活性成分
35%至95%(例如70%至95%)的稀释剂
0.1%至10%(例如2%至5%)的崩解剂
0至5%(例如0至3.5%)的助流剂
0.01%至5%(例如0.01%至1.5%)的润湿剂
0至10%(例如0.1%至2%)的粘合剂
0至5%(例如1%至3%)的润滑剂
在本发明的一个方面中,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,该可分散组合物包含从35%至70%(例如35%至50%)的不溶性稀释剂,例如微晶纤维素,如硅化微晶纤维素。
在本发明的一个方面中,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,该可分散组合物包含从35%至70%(例如35%至50%)的糖稀释剂,例如甘露醇。
在本发明的一个方面中,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,该可分散组合物包含从1%至10%(例如2%至5%)的崩解剂,例如交联羧甲基纤维素钠。
在另一个方面中,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,特别是颗粒和颗粒外级分,以重量计,基于该组合物的总重量,该组合物包含以下成分:
颗粒级分
1%至50%(例如2%至5%)的活性成分
1%至8%(例如5%至8%)的稀释剂
0.01%至2.5%(例如0.01%至1.5%)的润湿剂
0至10%(例如0.1%至2%)的粘合剂
0.1%至5%(例如0.1%至2%)的崩解剂
颗粒外级分
35%至87%(例如70%至87%)的稀释剂
1%至5%(例如2%至5%)的崩解剂
0.01%至2.5%(例如0.1%至1.5%)的润湿剂
0至5%(例如1%至3%)的润滑剂
在此描述的组合物(例如片剂组合物)背景下,可以将该组合物的特质描述为包含颗粒级分和颗粒外级分。组合物的这些级分最终彼此混合。然而,应当理解(例如,参见用于制备此类组合物的方法)这些级分的区别导致所得组合物的不同性质。
颗粒级分可以构成该组合物(例如片剂)总重量的以重量计多达50%,并且优选构成该组合物(或片剂)的以重量计在5%至20%之间(例如在5%至10%之间)。颗粒外级分可以构成该组合物(例如片剂)总重量的以重量计多达95%,并且优选构成该组合物(或片剂)的以重量计在50%至95%之间(例如在70%至95%之间)。
在此描述的本发明的组合物可以是颗粒和颗粒外级分的混合物或共混物,并且在经受适当的压缩技术之后,可以呈现(单位)剂型,如片剂。
在此描述的发明方面中,特别是上述的可分散组合物,总组合物重量(例如总片剂重量)可以为约100mg。存在的活性成分可以在从1至25mg之间(如1mg至5mg)之间的范围内,例如约2.5mg碱当量(2.75mg相应的HCl盐)或例如约5mg碱当量(5.5mg相应的HCl盐)。以这种方式,可以提供小儿(或老年)配制品,该小儿(或老年)配制品是可分散的并为预期群体(例如小儿群体,例如范围在0和12岁之间的儿童)提供剂量灵活性。
本发明还涉及用于制备本发明的组合物(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,如在此描述的)
-通过本发明(例如,如在此描述的)的方法获得的产品(例如本发明的组合物,例如在此描述的可分散片剂)。
如上所述,本发明的组合物优选包含不同的级分:颗粒级分和颗粒外级分。
因此,提供了用于制备本发明的组合物的方法,该方法包括:
(a)使用在此提及的颗粒级分的组分(优选通过使用含有如在此提及的粘合剂的粘合剂溶液(例如在水中))获得颗粒级分;
(b)使用在此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,颗粒级分(如在此所定义的)可以通过混合或掺和相关组分(干法制粒,辊式压实)或优选通过使用如在此提及的适合的粘合剂的湿法制粒来制备。干法制粒和湿法制粒技术是本领域技术人员已知的。
将获得的颗粒干燥和/或按大小分类(或筛分)。
然后将颗粒共混或共筛,并与颗粒外级分的组分(如在此定义的)共混。如果颗粒外层还包括润滑剂,这种掺和也固有地涉及润滑。
一旦本发明的组合物得以制备(例如如上所述,包括颗粒和颗粒外级分的混合),这种组合物可以任选地并且优选地转化为片剂形式。在本发明的方法的优选方面中,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从1mg至25mg的活性成分(碱当量,不考虑盐组分)。该单位优选含有从2mg至5mg的利匹韦林碱当量,优选2.5mg利匹韦林碱当量,即2.75mg利匹韦林HCl或5mg利匹韦林碱当量,即5.5mg利匹韦林HCl。
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。片剂的硬度适用于可分散片剂。
本发明的片剂可进一步被薄膜包衣以改进味道,以提供吞咽的容易性和/或极好的外观。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,特别是HPMC 2910 5mPa.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含增塑剂(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含有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,本发明的实用性源自活性成分及其盐,已知该活性成分及其盐显示对HIV的活性。
因此,在本发明的一个方面中,提供了适用于治疗HIV感染的根据本发明的组合物(例如片剂),或用于在治疗HIV感染中使用的根据本发明的组合物(例如片剂),或用于治疗HIV感染的根据本发明的组合物(例如片剂)。
此外,本发明还涉及如下描述的本发明的组合物(例如片剂)在制造用于治疗HIV感染的药物中的用途。
因此,在另一个方面中,本发明提供了一种治疗患有HIV感染或处于HIV感染危险的,特别是患有HIV感染的患者的方法,该方法包括向该患者给予治疗有效量的根据本发明的可分散组合物(例如片剂)。
本发明组合物可以单独使用或与其他治疗剂(如用于治疗病毒(例如HIV)感染的抗病毒剂、抗生素、免疫调节剂、或疫苗)组合使用。它们也可以单独使用或与用于预防病毒(例如HIV)感染的其他预防剂组合使用。
此外,抗逆转录病毒化合物和本发明的组合物的组合可以用作药物。因此,本发明还涉及一种产物,该产物含有(a)本发明的组合物,和(b)一种或多种其他抗逆转录病毒化合物,该化合物作为组合的制剂用于在抗HIV治疗中同时地、分开地或顺序地使用。不同的药物可以连同药学上可接受的载体在本发明的组合物中组合为单个制剂。因此,本发明还涉及如在此描述的可分散组合物,并且进一步包含一种或多种其他抗逆转录病毒剂。
所述其他抗逆转录病毒化合物可以是已知的抗逆转录病毒化合物,如苏拉明、喷他脒、胸腺五肽、栗精胺、葡聚糖(硫酸葡聚糖)、膦甲酸钠(膦甲酸三钠);核苷逆转录酶抑制剂,例如叠氮胸苷(3’叠氮基-3’-脱氧胸苷,AZT)、地达诺新(2’,3’-双脱氧肌苷;ddI)、扎西他滨(双脱氧胞苷,ddC)或拉米夫定(2’-3’-双脱氧-3’硫胞苷,3TC)、司他夫定(2’,3’-双脱氢-3’-脱氧胸苷,d4T)、阿巴卡韦、阿巴卡韦硫酸盐、恩曲他滨((-)FTC)、外消旋FTC等;非核苷逆转录酶抑制剂,如奈韦拉平(11环丙基-5,11-双氢-4-甲基-6H-二吡啶-[3,2-b:2’,3’-e][1,4]二氮杂卓-6-酮)、依法韦仑、地拉夫定、TMC-120、TMC-125等;TIBO(四氢-咪唑并[4,5,1-jk][1,4]-苯二氮卓-2(1H)-酮和硫酮)-类的化合物,例如(S)8氯-4,5,6,7-四氢-5-甲基-6-(3-甲基-2-丁烯基)咪唑并-[4,5,1jk][1,4]苯二氮卓-2(1H)-硫酮;α-APA(α苯胺基苯乙酰胺)类的化合物,例如α-[(2-硝基苯基)氨基]-2,6-二氯苯-乙酰胺等;反式激活蛋白质的抑制剂,如TAT-抑制剂,例如RO-5-3335或REV抑制剂等;蛋白酶抑制剂,例如茚地那韦、利托那韦、沙奎那韦、洛匹那韦(ABT-378)、奈非那韦、安普那韦、TMC-114、BMS-232632、VX-175等;融合抑制剂,例如T-20、T-1249等;CXCR4受体拮抗剂,例如AMD-3100等;病毒整合酶的抑制剂,像例如度鲁特韦或卡博特韦(cabotegravir);核苷酸样逆转录酶抑制剂,例如替诺福韦、替诺福韦二磷酸盐、富马酸替诺福韦二吡呋酯(TDF)、替诺福韦艾拉酚胺(半)富马酸酯(TAF)等;核糖核苷酸还原酶抑制剂,例如羟基脲等;CCR5拮抗剂,例如安立韦罗、盐酸阿拉韦罗(aplaviroc hydrochloride)、维立韦罗(vicriviroc)。
通过将利匹韦林与靶向病毒生命周期中不同事件的其他抗病毒剂一起给予,可以增强这些化合物的治疗效果。如上描述的组合疗法可以在抑制HIV复制方面发挥协同作用,因为组合的每个组分都作用于HIV复制的不同位点。与当该药剂作为单一疗法给予时相比,使用此类组合可以减少针对所需的治疗或预防效果所需的给定的常规抗逆转录病毒剂的剂量。这些组合可以减少或消除常规单一抗逆转录病毒疗法的副作用,同时不会干扰药剂的抗病毒活性。这些组合降低了对单一药剂疗法产生抗性的可能性,同时使任一相关毒性最小化。这些组合也可以增加常规药剂的功效,而不会增加相关的毒性。
本发明的组合物还可以与免疫调节剂组合给予,例如左旋咪唑、溴匹立明、抗人α干扰素抗体、干扰素α、白介素2、甲硫氨酸脑啡肽、二乙基二硫代氨基甲酸盐、肿瘤坏死因子、纳曲酮等;抗生素,例如喷他脒羟乙基磺酸盐等;胆碱能剂,例如他克林、利凡斯的明、多奈哌齐、加兰他敏等;NMDA通道阻断剂(例如美金刚),以预防或对抗感染和疾病或与HIV感染相关的疾病症状,如AIDS和ARC,例如痴呆。
如在此使用的与数值相连的术语“约”意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。
为了避免疑问,应当理解的是如果可能,可以将在此定义的每个通用或特定的优选、实施例、方面和实例与在此定义的任何其他通用或特定的优选、实施例、方面和实例进行组合,并且所有此类实施例包括在本申请中。
以下实例旨在说明本发明。
实验部分
该活性成分、利匹韦林及其药学上可接受的盐可以(例如)根据国际专利申请WO03/16306、WO 2004/016581和WO 2006/024668中描述的程序制备。
1)本发明的可分散组合物的制备
2.75mg利匹韦林HCl
乳糖一水合物
交联羧甲基纤维素钠
聚乙烯吡咯烷酮(例如聚维酮K30)
聚山梨醇酯20
净化水(加工过程中去除)
总量:8.73mg
甘露醇
微晶纤维素
十二烷基硫酸钠
交联羧甲基纤维素钠
硬脂酰富马酸钠
总量:100mg
通过湿法制粒制备利匹韦林HCl颗粒。将200目乳糖一水合物的第一1/2份装入合适的容器中。将利匹韦林HCl装入合适的容器中。将交联羧甲纤维素钠装入合适的容器中。将200目乳糖一水合物的第二1/2份装入合适的容器中。将该混合物共混。通过在合适的容器中装入纯化水和聚维酮来制备粘合剂溶液。添加聚山梨醇酯20。搅拌该混合物。在流化床制粒机(Glatt WSG 200)中进行制粒。将该粉末共混物在真空下装入制粒机。将粘合剂溶液喷雾到该混合物上。将干燥的材料从制粒机中排出、研磨并装入合适的容器中(步骤1)。颗粒含有31.48%的利匹韦林HCl。
使用合适的筛将含有颗粒的利匹韦林与甘露醇、微晶纤维素、交联羧甲基纤维素钠和十二烷基硫酸钠共筛,并使用合适的共混器共混该共筛共混物(步骤2)。将硬脂酰富马酸钠筛选并添加到步骤2的共混物中,并使用合适的共混器润滑该共混物(步骤3)。
使用适合的压片机将步骤3的共混物压缩成片剂。将所得片剂包装在合适的容器中(例如高密度聚乙烯(HDPE)瓶,例如具有防儿童开启的聚丙烯封口和干燥剂(例如在HDPE袋中的2g硅胶))。
2)鉴定和定量确定活性成分
为了测试储存在不同条件下的1)中描述的组合物的活性成分的测定(%w/w),使用以下条件:
HPLC操作条件:
柱:Zorbax Extend C18,100mm长×4.6mm内径,3.5μm粒度
柱温:45℃
流速:1mL/min
注射体积:10μL
检测:280nm下的UV
流动相:A:10mM乙酸铵缓冲液于水中
B:乙腈
洗脱模式:梯度:
分析时间:37分钟
相对保留时间(分钟):对于利匹韦林HCl是1.0。
测定结果(%w/w)和总降解产物(%w/w)(研究ID 151187:65个片剂于40cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
测定结果(%w/w)和总降解产物(%w/w)(研究ID 151188:65个片剂于75cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
3)溶解测试
为了测试1)中描述的组合物的溶解行为,使用以下条件:
装置:桨装置(USP类型2);
溶解介质:0.025%(w/v)聚山梨酯20(20)于0.01M HCl中
体积:900ml
温度:37℃;
转速:75rpm;
采样时间:5分钟、10分钟、15分钟、20分钟、30分钟、45分钟和60分钟。
通过HPLC测量利匹韦林HCl:
HPLC操作条件:
柱:X-terra,RP18,50mm x 4.6mm内径,3.5μm粒度或等效
柱温:升高或室温,或35℃±3℃
流速:1.2mL/min
注射体积:50μL
检测:280nm下的UV
流动相:A:10mM乙酸铵,pH 4.0
B:乙腈
洗脱模式:等度的(流动相A:流动相B)(45:55)
分析时间:2.5mina
a保留时间(导子):对于利匹韦林HCl是约1.7分钟
在45分钟时溶解的结果(%)(在45分钟时至少80%的a%溶解被认为对于临床测试是可接受的)(研究ID 151187:65个片剂于40cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)。
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
在45分钟时溶解的结果(%)(研究ID 151188:65个片剂于75cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
4)外观
产品的外观也会被评估(视觉),并且被认为是适当的:白色到灰白色的圆形片剂。
5)崩解时间
根据欧洲药典(Ph.Eur.)来评估产品的崩解。
崩解时间(分钟)的结果(研究ID 151187:65个片剂于40cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
崩解时间(分钟)的结果(研究ID 151188:65个片剂于75cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
6)分散体细精度
根据欧洲药典(Ph.Eur.)<2.9.1>测试分散体的细精度。验收标准是通过710μm的筛。
如上表所示存储的产品符合分散试验的细精度。
7)含水量
含水量由Karl fisher根据USP<291>方法I/EP<2.5.12>确定。
含水量的结果(%w/w)(研究ID 151187:65个片剂于40cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
含水量的结果(%w/w)(研究ID 151188:65个片剂于75cc HDPE瓶中,该瓶具有2g干燥剂;防儿童开启的聚丙烯封口)
a:整合近UV能量不少于200W.h/m2,整个照明不少于1200klux.hr
b:将片剂在培养皿中直接暴露于光ICH
c:将片剂在原始容器中暴露于光ICH
8)含量均一性
根据欧洲药典(Ph.Eur.)<2.9.40>或USP<905>确定含量均一性。满足剂量均一性要求(前10个剂量单位的接受值小于或等于L1(L1:不大于15.0)。
将在1)中描述的组合物在18-55岁的健康HIV阴性成人中的I期、开放标记、随机的(根据Williams设计)、四通交叉试验中进行了研究(研究TMC278IFD1008;NCT02561936)。在该研究的第一部分中,分散在水中的可分散片剂(10片2.5mg的利匹韦林碱当量)是在标准早餐后服用的(处理C),并与在标准早餐后服用的参考片剂(处理A)作对比。在该研究的第二部分中,分散在水中的可分散片剂(10片2.5mg的利匹韦林碱当量)是在标准早餐后或在禁食条件下服用的,或分散在橙汁(酸性饮料)中并在标准化的早餐后服用,或分散在水中并与酸奶一起服用。
在给药后168小时收集静脉血样品以确定利匹韦林的血浆浓度。使用经过验证的液相色谱-质谱(LC-MS/MS)方法进行血浆中利匹韦林的生物分析,定量下限为1.0ng/ml。
使用味觉问卷评定苦味、甜味和香味以评估适口性,使用四分量表(four-pointscale)以评估整体可接受性,以及使用五分视觉嗜好量表(five point visual hedonicscale)来评估总体接受性。
在喂食和禁食条件两者下,分散片剂的给予通常是安全的并且耐受性良好。在标准化的早餐(处理C与处理A)之后,利匹韦林的暴露高于25mg 参考片剂。
在禁食条件下服用的分散片剂的生物利用度低于与标准早餐一起服用时的分散片剂的生物利用度。当仅与酸奶一起服用时,与正常的卡路里、正常的脂肪早餐相比,生物利用度较低。与在水中相比,片剂在橙汁中的分散增加了生物利用度。总体而言,片剂显示出良好的生物利用度,可接受的适口性,并且耐受性良好。
处理A | 处理C | |
C<sub>max</sub>(ng/ml) | 96.1(±25.6) | 121(±26.2) |
AUC<sub>0-最后</sub>(ng*h/ml) | 3592(±1156) | 4310(±1147) |
AUC<sub>0-inf</sub>(ng*h/ml) | 3411(±1449) | 4367(±1106) |
Claims (14)
1.一种可分散组合物,该可分散组合物包含E-4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]-苯甲腈(利匹韦林)或其药学上可接受的酸加成盐作为活性成分,其中所述活性成分以颗粒形式存在于可分散组合物中,所述颗粒进一步包含药学上可接受的赋形剂(颗粒级分)。
2.根据权利要求1所述的组合物,其中这些颗粒的药学上可接受的赋形剂包含润湿剂。
3.根据权利要求1或2所述的组合物,其中这些颗粒的药学上可接受的赋形剂包含崩解剂。
4.根据前述权利要求中任一项所述的组合物,其中这些颗粒的药学上可接受的赋形剂包含稀释剂。
5.根据前述权利要求中任一项所述的组合物,该组合物在该颗粒外级分中包含稀释剂。
6.根据权利要求5所述的组合物,其中该颗粒外级分中的稀释剂是不溶性稀释剂。
7.根据前述权利要求中任一项所述的组合物,该组合物在该颗粒外级分中包含润湿剂。
8.根据前述权利要求中任一项所述的组合物,该组合物在该颗粒外级分中包含崩解剂。
9.根据前述权利要求中任一项所述的组合物,其中该组合物是片剂。
10.根据前述权利要求中任一项所述的组合物,其中该活性成分是利匹韦林HCl。
11.根据前述权利要求中任一项所述的组合物,用于在治疗HIV感染中使用。
12.根据权利要求11所述的组合物,用于在小儿和/或老年群体中使用。
13.根据前述权利要求中任一项所述的组合物,与用于治疗HIV感染的一种或多种其他治疗剂组合使用。
14.一种组合,该组合包含根据权利要求1至10中任一项所述的组合物和用于治疗HIV感染的一种或多种其他治疗剂。
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CN115397422A (zh) | 2019-11-29 | 2022-11-25 | 西皮欧生命科学有限公司 | 包含利匹韦林的组合物和其用于治疗肿瘤或癌症的用途 |
CN114392241B (zh) * | 2022-01-10 | 2023-07-25 | 安徽贝克生物制药有限公司 | 一种利匹韦林片及其制备方法 |
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EP3528791A1 (en) | 2019-08-28 |
CA3039562A1 (en) | 2018-05-03 |
DK3528791T3 (da) | 2024-01-29 |
PL3528791T3 (pl) | 2024-04-02 |
MX2019004767A (es) | 2019-07-01 |
MA46563A (fr) | 2019-08-28 |
PT3528791T (pt) | 2024-02-19 |
JP7197474B2 (ja) | 2022-12-27 |
US20200069579A1 (en) | 2020-03-05 |
EP4248947A2 (en) | 2023-09-27 |
TWI821163B (zh) | 2023-11-11 |
JP2023011659A (ja) | 2023-01-24 |
BR112019007564A2 (pt) | 2019-07-02 |
EP4248947A3 (en) | 2023-11-22 |
JP2020500168A (ja) | 2020-01-09 |
US11065198B2 (en) | 2021-07-20 |
ES2970870T3 (es) | 2024-05-31 |
RU2019115672A3 (zh) | 2021-01-21 |
WO2018077815A1 (en) | 2018-05-03 |
TW201828927A (zh) | 2018-08-16 |
EP3528791B1 (en) | 2023-12-06 |
HRP20240118T1 (hr) | 2024-04-12 |
KR20190073450A (ko) | 2019-06-26 |
HUE064823T2 (hu) | 2024-04-28 |
KR20240011873A (ko) | 2024-01-26 |
SI3528791T1 (sl) | 2024-04-30 |
RU2019115672A (ru) | 2020-11-24 |
LT3528791T (lt) | 2024-05-27 |
RS65159B1 (sr) | 2024-02-29 |
MA46563B1 (fr) | 2024-01-31 |
FI3528791T3 (fi) | 2024-01-30 |
US20220008333A1 (en) | 2022-01-13 |
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