CN101277683A - 普那卡生的延迟制剂 - Google Patents
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Abstract
本发明涉及由至少两层组成的延迟片剂,其中至少一层迅速释放药物1S,9S(RS,3S)N-(2-乙氧基-5-氧代-四呋喃-3-基)-6,10-二氧代-9-(异喹啉-1-酰基氨基)-1,2,3,4,7,8,9,10-八氢-6-H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺和/或其盐或衍生物和/或由其释放的酸,至少一层以延迟方式释放药物1S,9S(RS,3S)N-(2-乙氧基-5-氧代-四呋喃-3-基)-6,10-二氧代-9-(异喹啉-1-酰基氨基)-1,2,3,4,7,8,9,10-八氢-6-H-哒嗪并[1,2-a][1,2]-二氮杂-1-甲酰胺和/或其盐或衍生物和/或由其释放的酸,用于治疗自身免疫疾病、I型和II型糖尿病、类风湿性关节炎、骨关节炎和/或银屑病。
Description
本发明涉及包含普那卡生(pralnacasan)的延长释放制剂。
普那卡生(1S,9S(RS,3S)N-(2-乙氧基-5-氧代-四呋喃-3-基)-6,10-二氧代-9-(异喹啉-1-酰基氨基)-1,2,3,4,7,8,9,10-八氢-6-H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺及其盐和衍生物在WO 97/22619中公开,用于治疗例如自身免疫疾病、类风湿性关节炎、骨关节炎、I型和II型糖尿病和银屑病。在这方面有效的化合物是开链化合物3S(1S,9S)3-[6,10-二氧代-9(异喹啉-1-酰基氨基)-1,2,3,4,7,8,9,10-八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰氨基]-4-氧代丁酸,而普那卡生是其前药或药学活性剂(pharmaceuticalagent)。WO 97/22619还描述了迅速释放前药的标准片剂。
本发明的目的是提供延长释放片剂,其使得可能以仅仅两次每日剂量而使得可能均匀递送普那卡生和/或其盐和/或衍生物,同时与标准片剂相比总日剂量降低。
该目的通过由至少两层组成的延长释放片剂实现,其中至少一层迅速递送普那卡生和/或其盐和/或其衍生物(初始剂量),至少第二层以延长方式递送普那卡生和/或其盐和/或衍生物(维持剂量)。各层可以以夹层方式堆叠,但也可以排列成核和壳。
“迅速”递送意指至少60%普那卡生或其盐和/或衍生物在仅仅30分钟内自片剂释放。“延长”递送意指至少90%普那卡生或其盐和/或衍生物在180分钟后释放。在这种情况下,吸收窗从6小时延长至8小时。
在迅速递送药学活性剂的常规片剂中,普那卡生的功效不足或需要以如此高的剂量使用以至于担心不需要的副作用。但是,为避免单次高剂量而每天施用三次在患者顺应性方面不可取。另一方面,常规延长释放片剂因每天施用两次而同样不令人满意(历经2×6=12小时释放药学活性剂),因为,首先,药学活性剂的释放发生得太慢,以至于初始未达到足够高的治疗有效血药浓度,其次,在肠道下段(大肠)未释放的那部分药学活性剂在那里未被吸收因此保持无效。但是,常规片剂和延长释放片剂的组合也似乎是不可取的,因为这类片剂的两部分通常彼此具有反作用。
令人惊讶地发现:根据本发明的迅速递送药学活性剂、具有至少两层的延长释放片剂并没有受到延长释放部分的不利影响,即含有初始部分的一层或多层使得根据本发明的延长释放片剂的作用启动可能令人惊讶地不慢于标准片剂,并且延长释放部分的吸收足够长并完全,尽管该部分完全在消化道上段吸收,即延长释放部分不仅没有受到初始部分的不利影响,而事实上是令人惊讶地受到有利影响。这种作用方式对于组合片剂而言特别不可预期。
本发明的延长释放片剂令人惊讶地预防高血药浓度峰,其通常是药学活性剂毒性副作用的原因。通过使用本发明的延长释放片剂,患者顺应性得以改善,因为每天需要服用较少的大剂量药学活性剂。尽管有多层药学活性剂,所需延长释放片剂并不比标准片剂的体积更大。这特别对于老年患者极为重要和有利。
本发明的延长释放片剂优选由两层组成,其排列为核和壳、优选同心球形体或椭圆体,或堆叠的各层。分层片剂可以是圆形或卵形轮廓的片剂。在核-壳布局中,初始剂量优选位于外壳,延长释放剂量位于核区域。
优选两层的本发明片剂除每种情况下药学活性剂以外在每种情况下可包含一种或多种填充剂、优选两种或三种填充剂;一种或多种粘合剂、优选一种粘合剂;和一种或多种、优选一种润滑剂。在每一片剂的各个层中的填充剂、粘合剂和润滑剂可以不同。其数量在每种情况下也可以不同。优选三种不同的填充剂存在于延长释放层,而两种不同的填充剂存在于迅速释放层。
各层中存在的粘合剂和润滑剂优选是相同的。
延长释放层另外还包含一种或多种凝胶形成剂,尤其当延长释放层是片剂外层时。优选一种凝胶形成剂。
迅速释放层另外包含一种或多种崩解剂,优选一种崩解剂。
填充剂的实例是玉米淀粉、磷酸盐如磷酸钙、乳糖、例如乳糖D80、蔗糖如甘露醇或微晶纤维素、例如102型。优选乳糖、甘露醇或微晶纤维素。填充剂在各层中的含量是0-400mg/层、优选10-200、特别优选20-100。如果每层存在两种或三种填充剂,它们以约2∶1或2∶1∶1的比例存在。如果存在两种填充剂,它们优选是乳糖D80和甘露醇或微晶纤维素。
如果存在三种填充剂,它们优选是乳糖D80、微晶纤维素和甘露醇。
延长释放层优选包含三种填充剂,迅速释放层包含两种填充剂。
适合的粘合剂通常是纤维素醚或聚乙烯吡咯烷酮。优选5-30mg/层的羟丙基纤维素,优选10-20mg/层。
润滑剂可以是本领域技术人员已知的硬脂酸盐如硬脂酸镁和富马酸盐、例如硬脂酰富马酸钠。5-20mg的润滑剂存在于每层中,1-5mg润滑剂优选存在于迅速释放层。
延长释放层另外包含20-100mg/层、特别优选30-50mg/层的一种或多种凝胶形成剂,如羟丙基甲基纤维素或角叉菜胶,优选羟丙基甲基纤维素。迅速释放层另外包含至少一种崩解剂,如交联羧甲基纤维素或交联聚维酮,优选交联羧甲基纤维素,范围为5-20mg/层、优选6-15mg/层。
在延长释放层中相比在迅速释放层中,所有出现在两层中的片剂成分主要以比例1.5-1.0至3.0-1.0、优选2.0-1.0存在。
这还适用于药学活性剂。延长释放层包含200-600mg药学活性剂/层,优选300-500mg/层。迅速释放层包含50-400mg药学活性剂/层、优选100-300mg/层。
比例优选是400∶200mg/层。适合的药学活性剂是普那卡生和/或其衍生物和各个盐,以及各个活性化合物(游离酸)。
还可能存在普那卡生和/或其盐和/或其衍生物的混合物或各个游离酸的混合物。也可以应用普那卡生或其衍生物与游离酸的混合物。
本发明的延长释放片剂通过将药学活性剂制粒而制备。将这些颗粒与另外的赋形剂如填充剂、粘合剂和润滑剂混合。最后,尤其对于延长释放层,加入凝胶形成剂,向迅速释放层加入崩解剂。将两层压制在一起,得到片剂。
图1比较了本发明延长释放片剂(双层片)与迅速释放片剂和延长释放片剂(单层片)的活性成分释放。
令人惊讶的是,对于本发明的片剂,至少60%药学活性剂在仅仅30分钟后释放,至少90%在180分钟后释放。如图2所示,与迅速释放片剂相比,本发明的片剂由此使血中治疗浓度超过6小时的窄治疗窗而延长2小时。
本发明的延长释放制剂优选用于治疗自身免疫疾病、I型和II型糖尿病、类风湿性关节炎、骨关节炎和银屑病。一般而言,WO 97/22619中提及的所有病症均可用本发明的延长释放片剂治疗。
本发明的延长释放制剂可以以胶囊和片剂的形式口服施用。延长释放制剂优选每天施用一次。药学活性剂的剂量是0.01至100mg/kg体重每天,优选1至50mg/kg体重每天。
通过以下实施例(双层片)阐明本发明:
延长释放层
普那卡生 400
乳糖D80 62
羟丙基纤维素 18
微晶纤维素102型 30
羟丙基甲基纤维素4000mPas 40
甘露醇 30
硬脂酸镁 10
共计 590
迅速释放层
普那卡生 200
乳糖D80 31
交联羧甲基纤维素 10
羟丙基纤维素 9
微晶纤维素102型 15
硬脂酸镁 1.5
共计 266.5
完整片剂
HMR 3480 600
乳糖D80 93
羟丙基纤维素 27
交联羧甲基纤维素 10
微晶纤维素102型 45
羟丙基甲基纤维素4000mPas 40
甘露醇 30
硬脂酸镁 11.5
共计 856.5
数据以mg/片计
Claims (8)
2.权利要求1所述的延长释放片剂,其中片剂由两层组成,其以分层形式或作为核和壳排列。
3.权利要求1和2一项或多项所述的延长释放片剂,其中延长释放层作为核-壳布局的核存在。
4.权利要求1至3一项或多项所述的延长释放片剂,其中两层均包含至少一种填充剂、至少一种崩解剂和至少一种润滑剂。
5.权利要求1至4一项或多项所述的延长释放片剂,其中迅速递送层另外包含至少一种崩解剂。
6.权利要求1至4一项或多项所述的延长释放片剂,其中延长释放层包含至少一种凝胶形成剂。
7.权利要求1至6一项或多项所述的延长释放片剂,其中至少60%的药学活性剂在不超过30分钟后、至少90%在180分钟后自片剂释放。
8.权利要求1至7一项或多项所述的延长释放片剂,用于治疗自身免疫疾病、I型和II型糖尿病、类风湿性关节炎、骨关节炎和/或银屑病。
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DE102005048293.7 | 2005-10-08 | ||
DE102005048293A DE102005048293A1 (de) | 2005-10-08 | 2005-10-08 | Retardformulierung für Pralnacasan |
PCT/EP2006/009466 WO2007042160A1 (de) | 2005-10-08 | 2006-09-29 | Retardformulierung für pralnacasan |
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US7611728B2 (en) * | 2003-09-05 | 2009-11-03 | Supernus Pharmaceuticals, Inc. | Osmotic delivery of therapeutic compounds by solubility enhancement |
WO2005048979A2 (en) * | 2003-10-06 | 2005-06-02 | Torrent Pharmaceuticals Limited | Pharmaceutical composition having casing with multiple micro tablets |
WO2005051350A2 (en) * | 2003-10-28 | 2005-06-09 | Torrent Pharmaceuticals Limited | Water dispersible tablet |
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2005
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2006
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- 2006-09-29 WO PCT/EP2006/009466 patent/WO2007042160A1/de active Application Filing
- 2006-09-29 KR KR1020087008466A patent/KR101362679B1/ko not_active IP Right Cessation
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