CN102858324A - 包含阿片样激动剂和拮抗剂的双层药物制剂 - Google Patents

包含阿片样激动剂和拮抗剂的双层药物制剂 Download PDF

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CN102858324A
CN102858324A CN2011800137742A CN201180013774A CN102858324A CN 102858324 A CN102858324 A CN 102858324A CN 2011800137742 A CN2011800137742 A CN 2011800137742A CN 201180013774 A CN201180013774 A CN 201180013774A CN 102858324 A CN102858324 A CN 102858324A
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罗伯托·安吉利
威廉姆·拉法埃利
玛丽亚·阿黛尔·里加蒙蒂
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Abstract

描述了由双层片剂组成的速释制剂，其中一个层包含阿片样激动剂且另一个层包含阿片样拮抗剂。

Description

包含阿片样激动剂和拮抗剂的双层药物制剂
发明领域
本发明涉及含阿片样激动剂和阿片样拮抗剂的固体口服速释片剂，且具体涉及其中所述活性成分各自被包含在两个不同的层中的制剂。
现有技术
已知的是，基于阿片样物质的药物被广泛用于控制疼痛综合征，特别是在疼痛不能通过效力较低的疗法来控制时(如在术后疼痛或慢性肿瘤和非肿瘤疼痛的情况下)。
另一方面，文献详细记载了与这些药物的使用相关的许多及甚至严重的副作用，例如困倦、恶心、呕吐、便秘、精神混乱、瘙痒、头痛、尿潴留、焦躁不安的反应、呼吸抑制及肌阵挛。这些副作用影响了使用阿片样物质的治疗，有时由于它们差的耐受性甚至促使它们的停用，或不利地影响了患者的生活质量，特别是在需要长期治疗时。因此，考虑到用阿片样物质来控制疼痛的重要性，明显地已经进行了深入的研究，以克服上述缺点。
比如，已经考虑用止吐剂诸如甲氧氯普胺来对抗恶心和呕吐。
作为替代方案，已经考虑阿片样拮抗剂和阿片样激动剂的同时施用，例如在USP 5580876或WO 96/02251中)。意大利专利申请MI2001A000907报道了在正用阿片样物质治疗的患者中用非常低剂量的纳曲酮来减弱不想要的副作用。
专利申请EP 1 935 421描述了含有阿片样激动剂和阿片样拮抗剂的控释制剂，所述阿片样激动剂和所述阿片样拮抗剂混合到一起并且与改进两种药物的释放的化合物组合；所述制剂中拮抗剂的量在比激动剂的量低100-1000倍的范围内。
最后，WO 2005/107726描述了用于关节炎起源的腰痛的治疗的含混合到一起的阿片样激动剂和拮抗剂的组合物。
根据上述现有技术，很明显的是，明显地在维持阿片样物质的止痛功效的同时，药理学上控制阿片样物质的副作用的问题还未完全克服且因此需要不同的制剂，所述制剂能够应对目前已知的制剂仍然存在的缺点，其中同时向患者施用阿片样激动剂和阿片样拮抗剂。
发明概述
描述了固体口服速释制剂，所述制剂以含阿片样激动剂和阿片样拮抗剂的片剂的形式，其中所述两种活性成分被维持在不同的层中。
发明详述
本发明使得向患者给予含阿片样激动剂和拮抗剂的制剂成为可能，所述制剂能够使与阿片样物质的施用有关的副作用最小化。因此，本发明的目的是以含有作为活性成分的阿片样激动剂和拮抗剂两者的片剂的形式的用于口服施用的药物制剂，其中所述活性成分被包含在两个不同的层中。
两种活性成分处于相同的药物制剂内的两个不同的层中的事实意外地证明能够解决归因于阿片样物质的使用的副作用的问题。
两种活性成分的同时施用(拮抗剂以最低的剂量)意外地导致了拮抗剂的更快吸收，拮抗剂转而在阿片样激动剂能够结合到抑制性受体并从而发挥其镇痛效应之前阻断引起阿片样激动剂的副作用发作的兴奋性受体。
根据本发明，术语阿片样激动剂被用于指表现出鸦片的性质或吗啡样性质的一组物质。鸦片剂是在鸦片中发现的阿片样物质及它们的半合成衍生物。
根据本发明的阿片样激动剂的可能实例包括：羟考酮、氢吗啡酮、吗啡、可待因、丁丙诺啡、芬太尼、美沙酮。
术语阿片样拮抗剂被用于指占据阿片受体而不使其活化且能够使阿片受体对激动剂的响应减弱的物质。
根据本发明的阿片样拮抗剂的可能实例包括：纳曲酮、纳洛酮。
根据本发明的优选实施方式，包含在制剂中的阿片样拮抗剂的量在比阿片样激动剂的量低500至4000倍的范围内。
具体地，根据本发明的优选实施方式，制剂包含0.005mg的阿片样拮抗剂和在2.5-20.0mg的范围内的量的激动剂。
包含两种活性成分的两个层包括含有用于药理学领域的常用赋形剂比如稀释剂(例如乳糖)、抗结块剂(例如，玉米淀粉、交联羧甲基纤维素钠)、释放改进剂(例如，
Figure BDA00002133726600031
HR、Macrogol 6000)、助流剂(例如硅胶)、润滑剂(例如，硬脂酸镁)的混合物，且还可添加药物应用中容许的任意着色剂。
根据本发明的制剂的有益特征通过从通常用于固体口服制剂的许多可利用的选项中选择具体赋形剂来进一步改进。
对于包含阿片样激动剂的层的制备，以下是优选的：SD乳糖、预胶化玉米淀粉、颜料、Macrogol 6000、
Figure BDA00002133726600032
HR、且还可能的是硅胶和硬脂酸镁。
更优选地，上述组分以按有关层的各组分的总重量计算的以下重量百分比被包含：SD乳糖40-60％、预胶化玉米淀粉10-20％、颜料0.5-2％、Macrogol 600010-20％、
Figure BDA00002133726600033
HR 5-20％、硅胶0-2％、硬脂酸镁0-2％。对于包含阿片样拮抗剂的层的制备，以下是优选的：Granulac 200乳糖、玉米淀粉、交联羧甲基纤维素钠、聚乙烯吡咯烷酮K30，且还可能的是无水硅胶和硬脂酸镁。更优选地，上述组分以按有关层的各组分的总重量计算的以下重量百分比被包含：Granulac 200乳糖30-80％、玉米淀粉5-10％、交联羧甲基纤维素钠5-10％、聚乙烯吡咯烷酮K302-5％、无水硅胶0-2％、硬脂酸镁0-2％。
借助适合制备双层片剂的压片机，压制由上述组分组成的两种类型的颗粒。
然后，用包衣剂(例如HPMC Methocel E5)和增塑剂(例如柠檬酸三乙酯)使双层片剂经历薄膜包衣。例如，可如下所概述地制备本发明的双层片剂。
含阿片样激动剂的层
将混合物的组分-激动剂、稀释剂、抗结块剂、颜料(如果有)、释放改进剂和助流剂(如果有)过筛，然后在均化器中混合，在连续混合的同时可能向混合物中添加润滑剂。
含阿片样拮抗剂的层
通过将拮抗剂和粘合剂溶解在水或醇中，制备粘合剂溶液。然后，如下进行使产品成粒：在均化器中混合稀释剂和抗结块剂，添加粘合剂溶液。
将混合物标准化至需要的尺寸且在烘箱中干燥，然后，连同任意的抗结块剂和助流剂一起，将干燥的颗粒标准化至需要的尺寸。然后，完成最终的混合过程，可能添加润滑剂。
用合适的双层片剂压片机以压缩两个上述组合物来制备双层片剂，一个组合物包含阿片样激动剂且一个组合物包含拮抗剂。
由此制备的双层片剂还可用合适的包衣剂包衣。
下面是阐述本发明的几个非限制性实施例。
实施例1
含阿片样激动剂的层
含阿片样拮抗剂的层
Figure BDA00002133726600052
包衣
HPMC Methocel E5    4.5
柠檬酸三乙酯           0.5
总的包衣               5.0
制备
(a)含阿片样激动剂的层
用20目的筛使各组分(羟考酮盐酸盐，SD乳糖、预胶化玉米淀粉、颜料、Macrogol 6000、HR、硅胶)过筛，混合120转，然后添加硬脂酸镁，且继续混合25转。
(b)含阿片样拮抗剂的层
通过将纳曲酮盐酸盐和聚乙烯吡咯烷酮K30溶解在水或醇中，制备粘合剂溶液。将Granulac 200乳糖、玉米淀粉和交联羧甲基纤维素钠混合50转，然后用预先制备的粘合剂溶液进行制粒。
用5目筛标准化混合物，然后在40℃的温度下的烘箱(流化床)中干燥，直到实现重量减轻＜1.5％。
干燥颗粒连同硅胶和交联羧甲基纤维素钠一起通过18目筛标准化。
然后进行120转的最终混合，之后添加硬脂酸镁并再次混合25转。
双层片剂的制备
借助适合生产双层片剂的压片机，压制两种类型的颗粒，包含激动剂的部分称重为192.5mg，且包含拮抗剂的部分称重为80mg。
薄膜包衣液的制备
在合适的溶解器中，转移脱矿质水，添加HPMC Methocel E5且混合45分钟。然后，添加柠檬酸三乙酯并继续混合。
薄膜包衣
通过用预先制备的溶液来喷射，在包衣锅中给片剂包衣。
以与实施例1所描述的大致相同的方式来操作，得到如下所述的制剂。
实施例2
组分                    量(mg)
含阿片样激动剂的层
Figure BDA00002133726600071
含阿片样拮抗剂的层
Figure BDA00002133726600072
包衣
HPMC Methocel E5            4.5
柠檬酸三乙酯                0.5
总的包衣                    5.0
实施例3
包含阿片样物质的层
Figure BDA00002133726600081
含阿片样拮抗剂的层
Figure BDA00002133726600082
包衣
HPMC Methocel E5    4.5
柠檬酸三乙酯      0.5
总的包衣          5.0
实施例4
包含阿片样物质的层
Figure BDA00002133726600092
含阿片样拮抗剂的层
Figure BDA00002133726600093
总的层
包衣
HPMC Methocel E5            4.5
柠檬酸三乙酯                0.5
总的包衣                    5.0
实验性评估
正在用阿片样物质治疗的患者经历了鞘内筛查，其中副作用的证据极其明显。
施用含有或不含有纳曲酮的一剂阿片样物质，且在几个时间点监测不良事件或副作用和镇痛效应(anti-nociceptive effect)。
具体地，监测了在最低剂量的阿片样物质后有副作用证据的患有慢性(非肿瘤)脊柱痛的患者和非晚期肿瘤患者。实验性评估的结果概述在下面的表中。
Figure BDA00002133726600101
Figure BDA00002133726600111
Figure BDA00002133726600121
Figure BDA00002133726600131
Figure BDA00002133726600141
*0＝无；1＝轻度的；2＝中度的；3＝强烈的；4＝严重的

Claims (10)

1.以含阿片样激动剂和阿片样拮抗剂的双层片剂的形式的速释制剂，其中所述活性成分保持相互分离，它们各自在所述两个层中的一个中。
2.根据权利要求1所述的制剂，其中阿片样拮抗剂的量比所述阿片样激动剂的量低500-4000倍。
3.根据权利要求1和权利要求2所述的制剂，其中所述阿片样激动剂从以下当中选择：羟考酮、氢吗啡酮、吗啡、可待因、丁丙诺啡、美沙酮。
4.根据权利要求1和权利要求2所述的制剂，其中所述阿片样拮抗剂从以下当中选择：纳曲酮和纳洛酮。
5.根据权利要求1-4所述的制剂，其中含所述激动剂的层包含：SD乳糖、预胶化玉米淀粉、颜料、Macrogol 6000、
Figure FDA00002133726500011
HR、硅胶、硬脂酸镁。
6.根据权利要求5所述的制剂，其中含所述阿片样激动剂的层的所述组分以按前述层的各组分的总重量计算的以下重量百分比存在：SD乳糖40-60％、预胶化玉米淀粉10-20％、颜料0.5-2％、Macrogol 6000 10-20％、
Figure FDA00002133726500012
HR 5-20％、硅胶0-2％、硬脂酸镁0-2％。
7.根据权利要求1-6所述的制剂，其中含所述阿片样拮抗剂的层包含：Granulac 200乳糖、玉米淀粉、交联羧甲基纤维素钠、聚乙烯吡咯烷酮K30、硅胶、硬脂酸镁。
8.根据权利要求7所述的制剂，其中含所述阿片样拮抗剂的层的所述组分以按前述层的各组分的总重量计算的以下重量百分比存在：Granulac 200乳糖30-80％、玉米淀粉5-10％、交联羧甲基纤维素钠5-10％、聚乙烯吡咯烷酮K302-5％、硅胶0-2％、硬脂酸镁0-2％。
9.根据权利要求1-8所述的制剂，其中所述片剂被薄膜包衣。
10.根据权利要求1-9所述的制剂，由以下组成：
(a)
含所述阿片样激动剂的层
Figure FDA00002133726500021
含所述阿片样拮抗剂的层
Figure FDA00002133726500022
包衣
HPMC Methocel E5      4.5
柠檬酸三乙酯        0.5
总的包衣            5.0
(b)
含所述阿片样激动剂的层
Figure FDA00002133726500031
含所述阿片样拮抗剂的层
Figure FDA00002133726500032
包衣
HPMC Methocel E5            4.5
柠檬酸三乙酯                0.5
总的包衣                    5.0
Figure FDA00002133726500041
(c)
含所述阿片样激动剂的层
Figure FDA00002133726500042
含所述阿片样拮抗剂的层
Figure FDA00002133726500043
Figure FDA00002133726500051
包衣
HPMC Methocel E5            4.5
柠檬酸三乙酯                0.5
总的包衣                    5.0
(d)
含所述阿片样激动剂的层
Figure FDA00002133726500053
含所述阿片样拮抗剂的层
Figure FDA00002133726500054
Figure FDA00002133726500061
包衣
HPMC Methocel E5            4.5
柠檬酸三乙酯                0.5
总的包衣                    5.0
CN2011800137742A 2010-03-24 2011-03-23 包含阿片样激动剂和拮抗剂的双层药物制剂 Pending CN102858324A (zh)

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ITFI2010A000047A IT1398930B1 (it) 2010-03-24 2010-03-24 Formulazioni farmaceutiche bistrato contenenti agonisti ed antagonisti oppioidi.
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CN107820424A (zh) * 2015-04-02 2018-03-20 施万生物制药研发Ip有限责任公司 Mu类鸦片受体拮抗剂与类鸦片药剂的组合剂型
CN107820424B (zh) * 2015-04-02 2020-07-28 施万生物制药研发Ip有限责任公司 Mu类鸦片受体拮抗剂与类鸦片药剂的组合剂型
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EP2549984B1 (en) 2015-03-18
WO2011117306A1 (en) 2011-09-29
RU2012145095A (ru) 2014-04-27
PT2549984E (pt) 2015-07-24
US20130011479A1 (en) 2013-01-10
AU2011231638A1 (en) 2012-11-08
IT1398930B1 (it) 2013-03-28
PL2549984T3 (pl) 2015-08-31
BR112012024139A2 (pt) 2017-03-01
AU2011231638B2 (en) 2016-05-12
CA2794221A1 (en) 2011-09-29

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