CN1525851A - 抗滥用阿片样物质控释剂型 - Google Patents

抗滥用阿片样物质控释剂型 Download PDF

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CN1525851A
CN1525851A CNA028097297A CN02809729A CN1525851A CN 1525851 A CN1525851 A CN 1525851A CN A028097297 A CNA028097297 A CN A028097297A CN 02809729 A CN02809729 A CN 02809729A CN 1525851 A CN1525851 A CN 1525851A
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F��S����³��
F·S·卡鲁索
郭怀翃
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Abstract

组合的抗滥用，控释阿片样物质片剂包括一种在高于所需的来抑制阿片样物质欣快感作用的水平的阿片样物质拮抗剂(例如纳洛酮)，如果此组合被粉碎来破坏控释性质导致阿片样物质和阿片样物质拮抗剂作为一种立即释放产品作为一个单剂量被释放。当正常口服时药片的控释的性质预防阿片样物质拮抗剂的口服有效量的累积。阿片样物质拮抗剂被包含在控释骨架中并且和阿片样物质一起随时间被释放。

Description

抗滥用阿片样物质控释剂型
本申请享受优先权为美国临时申请号60/290,439(2001年5月11日提交)的权益。
发明背景
本发明涉及控释镇痛药物制剂。更具体地，本发明涉及抗滥用控释镇痛片剂。
相关的技术背景
人们很早就已知阿片样物质化合物既具有强效的镇痛性质也具有强大的滥用的潜在性。虽然阿片样物质在控制疼痛方面有高效，但是它也会成瘾。阿片样物质，尤其是海洛因，但是也包括吗啡，可待因，1，4-羟基二氢可待因酮(oxycodone)，二氢吗啡酮，氧吗啡酮和其它物质的滥用是现代社会中存在的一个问题。阿片样物质成瘾者可以从多种的非法来源获得药物。这些街头药物质量不可靠。因此，对于潜在的滥用者来说，处方药用的阿片样物质因为其高纯度和可靠的剂量作为一种药物来源是特别有吸引力的。
滥用者从片剂中提取药用的阿片样物质和其它组分。为此，药片被碾碎并经常被溶解。在其最终被注射或吸入以得到“快感”前，得到的物质可能会被进一步的处理。这种类型的静脉内或鼻内的滥用有很好的文献证明。
药用的阿片样物质滥用的潜在性不是一个新的问题。为了对抗阿片样物质滥用的效果，阿片类物质拮抗剂已经被用来阻断与阿片类物质滥用相联系的欣快感，并且用来诱导成瘾者的断瘾症状。以前使用的，并且现在仍在使用的一种阿片样物质拮抗剂是纳洛酮。纳洛酮是一种强大的阿片样物质受体的拮抗剂。纳洛酮当非肠道给药时是高有效的，但是当口服给药时效果差，这是因为它的在肝中的代谢并且，因此，具有高的口服∶非肠道效能比。当被注射给人类时，与0.2-0.4mg一样小的量就能够阻断阿片样物质受体并且防止使用者体验到药物的效果，无论是镇痛还是心情改善，欣快感。由于高口服∶非肠道效能比(～100)，纳洛酮的口服剂量的拮抗作用远低于纳洛酮的注射的作用。因为拮抗剂例如纳洛酮当口服时效果较差，它们还没有被用来阻止口服滥用并且已经局限于阻止非肠道的或鼻内的滥用。
然而，近来一种新型的阿片样物质激动剂的滥用已经出现，包括代替通过注射或吸入滥用的口服滥用。这种行为大量的涌现是因为可获得高-阿片样物质含量控释(CR)制剂。“咀嚼”包括粉碎阿片样物质制剂并取全部内容物，立刻平均分为2份或更多份剂量。这一行为立刻释放所有阿片样物质来产生一种“快感”。此粉碎可以如名称所暗示的在嘴里发生，但是也能通过其它方式发生来使阿片样物质立即可获得包括在注射或鼻内给药之前粉碎或溶解药片。
近来，包含大毫克剂量的阿片样物质的高效能处方的阿片样物质片剂已经被引入。这些片剂是控释片剂并且被设计来提供长达12小时或更长的疼痛缓解。因为这些片剂具有长时间的作用(以12小时替代速释制剂的4小时)，此片剂包含更高含量的阿片样物质化合物。对于潜在的滥用者来说，这些片剂是非常有吸引力的。这些片剂的高剂量给了他们一个简捷的途径来获得大量的阿片样物质。事实是它们是片剂中药物的质量和含量的医药品保证。因此，潜在的滥用者知道他或她在一个已知的剂量中正获得高纯度的药物。先前的包含相对低剂量阿片样物质的口服剂量制剂已不是口服滥用的通常目标。它们的速释剂型同时释放阿片样物质，但是如果不将许多低剂量单位一起使用，这些低剂量的阿片样物质对于口服滥用是不够的。相反，滥用者已经发现新的包含大量阿片样物质的CR片剂，它能通过咀嚼片剂或粉碎它们来在同一时刻一起释放所有的阿片样物质(速释)被口服滥用。本发明阻止这种口服滥用。
Oxycontin，一种由Purdue Pharma生产的控释1，4-羟基二氢可待因酮片剂，以每片160mg 1，4-羟基二氢可待因酮的浓度被利用。此高阿片样物质含量使得这种片剂对于滥用者是特别有吸引力的。控释阿片样物质的非法交易正变得更加普遍。为了从这种药片中获得欣快感效果(high)，滥用者会粉碎药片并通过溶解来提取阿片样物质化合物用来注射或鼻内给药。滥用者也可以仅通过在咀嚼药片或研磨它来破坏控释骨架(matrix)并将它转变成一种速释产品后口服药物来从药物中获得欣快感效果。因此，希望有一种制剂，它能防止如果控释片剂被粉碎来变成一种速释产品的口服滥用，而不显著地影响在完整的控释片剂中的阿片样物质的镇痛作用。
WO 01/58447公开了在一种控释的骨架中的阿片样物质激动剂和拮抗剂的药物组合物。拮抗剂以削弱或减少阿片样物质激动剂副作用的量，还以不足以阻止阿片样物质作用的量存在和被释放。优选的拮抗剂是纳曲酮，当口服或非肠道施用时它是高有效的。拮抗剂仅以非常小的量释放，低于阿片样物质100-1000倍。WO‘447没有公开关于在一剂中包含一种抗-滥用量的拮抗剂来预防滥用。低剂量的纳曲酮(0.25或1μgkg-1hr-1)的静脉内使用，也当作具有削弱作用被公开。
WO‘447没有提出拮抗剂在其CR制剂中的释放速度，但是向本领域技术人员指引了Crain专利(美国专利号5,767,125；5,580,876；5,512,578；和5,472,943)。这些Crain专利共同公开了具有“极低”剂量的特定的拮抗剂的速释制剂来选择性地只阻断兴奋的阿片样物质受体来削弱阿片样物质副作用，而不阻断抑制的受体，它会导致阿片样物质阻断。这些剂量是微微摩尔量级的。Crain‘578暗示只有纳曲酮的口服给药是有用的，并且1μg剂量对于通过选择性地阻断兴奋的阿片样物质受体并留下抑制的阿片样物质受体自由地来接受阿片样物质激动剂(它可能以具有相似的镇痛作用的低于普通剂量的剂量来给药)来削弱阿片样物质副作用是足够的。纳曲酮的普通口服剂量约为50mg相对于Crain‘578专利中描述的纳曲酮的1μg的极低”剂量。
现有技术没有讨论用来阻止滥用的包含激动剂和拮抗剂的控释制剂。相应的，在高阿片样物质含量控释制剂流行的今天对于阻止滥用的组合物是有需求的。
发明概述
抗滥用，控释阿片样物质片剂是一种包含一种具有高口服∶非肠道效能比(也就是口服∶非肠道＞1)的阿片样物质拮抗剂(例如纳洛酮)的组合物，在控释制剂给药的一个长时期内不足以阻断阿片样物质作用或削弱阿片样物质副作用的水平，但是如果所有立刻施用时高于所需的来抑制阿片样物质欣快感作用的水平。如果组合物片剂被粉碎来破坏控释性质，阿片样物质和阿片样物质拮抗剂会如单剂量的速释制剂一样被释放，并且拮抗剂阻断激动剂的欣快感作用。阿片样物质拮抗剂被包含在一种控释骨架中并且和阿片样物质激动剂一起随时间释放。
发明详述
本发明遵循的原理即特定的阿片样物质拮抗剂在低口服剂量是无效的。因此，可以从包含大量的，口服有效量的拮抗剂的片剂来通过一段长的时期施用低口服剂量(控释)，而不相反地影响阿片样物质的作用。然而，如果拮抗剂被全立刻给予，它会阻断阿片样物质的作用并且会在有依赖性的个体身上诱发断瘾。
本发明用于控释组合物。术语“控释”或“CR”当在这里使用时，意指片剂在一段长的时期内释放一种活性药物成分，通常为4小时，一般为8-12或直到24小时。测定其的一个方法是核对想要的剂量表。任何想要比低于每四小时一次服用频率低的片剂应该被认为是控释，不考虑标签是控释，持续释放，长期释放等。通常，这些片剂包含聚合物骨架，其可能是交联的。这种控释制剂的例子有Contin系统(由Purdue Fredrick Pharmaceuticals生产)，或TimerX系统(由Pennwest Pharmaceuticals生产)。其它控释聚合物也能被使用，例如甲基丙烯酸酯(Eudragit)，羟丙基甲基纤维素(HPMC)，或Carbopol。本发明可以和这些或其它控释制剂一起被使用。
本发明的片剂包含在一个控释骨架内的一种阿片样物质激动剂和一种阿片样物质拮抗剂。拮抗剂以这样的一个水平存在，并且以这样的一个速度分配，即当口服一个完整的控释药片时它不会阻断阿片样物质激动剂的作用。粉碎的药片会像一种速释制剂一样立刻完全释放足够的拮抗剂来阻断阿片样物质反应并且也会诱发节欲。拮抗剂需要达到一个有效量来工作，所以他们的低释放结合快代谢指它们维持在正常的，被推荐的，治疗的，非滥用的无效的低的水平。这种拮抗剂的低水平能在长期内被释放而不影响阿片样物质激动剂的治疗作用。甚至在此长期的持续释放中，拮抗剂不会积累到阻断水平，因为在它能积累到这一水平前就已经被代谢了。由于阿片样物质拮抗剂作用的性质，拮抗剂的水平应该随着片剂中的阿片样物质的量变化。取决于拮抗剂，口服∶非肠道效能比和释放速度，使用的拮抗剂的水平也会变化。无论如何，应该有足够的拮抗剂来阻断阿片样物质的作用(快感)并在有依赖性的个体上诱发断瘾，如果药片被粉碎，将制剂转化成速释。在正常情况下，释放速度对于阻断阿片样物质作用是不足够的，对于选择性地阻断兴奋的阿片样受体来削弱阿片样物质副作用也是不适合的。对于纳洛酮来说，目前优选的拮抗剂，可以认为15mg(立即释放)应该开始阻断阿片样物质受体并引起断瘾。
在这里公开的具体的阿片样物质激动剂，拮抗剂，CR骨架和组合物仅仅是代表性的。其它激动剂，拮抗剂，骨架和组合物也可以和这里教导的联合使用。
阿片样物质激动剂可以是任何通常用作镇痛剂的激动剂，包括，但不限于吗啡，1，4-羟基二氢可待因酮，羟甲左吗喃，杜冷丁，氢可酮，可待因，双氢可待因，氢吗啡酮，丙氧芬，美沙酮和羟吗啡酮。具体的，在一种控释剂型中的任何成瘾的阿片样物质都是本发明的目标。更特别的，控释的1，4-羟基二氢可待因酮最近已经成为了滥用的目标，因此在本发明中是一个可使用的好的候选药物。当然，阿片样物质激动剂的释放速率被确定来获得想要的镇痛效果。
拮抗剂的效能被测量作为口服∶非肠道效能比，它指出了为获得与有效的非肠道剂量相当的效应口服所需的拮抗剂的量。例如，一种具有口服∶非肠道效能比为10∶1的拮抗剂需要10倍的非肠道剂量来达到口服有效。在这里使用的阿片样物质拮抗剂当非肠道施用时会比口服施用时有更大的拮抗效应(口服∶非肠道效能比＞1)。相应地，当在相对低的水平非肠道或鼻内施用时，所需的拮抗剂阻断阿片样物质作用并诱发断瘾。与此同时，当被口服施用作为被推荐的，治疗应用时，这些拮抗剂需要相对高的水平来达到有效。因此，有效的非肠道/吸入剂量当口服施用时是无效的。当是纳洛酮时，优选的，口服∶非肠道效能比至少约为10∶1，更优选的至少约为25∶1，并且最优选的至少约为100∶1。合适的阿片样物质拮抗剂当注射施用时比当口服施用时具有实质上更大的有效性，包括但不限于：纳洛酮；纳曲酮；N-环丙基甲基-7，8-二氢-14-羟基去甲吗啡酮或21-环丙基z，-(1-羟基-1-甲基乙基)-6，14-内-桥亚乙基-四氢去甲蒂巴因(或diphenorphine)和其药学上可接受的盐。
先前就已知阿片样物质拮抗剂，例如纳洛酮，能阻断阿片样物质受体并减少或消除阿片样物质的作用。这些拮抗剂在某些情况下在治疗阿片样物质过量及帮助治疗成瘾方面是有用的。通过阻断阿片样物质受体，这些拮抗剂逆转并阻断对阿片样物质的反应。高口服∶非肠道效能比的拮抗剂，例如纳洛酮，虽然当注射时是非常有效的，但当口服施用时效果较差。因此，一种被设计用来口服给药的剂型能含有有效量的阿片样物质拮抗剂，而不相反地影响阿片样物质的治疗效果。相似的，拮抗剂的这一水平不会削弱阿片样物质的副作用。当以低水平存在时，这种拮抗剂在阻止静脉内的或鼻内滥用方面将会是有效的，但是在阻止口服滥用时将会是无效的。如果片剂包括足够量的拮抗剂来阻止口服滥用，拮抗剂也会减少或抑制药物的治疗效果。一个在CR制剂中包含口服有效量的拮抗剂在正常使用下释放非有效量的拮抗剂的药片能够有效地低抗口服和非肠道滥用，而不会减小在正常使用下的阿片样物质的有效性。
组合物中的拮抗剂的量依赖于拮抗剂的相对强度，阿片样物质的量和强度，拮抗剂的释放速度和口服∶非肠道效能比。在任何情况中，当打算口服施用整个剂型时，拮抗剂类型，口服∶非肠道效能比，数量和释放速率的结合不会导致阿片样物质作用的阻塞或其副作用的削弱。
控释阿片样物质片剂的浓度随使用的特定的阿片样物质变化。以1，4-羟基二氢可待因酮为例，10，20，40，80和160mg的浓度都能在控释处方中使用。在这种片剂中的阿片样物质拮抗剂(例如纳洛酮)的量也可以在约2mg到40mg或更多之间变化。在一个药片中应该至少有5到20mg(优选10到20mg)纳洛酮来阻止通过咀嚼多个小的，低剂量药片或一个高浓度药片的口服滥用。也就是说，通过结合2个或多个低剂量药片的被滥用的剂量的积累也应该会累积到拮抗剂的有效量。高剂量阿片样物质片剂应该包含不积累的有效量的拮抗剂。通过非肠道或鼻内给药的滥用的预防也会被完成，因为在注射或吸入的情况下，只需要约0.2到0.4mg的纳洛酮来拮抗阿片样物质作用，来诱导在有依赖性的个体上的节欲并预防滥用。因此，所需的来预防口服滥用的较大的量必然也会预防通过注射或鼻内给药的滥用。
对于具有10或20mg片剂浓度的1，4-羟基二氢可待因酮片剂，纳洛酮，使用的拮抗剂的量可以在5到40mg范围内变化。当药片浓度升高时，阿片样物质和阿片样物质拮抗剂的比在1∶3到4∶1之间变化，因此一个160mg的阿片样物质片剂可以包含80mg阿片样物质拮抗剂。虽然比例能够变化，但是为所有片剂浓度选择一个比例是优选的。医生愿意让病人使用许多低剂量片剂，它们能累加到想要的剂量。如果一个恒定比例是维持的，这是最容易的。因此，一个关于药片浓度的恒定的比例是有用的，尽管比例可以是在前面所述的范围内的任何合适的比例。
药物滥用者在寻找击败抗滥用措施的途径时是有创造性的。目前已经想出了口服滥用的许多方法。如上所述，应该记住本发明的组合物包含足够的对口服有效的拮抗剂并且，因此，必须包含非肠道或鼻内有效的阻断量。相应的，非肠道和鼻内滥用不在此讨论。
滥用者可以“咀嚼”一个单个的大剂量药片来获得被滥用剂量的阿片样物质的立即释放。包含这些被滥用的量的阿片样物质的组合物应该包含足够的拮抗剂来阻断通过“咀嚼”的滥用。
两个或更多较低剂量的药片可以一起被“咀嚼”来得到一个被滥用的剂量。到此地步每一个药片自己不包含口服有效量的拮抗剂，当与一个被滥用的剂量结合时，结合的拮抗剂应该是口服有效的。也就是说，例如，一个10mg药片不足以达到快感，则它不需要包含完全口服有效量的拮抗剂。如果两个10mg药片足以达到快感，则它们应该包含一个结合的量的拮抗剂，它对于阻断阿片样物质作用是口服有效的。
另外，两个或多个高-剂量药片能被一起口服，而不粉碎，来达到“快感”。这种结合将利用CR性质来持续快感因为整个的药物周期直到12小时。这种类型的滥用不普遍，因为大多数滥用者希望得到通过粉碎的药片的立即释放提供的即刻的快感或急流(rush)。这种结合，按照本发明的一个具体实施方式，当口服不咀嚼时也应当释放阻断量的拮抗剂。这种安排也会预防意外的过量的可怕的反应。虽然这种安排的类型在许多情况下是有益的，但是它可能局限于开处方的医生的选择，并且因此可能不会在所有的情况下都合适。按照此具体实施方式的片剂不是优选的，但是肯定也在本发明的范围内。
本发明的片剂可以考虑任何的上述的滥用方式独立的或其任何的结合。
本发明的基本的优先的前提是片剂包括1)拮抗剂的量是对阻断阿片样物质作用口服有效的和2)拮抗剂是可获得的，普通的，只是在对阻断阿片样物质作用或削弱阿片样物质副作用的无效的水平。达到此的方式中的一种是控制拮抗剂的释放速度。拮抗剂的释放速度最好依照阿片样物质激动剂的释放速度来考虑。此速度被控制在阿片样物质的释放速度的大约100％到0％之间，优选100％到25％。表1显示了作为释放百分率的阿片样物质和拮抗剂的释放速度。在0％的情况下，拮抗剂是不释放的除非药片被粉碎。但是，那是另一份申请的目的。
就纳洛酮来说，短的半衰期(约一小时)确保纳洛酮不会累积到阻断水平，甚至当与阿片样物质以相同的速度释放时。在较慢的释放制剂中(50％和75％)，不释放的部分在保留10-12小时后通过大肠，在那里吸收速度远比在胃和小肠内低。相应地，超过10-12小时后释放的拮抗剂的量不会引起任何阻断或削弱作用。
此释放速度确保在正常使用中拮抗剂没有阻断或削弱作用。然而，在CR性质被破坏时存在口服有效阻断剂量的拮抗剂。
使用的CR骨架的类型和应用会决定释放速度。释放速度的处理，甚至是两个有不同的速度的化合物的释放速度的处理，在现有技术中是已知的。可以使用任何已知的或晚些开发的CR技术。很重要的应该记住的是拮抗剂不应该容易地从激动剂中被区别或分离出来，因为滥用者可能会在破坏CR制剂前使用机械分离技术。
表1：从CR制剂释放的释放速度
                              拮抗剂
                    (作为激动剂释放速度的百分比)
          激动剂     100％      50％       25％
1小时     20-30％    20-30％    10-15％    5-7.5％
4小时     60-70％    60-70％    30-35％    15-17.5％
10小时    ＞90％     ＞90％     45-50％    22.5-25％
释放速度是激动剂或拮抗剂相对于它们在组合物中的总量的百分比。
药片可以用任何传统的制备控释片剂的方法来制备。两个基本的方法是湿法(包括湿制粒)和干法(包括直接混合和碾压过程)。这些方法的有代表性的组合物如下被再生产。
表2：对于不同浓度的1，4-羟基二氢可待因酮片剂的优选的纳洛酮范围
1，4-羟基二氢可待因酮(mg)   10    20    40    80     160
纳洛酮(mg)                  2-10  4-20  8-40  16-80  20-160
对于氧吗啡酮，控释片剂的剂量可以是10，20或40mg且纳洛酮剂量变化可以与为1，4-羟基二氢可待因酮列出的一致。
优选的1，4-羟基二氢可待因酮∶纳洛酮的比例是5∶1到1∶1。
表3：含纳洛酮的1，4-羟基二氢可待因酮盐酸盐10-mg片剂的制剂1
组成                             mg/片        百分比(以重量计)
1，4-羟基二氢可待因酮盐酸盐       10.00         2.22％
纳洛酮                            10.00         2.22％
乳糖(喷雾干燥)                    281.50        62.56％
羟丙基甲基纤维素                  135.00        30.00％
K100M
二氧化硅                          9.00          2.00％
硬酯酸镁                          4.50          1.00％
总计：                            450.00        100.00％
表4：含纳洛酮的1，4-羟基二氢可待因酮盐酸盐10-mg片剂的制剂2
组成                             mg/片        百分比(以重量计)
1，4-羟基二氢可待因酮盐酸盐       10.00         3.77％
纳洛酮                            10.00         3.77％
乳糖(喷雾干燥)                    157.55        59.45％
羟丙基甲基纤维素                  79.50              30.00％
K100M
二氧化硅                          5.30               2.00％
硬酯酸镁                          2.65               1.00％
总计：                            265.00             100.00％
表5：含纳洛酮的1，4-羟基二氢可待因酮盐酸盐10-mg片剂的制剂3
组成                              mg/片             百分比(以重量计)
1，4-羟基二氢可待因酮盐酸盐        10.00              8.33％
纳洛酮                             10.00              8.33％
乳糖(喷雾干燥)                     60.40              50.33％
羟丙基甲基纤维素                   36.00              30.00％
K100M
二氧化硅                           2.40               2.00％
硬酯酸镁                           1.20               1.00％
总计：                             120.00             100.00％
替换的组合也可以被使用。优选的，本发明的片剂将会有如下的组合：
材料                                      含量(％)
1，4-羟基二氢可待因酮盐酸盐，USP           2.000-35.000
纳洛酮                                     2.000-20.000
微晶纤维素，NF(Avicel PH102)               10.000-50.000
铵甲基丙烯酸酯共聚物，NF(Eudragit RSPO)    30.000-70.000
胶体二氧化硅，NF(Cab-O-Sil)                0-5.000
月桂基硫酸钠，NF                           0-5.000
氢氧化镁，USP                              0-2.000
聚维酮，USP                                0-15.000
硬酯酸，NF                         0-5.000
硬酯酸镁，NF                       0-5.000
至于制剂1-3的溶解按照USP XXIV仪器3(ReciprocatingCylinder)来进行。仪器3用来模仿人类的胃肠道环境。第1小时是在pH1.2的0.1N HCl中。第2和第3小时是在pH4.5的10mM磷酸钾一价碱中。3小时后环境是pH6.8的10mM磷酸钾一价碱。所有溶解的容器包含250mL的溶解溶液。滴速设置在每分钟10滴。水浴温度设置在37.5℃。HPLC参数如下设置：柱-Inertsil ODS 3,50mm×4.6mm，3μm颗粒大小。流动相：80％30mM己烷磺酸钠pH3.0+/-1,20％乙腈。注射量是75μl。柱温是35℃，流动速度设置在1.0mL/min。波长设在225nm。流动时间(Run time)是5.5分钟。
制剂1-3的溶解结果如下：
                                 制剂1
       未粉碎的药片                       粉碎的药片
时间  溶解的                  溶解的    溶解的                   溶解的
       1，4-羟基二氢可待因酮   纳洛酮    1，4-羟基二氢可待因酮    纳洛酮
       的百分率                的百分率  的百分率                 的百分率
0      0.0                      0.0        0.0                       0.0
1      29.8                     27.8       88.2                      94.6
2      47.8                     45.4
3      59.8                     57.4
4      68.5                     65.9
8      91.1                     87.5
12     100.7                    97.9
                                 制剂2
       未粉碎的药片                粉碎的药片
时间  溶解的                 溶解的     溶解的                  溶解的
       1，4-羟基二氢可待因酮  纳洛酮     1，4-羟基二氢可待因酮   纳洛酮
       的百分率               的百分率   的百分率                的百分率
0      0.0                     0.0         0.0                      0.0
1      40.1                    37.0        104.9                    102.8
2      63.2                    60.3
3      77.3                    75.3
4      86.5                    85.2
8      105.6                   106.1
12     110.5                   112.6
                                制剂3
       未粉碎的药片                 粉碎的药片
时间  溶解的                  溶解的    溶解的                  溶解的
       1，4-羟基二氢可待因酮   纳洛酮    1，4-羟基二氢可待因酮   纳洛酮
       的百分率                的百分率  的百分率                的百分率
0      0.0                      0.0        0.0                      0.0
1      59.0                     52.5       100.5                    90.9
2      85.4                     78.0
3      97.4                     90.3
4      102.5                    95.9
8      105.4                    99.7
12     105.4                    99.8
从这些试验中可以看到，很明显在正常的，非粉碎的使用中，随时间释放的拮抗剂(这里是纳洛酮)的量不足以阻断阿片样物质的作用。甚至在实施例3中，它具有拮抗剂的最高的初始释放速度，在第一小时也只释放了约5mg纳洛酮。由于纳洛酮的短的半衰期和慢的释放速度，拮抗剂不会在体内累积达到阻断阿片样物质作用的水平。另一方面，在粉碎的片剂中，基本上在第一个小时所有的拮抗剂都释放。因此，一种阿片样物质阻断量的拮抗剂易于用来阻止口服和其它形式的滥用。不考虑使用的拮抗剂，拮抗剂含量、释放速度和拮抗剂半衰期的结合达到了本发明的目标，即当作为立即释放施用时阻断阿片样物质作用，但是当作为有意的和被推荐的控释制剂施用时不会阻断阿片样物质作用。
众所周知，不同的阿片样物质具有不同的相对的强度。通常，它们被比较并涉及决定每一个的相对剂量的标准。虽然本申请是依据1，4-羟基二氢可待因酮来讨论了阿片样物质的量，但是本领域技术人员会很容易地理解其它阿片样物质，更强的或更弱的，可以以相当的剂量被使用。相同的，拮抗剂相似地被选择和订剂量。
本发明的范围不局限于上述的实施例，它们被提供只是出于说明的目的。上面的描述只是记载在片剂的范围内。其它能够被制成CR制剂的口服剂型也能被使用。可用的口服剂型有胶囊，囊片，微球，凝胶帽，甚至液体制剂。

Claims (20)

1.一种口服药物组合物包括：
一种控释骨架；
一种阿片样物质激动剂；
一种阿片样物质拮抗剂，其当非肠道施用时比当口服施用时具有更大的拮抗作用；
其中当控释骨架被破坏和组合物为了立即释放而不适当地给药时所述的阿片样物质拮抗剂以阻断阿片样物质作用和/或诱发断瘾的口服有效量存在于组合物中；
其中所述的控释骨架是为了控制阿片样物质拮抗剂的释放速度而被选择和混合，这样在合适的口服给药方式下拮抗剂的水平对于通过阻断抑制性的和兴奋性的受体来阻断阿片样物质作用或对于通过选择性地阻断兴奋性受体来削弱阿片样物质的副作用是无效的。
2.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的释放速度是阿片样物质激动剂的释放速度的约100％至约25％。
3.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的释放速度是阿片样物质激动剂的释放速度的约100％。
4.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的释放速度是阿片样物质激动剂的释放速度的约50％。
5.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的释放速度是阿片样物质激动剂的释放速度的约25％。
6.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的口服：非肠道效能比是至少约10∶1。
7.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的口服：非肠道效能比是至少约25∶1。
8.根据权利要求1的药物组合物，其中阿片样物质拮抗剂的口服：非肠道效能比是至少约100∶1。
9.根据权利要求1的药物组合物，其中所述的阿片样物质激动剂选自吗啡，1，4-羟基二氢可待因酮，羟甲左吗喃，杜冷丁，氢可酮，可待因，双氢可待因，氢吗啡酮，丙氧芬，美沙酮或羟吗啡酮。
10.根据权利要求1的药物组合物，其中阿片样物质拮抗剂选自纳洛酮；纳曲酮；N-环丙基甲基-7，8-二氢-14-羟基去甲吗啡酮；和21-环丙基z，-(1-羟基-1-甲基乙基)-6，14-内-桥亚乙基-四氢去甲蒂巴因(或diphenorphine)和它们的药学上可接受的盐。
11.根据权利要求1的药物组合物，其中所述的阿片样物质拮抗剂是纳络酮。
12.根据权利要求1的药物组合物，其中所述的阿片样物质激动剂是1，4-羟基二氢可待因酮。
13.根据权利要求1的药物组合物，其中所述的阿片样物质激动剂以与约10-160mg的1，4-羟基二氢可待因酮剂量的药学上的相当的浓度存在。
14.根据权利要求1的药物组合物，其中拮抗剂的释放速度为组合物的一个单剂量不会提供有效的拮抗剂的口服有效量，而当组合物的两个或更多剂量结合时-粉碎或不粉碎-来获得阿片样物质激动剂的一个滥用剂量时，阿片样物质拮抗剂在口服有效阻断水平是有效的。
15.一种药物组合物包括：
一种控释骨架；
一种阿片样物质激动剂；
一种阿片样物质拮抗剂，当非肠道施用时比当口服施用时具有更大的拮抗作用；
其中所述的阿片样物质拮抗剂以与在组合物中的阿片样物质激动剂的滥用量的数目成比例的量存在于组合物中，这样如果CR骨架被破坏并且组合物的两个或多个剂量被结合来产生一个阿片样物质激动剂的滥用量，则当口服时阿片样物质拮抗剂的量对于阻断阿片样物质作用和/或诱发断瘾是足够的；
其中所述的控释骨架是为了控制阿片样物质拮抗剂的释放速度而被选择和混合，这样在合适的口服给药方式下拮抗剂的水平对于通过阻断抑制性的和兴奋性的受体来阻断阿片样物质作用或对于通过选择性地阻断兴奋性受体来削弱阿片样物质的副作用是无效的。
16.根据权利要求15的药物组合物，其中拮抗剂的释放速度为组合物的一个单剂量不会提供有效的拮抗剂的口服有效量，而当组合物的两个或更多剂量结合时-粉碎或不粉碎-来获得阿片样物质激动剂的一个滥用剂量，阿片样物质拮抗剂在口服有效阻断水平是有效的。
17.一种口服药物组合物包括：
一种控释骨架；
约10-160mg 1，4-羟基二氢可待因酮；
约2-160mg纳洛酮；
其中1，4-羟基二氢可待因酮与纳洛酮的比例约为4-5∶1至1∶1；
其中所述的控释骨架被选择和混合是为了控制1，4-羟基二氢可待因酮的释放速度来维持药物有效性长达12小时并且为了控制纳洛酮的释放速度即在合适的口服给药方式下纳洛酮的水平对于通过阻断抑制性的和兴奋性的受体来阻断阿片样物质作用或对于通过选择性地阻断兴奋性受体来削弱阿片样物质的副作用是无效的。
18.一种口服药物组合物包括，以重量百分比计；
约3-35％阿片样物质激动剂；
约2-20％阿片样物质拮抗剂；
约10-50％微晶纤维素，NF；
约30-70％铵甲基丙烯酸酯共聚物，NF；和至少一种选自如下的辅料：
至多约5％胶体二氧化硅，NF；
至多约5％月桂基硫酸钠，NF；
至多约2％氢氧化镁，USP；
至多约15％聚维酮，USP；
至多约5％硬脂酸，NF；和
至多约5％硬脂酸镁，NF；
其中所述的组合物是一种控释制剂适应于在一个治疗有效的速度释放1，4-羟基二氢可待因酮，并且在当控释制剂被以完整形式口服时对于阻断阿片样物质作用和/或诱发断瘾无效的速度释放所述纳洛酮。
19.根据权利要求18的口服药物组合物，其中所述的阿片样物质激动剂选自吗啡，1，4-羟基二氢可待因酮，羟甲左吗喃，杜冷丁，氢可酮，可待因，双氢可待因，氢吗啡酮，丙氧芬，美沙酮和羟吗啡酮并且阿片样物质拮抗剂选自纳洛酮；纳曲酮；N-环丙基甲基-7，8-二氢-14-羟基去甲吗啡酮；和21-环丙基z，-(1-羟基-1-甲基乙基)-6，14-内-桥亚乙基-四氢去甲蒂巴因(或diphenorphine)和它们的药学上可接受的盐。
20.根据权利要求18的口服药物组合物，其中所述的阿片样物质激动剂是1，4-羟基二氢可待因酮且所述的阿片样物质拮抗剂是纳洛酮。
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