CN1511030A - 含有辣椒碱的抗滥用药物组合物 - Google Patents
含有辣椒碱的抗滥用药物组合物 Download PDFInfo
- Publication number
- CN1511030A CN1511030A CNA028103890A CN02810389A CN1511030A CN 1511030 A CN1511030 A CN 1511030A CN A028103890 A CNA028103890 A CN A028103890A CN 02810389 A CN02810389 A CN 02810389A CN 1511030 A CN1511030 A CN 1511030A
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- China
- Prior art keywords
- capsaicin
- compositions
- opioid
- exists
- dosage form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 title claims abstract description 252
- 235000017663 capsaicin Nutrition 0.000 title claims abstract description 119
- 229960002504 capsaicin Drugs 0.000 title claims abstract description 112
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 5
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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Abstract
一种口服使用的药物组合物含有有效组分、辣椒碱和其他典型填充剂和赋形剂。该组合物优选是固体口服剂型的形式。透皮给药组合物也属于本发明的范围内。除了有效药学组分该组合物包含一定量的辣椒碱,其发挥阻止该组合物鼻内、静脉内或口服滥用的作用。该组合物阻止滥用者烟酸处方药物片剂用于滥用喷鼻、注射或摄入。
Description
发明领域
本发明涉及包括阻止滥用的体系的抗滥用药物组合物。更加具体地,本发明涉及含有有效量的药物化合物和辣椒碱或辣椒碱生物碱(capsaicinoid)化合物的组合物。非常具体地,本发明涉及含有有效量的药物化合物,和当根据需要经口服或透皮给药时能够阻止鼻内、口服和静脉内滥用的量的辣椒碱化合物。
相关技术
许多药物化合物,包括烟碱类和阿片样物质,以及非烟碱类和非阿片样物质的医学效果是公认和不容置疑的。不幸的是,对许多这样的药物滥用和成瘾同样是无争议的。尤其是阿片样物质。滥用者,为了获得最大限度的效果,常常从鼻喷入粉状或溶解的药物形式或者制备药物的溶液并注射它。另外,滥用者可以在处方药片和胶囊中可以寻找到成瘾性物质的便捷供应。阿片样物质是,也许是,这些药物中最成瘾和最被滥用的。在此使用的阿片样物质是指鸦片产品或其类似物或其他当用作药物时作用在阿片样物质受体上的药物,包括但不限于可待因、二氢可待因、丁丙诺啡、芬太尼、氢可酮、二氢吗啡酮、羟甲左吗喃、度冷丁、美沙酮、吗啡、纳布啡、羟考酮、羟氢吗啡酮、镇痛新,和丙氧芬、曲马多。此外,已经被滥用的其他药物包括下列种类的药物:例如,苯并二氮杂卓类,例如安定,和NMDA拮抗剂,例如氯胺酮。
随着控释片剂和其他制剂的发展,越来越多数量的有效药物化合物可以配制为单一片。由于这些制剂以更高的效能和方便性为患者提供益处,各种制剂也为成瘾者提供了更多和更方便数量的滥用药物。所以,人们已经在寻找新的和更好的阻止滥用的方法。由于证明鼻内和静脉内滥用是由这些药物获得欣快效应,即“高潮”,最理想和最危险的方法,阻止这样的使用将是有益的。阻止口服滥用也非常有帮助。
已知辣椒碱,是在辣椒和Capsicium属的其他种内发现的天然成分,是刺激性的,特别是对粘膜,例如鼻道内的粘膜。目前发现其在“辣椒喷剂”中使用的名声,外行用作催泪。在这种情形中,辣椒喷剂有效阻止可能的攻击者从而有足够的时间逃跑。辣椒碱在试验上也提供将其注射到皮肤或肌肉中来研究人体神经病性疼痛。已经发现以这种方式注射少量的辣椒碱引起了持续数小时的疼痛。其他辣椒碱类似物或辣椒碱生物碱也似乎表现出类似效果。在本说明书和权利要求中,术语“辣椒碱”用来表示辣椒碱,并且术语“辣椒碱生物碱”用来代表更宽泛种类的化合物包括天然或合成的辣椒碱、其类似物,和其他衍生物和在所属领域统称为辣椒碱生物碱的化合物。
研究表明辣椒碱可以与多种具有阳性镇痛结果的阿片样物质联合。还没有发现辣椒碱会拮抗或干扰阿片样物质的生物利用度。美国专利No4,599,342曾提出辣椒碱和阿片样物质以某种比例时在产生镇痛中具有协同作用。该专利中所示的辣椒碱与阿片样物质的比例为20000∶1至1∶20。该’342专利还证明在口服剂型中,对于平均成人来说辣椒碱的最小有效剂量是约100mg或约1.3mg/kg,条件是保持辣椒碱与阿片样物质的比例。剂量范围最高为2000g。美国专利No4,681,897提出了与非阿片样物质镇痛剂例如非甾族镇痛/抗炎药物(NSAID类)的类似协同作用。建议平均成人的最小辣椒碱含量为50mg(0.85mg/kg),条件是保持类似辣椒碱与镇痛剂的比例。在此可接受的剂量可以至多为2000mg。然而,在’897专利中,剂型均是口服或透皮使用的。
令人感兴趣地,虽然发现辣椒碱本身具有镇痛性质,它在测试其他镇痛剂时仍然用作刺激物或引发咳嗽、打喷嚏,和其他疾病效果。所以,辣椒碱似乎用于相反的目的。一方面,它是一种刺激物,引起咳嗽、打喷嚏、疼痛和其他效果,另一方面声称它在疼痛的动物模型中增强镇痛。
由于成瘾物质的高效和高含量形式,这在医学上是认可的,变得更容易以固体口服剂型和透皮制剂获得,所以需要允许所述物质经口服或透皮途径的有效医学使用,但同时阻止鼻内和/或静脉内滥用的新组合物和方法。本发明提供解决这个问题的方案。
发明概述
口服使用的药物组合物含有有效量的组分、辣椒碱和用于制剂的其他物质。所述的组合物优选是固体口服剂型的形式,一般为片剂或胶囊。透皮给药的组合物也属于本发明的范围。除了有效药物组分,所述的组合物含有一定量的发挥阻止组合物鼻内、口服或静脉内使用作用的辣椒碱。这样的组合物阻止滥用者粉碎处方药物片剂来成瘾性喷鼻和/或注射。辣椒碱可以直接掺混在剂型中,或者可以螯合(sequester)来减少或消除其释放。此外,提高辣椒碱作用的附加物质可以含在片剂内。
优选实施方式的详述
本发明的组合物能够将潜在成瘾的物质在医学上有效口服给药,该组合物阻止其经鼻内、经口服或经静脉内滥用。由于阻止性成分在喷鼻或注射时非常刺激,本发明自然包括了固体口服剂型例如丸剂、片剂、胶囊等等。还包括液体填充的固体口服剂型,因为它们同样地被滥用。本发明着重于片剂和胶囊,因为这些剂型会分配给患者使用。所以,这些剂型更可能成为滥用的靶向。还包括透皮使用。尤其是,不与粘膜结肠或其他辣椒碱敏感膜结肠的所有剂型都可以根据本发明的实施方式制备。不应当根据本发明配制设计用来进入静脉内或鼻内系统的剂型。
据此,所述的组合物优选配制为固体口服剂型来给药。所属领域熟知的是,这样的剂型可以含有多种非活性成分例如填充剂、赋形剂和定时释放制剂(包括缓释、延迟释放等)。所述的组合物及其利用的剂型可以通过已知技术配制,并且不意味着局限于任何具体制剂方法或形式。为了方便,并且不构成对本发明范围的限定,术语“片剂”是指上述所有剂型。
所述的组合物还含有有效量的药物组分。药物组分的实际量应依赖于组分的本质、片剂的强度、被治疗的病症和患者的规模以及其他许多因素而变化。较大剂量和定时释放的制剂能够含有足够的传统上需要在一天内施用两次或多次的药物组分。这些片剂分别可以含有多种可潜在滥用剂量的活性成分。可潜在滥用的剂量应依赖于活性成分而改变用量。这种用量很容易确定。这些高含量制剂特别容易滥用;为滥用者提供浓缩的阿片样物质的滥用。此外,一些药物镇痛药同时由阿片样物质和其他镇痛药物组成,例如对乙酰氨基酚、阿斯匹林,和其他非甾族抗炎药。本发明的范围还包括这些联合镇痛药物。
加入辣椒碱,由此当片剂被压碎并经鼻内通过喷鼻摄取时,或经静脉内通过注射由压碎剂型得到的溶液摄取时,立刻感到辣椒碱的严重刺激效应。这些刺激效应包括,但不限于,咳嗽、打喷嚏、灼伤和疼痛。与辣椒碱有关的疼痛和不适可以保持数分钟或可能保持数小时,并且应阻止后续或连续滥用。如果所述的组合物被压碎和喷鼻,将引起疼痛和剧烈喷嚏。此外,辣椒碱引起的喷嚏可能引起滥用者排斥阿片样物质并由此预防立刻滥用。直接注射到静脉内的辣椒碱可能不会产生疼痛,但如果滥用者稍微偏离静脉,就会遭受皮下辣椒碱导致的疼痛。这将对进一步滥用提供阻止作用。片剂也可以阻止口服滥用。口服滥用可能以两种方式出现。首先,滥用者可以直接咀嚼片剂。这会破坏片剂的任何控释基质并立刻释放出全部的阿片样物质。由此给滥用者提供强烈的欣快感或“高潮”。口服滥用阿片样物质片剂的另一方法是通过压碎和溶解该片剂。滥用者随后饮用该溶液来获得全部阿片样物质的即时释放,再次产生“高潮”。或者,当片剂被压碎和溶解,或被咀嚼时,按照本发明含有辣椒碱可以具有辣味,或者可能引起疼痛。在对辣椒碱作用敏感的个体中,由于辣椒碱的辣味或产生的疼痛帮助阻止进一步滥用。
辣椒碱可以以两种主要方式加入。首先,辣椒碱可以直接掺混在片剂的基质中。由此防止通过压碎片剂的滥用,因为这种作用将释放辣椒碱并给潜在滥用者带来严重的不适。这样的片剂优选被包衣来延迟辣椒碱的释放直至片剂到达患者的胃中为止。
或者,辣椒碱可以螯合在片剂中使片剂被摄取时不被释放。螯合辣椒碱的优选方法是通过将其包封。由此该片剂应包括两种独立的基质。首先,并且一般是较大量的基质应含有片剂的活性成分(即阿片样物质或其他药物)。第二基质应含有辣椒碱。第二基质可以是均相控释基质(辣椒碱存在于能够在12-24小时内释放少于20%的辣椒碱的超缓释基质)。或者,可以被即时释放基质包封,例如,辣椒碱存在于即时释放基质中,该即时释放基质外周用防止辣椒碱释放的基质包封,除非该包衣被破坏(通过咀嚼或压碎片剂)。所述的“即时释放基质”可以包括传统制剂组分,或者可以单独含有辣椒碱。此外,辣椒碱,无论是在这个或另一个基质中,可以与其他物质混合,或者在化学上直接改变,由此使它对滥用者来说更加刺激或疼痛,例如通过提高溶解度,或者提高某些其他方法。
虽然在本说明书全文中术语“辣椒碱”是指滥用阻止物质,应当注意也可以使用其他滥用阻止化合物,尤其是当化合物被包封时。因此,应当理解本发明使用的滥用阻止剂包括任何潜在有损或刺激粘膜、但不引起持续损伤的物质,包括,但不限于辣椒碱和通式的辣椒碱衍生物:
其中R1是-NHC(O)-、-NHC(O)O-、-NHC(O)NH-、-NHC(S)NH-、-NHS(O2)-,或-C(O)NH-;
R2是直链或支链C5-C11烷基、C11-C23链烯基、C11-C23链炔基,或C11-C23链烷二烯基;
R3是OH或C1-C4酯;和
R4是OH或OCH3。
特别优选的辣椒碱衍生物(也称作辣椒碱类似物)是N-香草基-9E-十八烯酰胺、8-甲基-N-香草基-6-壬烯酰胺(辣椒碱)、二氢辣椒碱、去甲二氢辣椒碱、高辣椒碱、去甲辣椒碱,和nomorcapsaicin。总称和分别地,这些化合物(包括辣椒碱本身)在此被称作辣椒碱生物碱”。
显然,最希望使用那些当与粘膜接触时非常可能引起身体不适但无损伤的化合物。那些化合物在被消耗时也最可能产生热感。具体化合物产生的热感可以利用Scoville Units测定,它是一种松散依赖于辣椒碱生物碱存在的相对热感的主观判断等级。较高的Scoville分值表示热感的程度较高。在辣椒碱生物碱中,那些具有最高Scoville分值的是辣椒碱、去甲二氢辣椒碱和二氢辣椒碱,使这些物质成为本发明首选的化合物。这些化合物证明如下。这些物质,和其他辣椒碱生物碱的混合物,也包括在上述辣椒碱的定义中并适用于本发明。
本发明还利用当释放到粘膜内时引起刺激或不适的其他化合物,条件是这些化合物螯合穿过进入或通过机体但不在口腔内释放。例如,组胺类可以用来产生喷嚏并变应性反应症状。
辣椒碱的最小量应产生预期的阻止效应。该最小量应含在各个片剂中而无论片剂强度如何。低于该最小量的量可能无法有效阻止坚定的成瘾者。更高量的辣椒碱应包括在含有较大剂量或定时释放剂量的片剂中从而避免辣椒碱的稀释,和其阻止滥用作用,因为这些剂量更可能被潜在滥用者分裂。此外,在那些辣椒碱被螯合或包封的情形中,可以包括附加的辣椒碱,因为当辣椒碱不被释放时就不会存在副作用的机会。然而,辣椒碱应维持在阻止滥用的范围内。应当避免过多的辣椒碱,因为它可以产生将胜过阻止滥用作用的镇痛效益。然而,辣椒碱含量应当足够高以克服片剂中其他组分可能产生的掩蔽作用。无论何种情形,本发明在片剂产生成瘾剂量中提供阻止量的辣椒碱,从而阻止滥用。
由于辣椒碱对粘膜和血管粘膜来说非常刺激,极其少量的辣椒碱将会有效。已经证明当引入到人的鼻粘膜中时仅75微克就可引起分泌、喷嚏和/或咳嗽。所需辣椒碱的最小量可以受到许多因素的影响,包括药物组分的相对强度,和其他片剂组分的掩蔽作用。由于一些药物更加可能提供一种特定途径被滥用,所以当决定如何最好地将辣椒碱引入到片剂时也可以考虑最潜在的滥用途径。经鼻内滥用的药物可能需要的辣椒碱量不同于经静脉内或经口服滥用所需要的。
表1举例说明以不同片剂制剂中含有阿片样物质、羟氢吗啡酮和辣椒碱的优选组合物。其他片剂组分没有包括在该表中。IR是指即时释放制剂且ER是指长效释放制剂。在羟氢吗啡酮的情况中,当最小下列是2.5mg时,优选辣椒碱少于125微克。该量应当足以阻止滥用同时很好地处于口服和胃肠道可接受性的范围内。可以采用高于此用量的量,但小于125微克的量应足以阻止滥用。
表1 羟氢吗啡酮含量(mg)和优选的辣椒碱含量(mg)
羟氢吗啡酮IR辣椒碱 | 2.5mg<0.125mg | 5mg<0.25mg | 10mg<0.5mg | |||
羟氢吗啡酮ER辣椒碱 | 5mg<0.25mg | 10mg<0.5mg | 20mg<1.0mg | 40mg<2.0mg | 80mg<4.0mg | |
羟氢吗啡酮ER辣椒碱 | 10mg<0.5mg | 20mug<1.0mg | 40mg<2.0mg | 80mg<4.0mg |
如上所述,在确定辣椒碱的量时考虑包括药物组分的量及其强度。由于羟氢吗啡酮是一种更强的阿片样物质,小于125微克辣椒碱的优选量,应当在含有其他低效阿片样物质或其他药物的片剂中有效。然而,可以采用更多的辣椒碱,尤其是当考虑较高的最小剂量时。譬如,如果低效药物组分以5mg存在,辣椒碱优选以小于250mg微克存在,并且可以在125微克或更少下奏效。此外,在片剂中更多的阿片样物质使该片剂更可能被滥用,由此更加需要应用本发明。
如上所述,本发明的目的是制备片剂,该片剂在使用时给滥用者带来疼痛,并且由此阻止这样的滥用。试滥用可以是经鼻(通过喷鼻)或静脉内(通过注射)。由于鼻道的敏感性,当在较低浓度时就出现鼻子不适。然而,辣椒碱生物碱单用可能带来问题。也就是,阿片样物质一般是水溶性的,而辣椒碱不是。辣椒碱和辣椒碱生物碱趋于疏水性。由此,辣椒碱通过注射或通过将片剂溶解随后鼻内给药的单独使用可能对滥用无效。
当含有阿片样物质和辣椒碱的片剂溶解在水中时,辣椒碱将沉淀同时阿片样物质溶解。随后分离该液体并注射或喷鼻,残留下辣椒碱。这就破坏了辣椒碱的抗滥用目的。这个问题通过向该片剂中加入乳化剂来解决。当将片剂溶解时,乳化剂使辣椒碱保留在溶液内从而在如果喷鼻或注射时起效。需要多少乳化剂将依赖于所用的乳化剂和具体使用的辣椒碱生物碱。
然而,对于辣椒碱和十二烷基硫酸钠,测定下列比例有效。
十二烷基硫酸钠(mg) | 辣椒碱(mg) |
0.56 | 忽略 |
1.06 | 0.014 |
2.06 | 0.133 |
3.06 | 0.259 |
4.00 | 0.298 |
5.06 | 0.364 |
这些比例是通过测试多少辣椒碱保留在具有不同浓度的十二烷基硫酸钠的溶液内而不沉淀出来来测定得到的。所示十二烷基硫酸钠是最小量。如果使用附加十二烷基硫酸钠,本发明将仍然实施。在实践中,应使用过量的乳化剂来确保有足够的乳化剂来乳化所有辣椒碱。另外,乳化剂的缺点将不会造成本发明无法实施。更准确地说可以减弱其效果。
任何适当的乳化剂可以用于本发明的片剂中。适当的乳化剂包括,但不限于,硬脂酸盐例如硬脂酸钠,脱水山梨糖醇一硬脂酸酯和脱水山梨糖醇三硬脂酸酯,甘油一酯和二酯,月桂硬脂酸酯(盐),油酸酯(盐),二醇类,或docusate钠。
这个优选实施方式讨论了辣椒碱和羟氢吗啡酮的本发明组合物,虽然其他阿片样物质和非阿片样物质可以用作有效药物组分。本发明所述的,不限于在此公开的具体组合物,但对于多种具有潜在滥用的药物化合物是有效的。此外,滥用阻止药物不限于引起灼伤感的化合物,而优选辣椒碱生物碱和辣椒碱类似物。
如上面描述的,所述的滥用阻止药物(辣椒碱或其他刺激物)可以直接与活性药物组分一起掺混在药学可接受基质中,或者该药物可以掺混在单独的基质中或包封。当滥用阻止药物被掺混在独立的基质中时,该药物的量可以明显增加,但在滥用阻止量的范围内。应当注意,滥用者得到的滥用阻止药物的量(在辣椒碱或辣椒碱生物碱的情形中)也可以通过片剂中乳化剂的量来控制。通过使乳化剂保持在正确的水平,可以提高滥用阻止药物在片剂中的量,但不达到滥用者给药中的过量药物。这是因为过量的辣椒碱生物碱在片剂溶解时会沉淀出来。
所述的滥用阻止药物可以掺混在不释放该药物基质中直至该基质经压碎被破坏,或者可以形成微囊,其同样不释放该药物直至被压碎。由于该药物不释放给合法使用者,所以药物的量可以高于可掺混在标准片剂中的水平。
在本发明的这个实施方式中,辣椒碱生物碱含在与阿片样物质分开的基质内。这种独立基质可以以多种不同的方式形成。一种适当的结构是均匀控释基质并且阿片样物质拮抗剂分散在其中。控释基质配制且制粒成为极小的颗粒。这些颗粒随后掺混在片剂的主基质中。以这种方式,辣椒碱生物碱含在构成整个片剂的组成部分的独立控释基质内。在消化时,含有阿片样物质的主基质,溶解,释放阿片样物质并且也释放出在固体少释或非释放基质内含有辣椒碱生物碱的颗粒。该颗粒随后穿过并排出机体,仅仅释放出少量的辣椒碱生物碱,或者完全不释放。
本发明片剂的另一种可能构造是将辣椒碱生物碱掺混在即时释放基质中。该基质可以随后制粒并用非释放包衣例如丙烯酸聚合物涂层。所述的颗粒随后掺混在即时释放或控释阿片样物质片剂中。在给药时,所述的片剂以预定速率释放阿片样物质,但包衣颗粒不释放辣椒碱生物碱。合适地,所述的颗粒穿过消化道并从患者中消除。以这种方式,包衣颗粒发挥赋形剂的作用并且,在正常情况下,没有任何药理学作用。任何适当的控释或即时释放基质可以用于辣椒碱生物碱,只要与适当的非释放包衣一起使用。
或者,利用即时释放基质可以生成低释放速率颗粒并用低释放速率包衣包围生成的颗粒,虽然本发明的说明书在一个实施方式中描述了“非释放”基质,但在说明“非释放”处可以发生辣椒碱生物碱的某种渗漏。所以,在此使用的“非释放”的定义,应当包括任何在正常的口服给药条件下减少释放的基质,其在口服给药的正常条件下在约12小时内释放少于20%的辣椒碱生物碱。显然,在此所述的“非释放”基质无一用于完全包封辣椒碱生物碱从而防止片剂被粉碎或注射时释放。此外,适当的非释放包衣可以在含辣椒碱生物碱的粒状基质上用若干已知包衣共同形成。例如,含辣椒碱生物碱的颗粒可以被只能够在pH小于5(或3)的释放材料的包衣覆盖,其随后被只能够在pH大于5(或7或9)的释放材料的包衣覆盖。通过这种方式,当该片剂被摄取,外包衣防止该材料的释放同时颗粒残留在胃中,并且一旦该片剂穿过胃进入肠道内包衣防止材料的释放,其中pH升高到足以溶解外包衣。所属领域技术人员能够配制适合本发明片剂的适当基质。
辣椒碱生物碱无需完全包封成为惰性。可能希望允许一些辣椒碱生物碱的释放,如果少量将通过协同作用来提高阿片样物质的有效性。所以,依赖于制剂,包封可以提供多种的不同辣椒碱生物碱的释放
最优选使用本发明含有存在高滥用潜在性的阿片样物质的片剂。本发明使用的阿片样物质激动剂如上所述且可以是一般用作镇痛剂的激动剂,优选包括吗啡、羟考酮、氢可酮、可待因、二氢可待因、二氢吗啡酮、丙氧芬、美沙酮,和羟氢吗啡酮。具体而言,任何以口服片剂形式成瘾的阿片样物质是本发明的靶向。更加具体地,控释羟氢吗啡酮目前成为滥用的目标且因此成为应用本发明的良好候选物。然而,虽然控释片成为非常新的问题,但本发明的片剂可以用于即时释放片和控释形式中,如上所述。
本发明的片剂用于可滥用的药物,主要是阿片样物质。所述片剂的其他方面应当仍然与目前制备的片剂相同。此外,作为现有技术的阿片样物质片剂,本发明的片剂可以是组合片,包括其他药物例如对乙酰氨基酚、阿斯匹林、萘普生钠、布洛芬,其他甾族和非甾族抗炎药、COX-2抑制剂、加巴喷丁、pregabalin或其他类似药物。
Claims (28)
1.一种组合物含有:
药学活性组分;
辣椒碱生物碱;
其中该组合物用于后续配制为选自固体口服剂型和透皮剂型的最终剂型;和
其中该辣椒碱生物碱以使该最终剂型在与粘膜或血管膜接触时含有有效引起至少一种选自咳嗽、喷嚏、分泌和疼痛的反应的量存在。
2.权利要求1的组合物,其中该药物活性成分是阿片样物质。
3固体口服给药组合物含有:
有效量的药学活性成分;和
当与粘膜或血管膜或皮肤或肌肉接触时有效引起至少一种选自咳嗽、喷嚏、分泌和疼痛的反应的量的辣椒碱生物碱。
4.权利要求3的固体口服给药组合物,其中该药物活性成分是阿片样物质。
5.权利要求4的组合物,其中该阿片样物质选自羟考酮、二氢吗啡酮和羟氢吗啡酮。
6.权利要求5的组合物,其中该阿片样物质以2.5mg存在且该辣椒碱以少于0.125mg存在。
7.权利要求5的组合物,其中所述的阿片样物质以5.0mg存在且该辣椒碱以少于0.250mg存在。
8.权利要求5的组合物,其中所述的阿片样物质以10mg存在且该辣椒碱以少于0.5mg存在。
9.权利要求5的组合物,其中所述的阿片样物质以20mg存在且该辣椒碱以少于1.0mg存在。
10.权利要求5的组合物,其中所述的阿片样物质以40mg存在且该辣椒碱以少于2.0mg存在。
11.权利要求5的组合物,其中所述的阿片样物质以80mg存在且该辣椒碱以少于4.0mg存在。
12.一种固体口服给药组合物含有:
多个有效剂量的一种药学活性成分;
对于多个药学剂量之一的所述药学活性成分来说当与粘膜或血管膜接触时有效引起至少一种选自咳嗽、喷嚏、分泌和疼痛的反应的量的辣椒碱生物碱。
13.权利要求12的组合物,其中该组合物是控释制剂。
14.权利要求12的固体口服给药组合物,其中该药学活性成分是阿片样物质。
15.权利要求12的组合物,其中该阿片样物质是羟氢吗啡酮。
16.权利要求12的组合物,其中羟氢吗啡酮以10mg存在且该辣椒碱以少于0.5mg存在。
17.权利要求12的组合物,其中羟氢吗啡酮以20mg存在且该辣椒碱以少于1.0mg存在。
18.权利要求12的组合物,其中所述的羟氢吗啡酮以40mg存在且该辣椒碱以少于2.0mg存在。
19.权利要求12的组合物,其中所述的羟氢吗啡酮以80mg存在且该辣椒碱以少于4.0mg存在。
20.权利要求2的组合物,其中所述的辣椒碱直接掺混在含有所述阿片样物质的基质中
21.权利要求2的组合物,其中所述的辣椒碱掺混在与所述活性成分基质分开的第二基质中。
22.权利要求2的组合物,其中所述的辣椒碱包封在当该组合物经口服给药时不正常释放所述辣椒碱的材料内。
23.权利要求22的组合物,其中辣椒碱包封在当经口服给药时在12小时内释放仅20%的材料内。
24.权利要求1的组合物,其中所述的辣椒碱生物碱包封在在当经口服给药时在12小时内释放不超过20%的材料内。
25.权利要求2的组合物,其中所述的药学活性成分选自阿片样物质、非甾族抗炎药(NSAID类)、COX-1和COX-2抑制剂、苯并二氮杂卓类,和NMDA拮抗剂。
26.一种组合物含有:
药学活性成分;
组胺;
其中该组合物用于后续配制为选自固体口服剂型和透皮剂型的最终剂型。
27.权利要求26的组合物,其中所述的药学活性成分是阿片样物质。
28.权利要求27的组合物,其中所述的组胺包封在当该组合物经口服给药时不正常释放所述辣椒碱的材料内。
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2002
- 2002-04-08 US US10/118,110 patent/US20030064122A1/en not_active Abandoned
- 2002-05-16 CN CNA028103890A patent/CN1511030A/zh active Pending
- 2002-05-16 DE DE60231298T patent/DE60231298D1/de not_active Expired - Fee Related
- 2002-05-16 CA CA002447807A patent/CA2447807C/en not_active Expired - Fee Related
- 2002-05-16 EP EP02736910A patent/EP1392270B1/en not_active Expired - Lifetime
- 2002-05-16 ES ES02736910T patent/ES2321589T3/es not_active Expired - Lifetime
- 2002-05-16 WO PCT/US2002/015553 patent/WO2002094254A2/en active Application Filing
- 2002-05-16 AT AT02736910T patent/ATE423556T1/de not_active IP Right Cessation
- 2002-05-16 AU AU2002309885A patent/AU2002309885B2/en not_active Ceased
- 2002-05-16 JP JP2002590972A patent/JP4315687B2/ja not_active Expired - Fee Related
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2009
- 2009-04-08 JP JP2009094439A patent/JP2009149696A/ja active Pending
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EP1392270B1 (en) | 2009-02-25 |
US20030064122A1 (en) | 2003-04-03 |
DE60231298D1 (de) | 2009-04-09 |
EP1392270A2 (en) | 2004-03-03 |
WO2002094254A3 (en) | 2003-03-27 |
JP2005515153A (ja) | 2005-05-26 |
CA2447807A1 (en) | 2002-11-28 |
JP2009149696A (ja) | 2009-07-09 |
JP4315687B2 (ja) | 2009-08-19 |
WO2002094254A2 (en) | 2002-11-28 |
CA2447807C (en) | 2009-10-13 |
ATE423556T1 (de) | 2009-03-15 |
ES2321589T3 (es) | 2009-06-09 |
AU2002309885B2 (en) | 2007-11-01 |
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