CN1863513A - 防止滥用的剂型 - Google Patents
防止滥用的剂型 Download PDFInfo
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Abstract
本发明涉及一种不被挤出的热成型的防止滥用的安全的剂型,它包括除了具有可能被滥用的一种或几种活性成分外,还包括至少一种具有至少500N的断裂强度的合成的或天然的聚合物,和任选地生理上可接受辅剂。本发明还涉及制造所述剂型的对应的方法。
Description
本发明涉及一种经挤出而不脱色的热成型的防止滥用的剂型,它包括除了一种或多种具有滥用可能性的活性成分(A)以及任选地生理可接受的辅助物质(B)外,还包括至少一种合成的或天然的聚合物(C)以及任选地至少一种蜡(D),其中组分(C)和任选地存在的组分(D)均显示至少500N的断裂强度。本发明还涉及根据本发明的剂型的制备方法。
许多药物活性物质除了在它们适合的用途中具有的优良活性外,还具有被滥用的可能,即它们可以被滥用者使用而产生不是预期的效果。例如,对于抵御十分剧烈的疼痛具有很强的活性的鸦片,经常被滥用者用于产生麻醉或欣快的状态。
为了使滥用成为可能,对应的剂型,如片剂或胶囊被滥用者粉碎,例如在研钵中研碎,用优选的含水的液体将活性成分从得到的粉末中提取出来,并且将得到的溶液任选地通过棉绒或纤维素填充物进行过滤后,被非肠道,特别是静脉给药。与滥用的口服给药相比,这种给药方式的另一个现象是进一步加快了活性成分水平的提高,给滥用者所需要的效果,即“突跳”或“冲击”。如果这种粉末药剂经鼻给药,即吸入的话,也可以获得这种突跳。即使口服滥用大量的的含有滥用可能性的活性成分的剂型也不能使滥用者产生所需要的突跳。为了被滥用,这种剂型也被粉碎并且进行提取。
US-A4070494建议向剂型中增加一种可膨胀的制剂以防止滥用。当添加水来提取活性成分时,这种制剂膨胀并且确保从凝胶中分离出来的滤液仅含有少量的活性成分。
在WO 95/20947中公开的多层片剂是基于与防止非肠道滥用的相似的方法,所述的片剂含有可能滥用的活性成分和至少一种凝胶形成剂,每一种在不同的层。
WO 03/015531 A2公开了防止非肠道滥用的另一种方法。其中描述了含有鸦片与作为嫌恶剂的染料的剂型。释放颜色使剂型改变的目的是防止滥用者使用已被改变的剂型。
另一种使滥用复杂化的公知的方案包括将活性成分的拮抗剂添加到剂型中,如就鸦片来说的纳洛酮或纳曲酮,或引起生理性防御反应的化合物,如吐根(吐根)的根。
然而,因为在多数滥用的情况下将包括适于滥用的活性成分的剂型进行粉碎仍然是必要的,所以本发明的目的是使可能的滥用者通常使用的将剂型粉碎滥用的方法复杂化或予以阻止,并且相应提供一种用于具有滥用可能性的活性成分的剂型。它确保了当正确给药时,达到需要的治疗效果。但是,活性成分不能通过简单的粉碎转变成适于滥用的剂型。
所述的目的已经通过提供根据本发明提供的通过挤出不脱色的热成型的防止滥用的剂型而达到,该剂型包括除了一种或多种具有滥用可能性的活性成分(A)外;还包括至少一种合成的或天然的聚合物(C)以及任选地至少一种蜡(D),其中组分(C)和任选地存在的组分(D)均显示至少500N的断裂强度。
使用具有所述的最小断裂强度(如本申请所述测量的)的聚合物,优选其数量使该剂型也显示这样的至少500N的最小断裂强度,这意味着将该剂型用常规的方法进行粉碎是相当难的。因此,使随后的滥用相当地复杂或阻止其滥用。
如果粉碎不完全,则非肠道,尤其是静脉给药不能安全进行或者活性成分的提取对于滥用者来说需花太长时间,或者当被口服时没有“突跳”,因为释放不是同时的。
根据本发明,粉碎是指采用滥用者可利用的常规的粉碎方式,如研钵和研杵、锤子、短锤或其他用力粉碎的常用工具将剂型粉末化。
根据本发明的剂型适于防止活性成分,优选具有滥用可能性的药物活性成分的非肠道、经鼻和/或经口的滥用。
具有滥用可能性的药物活性成分如它们的用量和制备方法是本领域技术人员公知的,而且它们也可以以根据本发明的剂型形式存在,如它们的对应的衍生物、特别是酯或醚;或在每种情况下的对应的生理上可接受的化合物,特别是它们的盐或溶剂化物形式以及外消旋体或立体异构体。根据本发明的剂型也适合施用在一种剂型中两种或多种药物活性成分。该剂型优选仅包括一种特定的活性成分。
根据本发明的剂型特别适合防止选自类鸦片、安定剂,优选苯并二氮杂类、巴比妥盐、刺激剂和其它的麻醉剂的药物活性成分的滥用。
根据本发明的剂型也特别适合防止类鸦片、安定剂或另一种选自下列的麻醉剂:N-{1-[2-(4-乙基-5-氧基-2-四唑啉-1-基)乙基]-4-甲氧基甲基-4-哌啶基}-N-丙酰苯胺(阿芬他尼)、5,5-二烯丙基巴比妥酸(阿洛巴比妥)、烯丙罗定、阿法罗定、8-氯-1-甲基-6-苯基-4H-[1,2,4]三唑[4,3-a][1,4]-苯并二氮杂(三唑安定)、2-二乙基氨基苯并·乙基(甲)酮(二乙氨苯丙酮)、(±)-a-甲基-苯乙胺(苯丙胺)、2-(a-甲基苯乙氨基)-2-苯基丙酮腈(amphetaminil)、5-乙基-5-异戊基巴比妥酸(异戊巴比妥)、阿尼利定、阿扑可待因、5,5-二乙基巴比妥酸(巴比妥钠)、苄基吗啡、bezitramide、7-溴-5-(2-吡啶)-1H-1,4-苯并二氮杂-2(3H)-酮(溴吡二氮杂)、2-溴-4-(2-氯苯基)-9-甲基-6H-噻吩并[3,2-f][1,2,4]三唑-[4,3-a][1,4]二氮杂草(溴替唑仑)、17-环丙基甲基-4,5a-环氧基-7a[(S)-1-羟基-1,2,2-三甲基-丙基]-6-甲氧基-6,14-内-桥亚乙基吗啡喃-3-醇(丁丙诺啡)、5-丁基-5-乙基巴比妥酸(丁巴比妥)、丁啡喃、(7-氯-1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂-3-基)二甲基氨基甲酸酯(卡马西泮)、(1S,2S)-2-氨基-1-苯基-1-丙醇(去甲伪麻黄碱/D-去甲伪麻黄碱)、7-氯-N-甲基-5-苯基-3H-1,4-苯并二氮杂-2-基胺-4-氧化物(甲氨二氮杂)、7-氯-1-甲基-5-苯基-1H-1,5-苯并二氮杂-2,4(3H,5H)-二酮(氧异安定)、5-(2-氯苯基)-7-硝基-1H-1,4-苯并二氮杂-2(3H)-酮(氯硝西泮)、氯尼他秦、7-氯-2,3-二氢-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-羧酸(氯氮杂)、5-(2-氯苯基)-7-乙基-1-甲基-1H-噻吩并[2,3-e][1,4]二氮杂-2(3H)-酮(clotiazepam)、10-氯-11b-(2-氯苯基)-2,3,7,11b-四氢化唑-[3,2-d][1,4]苯并二氮杂-6(5H)-酮(氯羟喹)、(-)-甲基-[3β-苯甲酸基-2β(1aH,5aH)-托烷羧酸酯](可卡因)、4,5a-环氧基-3-甲氧基-17甲基-7-吗啡喃-6a-醇(可待因)、5-(1-环己基)-5-乙基巴比妥酸(环巴比妥)、cyclorphan、环丙诺啡、7-氯-5-(2-氯苯基-1H-1,4-苯并二氮杂-2(3H)-酮(地洛西泮)、地索吗啡、右吗拉胺、吗拉胺、(+)-(1-苄基-3-二甲基氨基-2-甲基-1-苯丙基)丙酸酯(右丙氧芬)、地佐辛、diampromide、diamorphone、7-氯-1-甲基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(安定)、4,5a-环氧基-3-甲氧基-17-甲基-6a-吗啡醇(二氢可待因)、4,5α-环氧基-17-甲基-3,6a-吗啡二醇(二氢吗啡)、dimenoxadol、地美庚醇、二甲基thiambutene、dioxaphetylbutyrate、dipipanone、(6aR,10aR)-6,6,9-三甲基-3-戊基-6a,7,8,10a-四氢-6H-苯并[c]色烯-1-醇(dronabinol)、eptazocine、8-氯-6-苯基-4H-[1,2,4]三唑[4,3-a][1,4]苯并二氮杂(艾司唑仑)、乙痛新、乙基甲基thiambutene、乙基[7-氯-5-(2-氟苯基)-2,3-二氢-2-氧代-1H-1,4-苯并二氮杂-3-羧酸酯](乙基loflazepate)、4,5a-环氧基-3-乙氧基-17-甲基-7-吗啡喃-6α-醇(乙基吗啡)、etonitazene、4,5α-环氧基-7α-(1-羟基-1-甲基丁基)-6-甲氧基-17-甲基-6,14-内-亚乙烯基-吗啡喃-3-醇(埃托酚)、N-乙基-3-苯基-8,9,10-三降冰片基-2-基胺(fencamfamine)、7-[2-(α-甲基-苯乙氨基)-乙基]-茶碱)(芬乙茶碱)、3-(α-甲基苯乙氨基)丙腈(fenproporex)、N-(1-苯乙基-4-哌啶)丙腈(芬太尼)、7-氯-5-(2-氟苯基)-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(氟代苯甲二氮杂)、5-(2-氟苯基)-1-甲基-7-硝基-1H-1,4-苯并二氮杂-2(3H)-酮(氟硝西泮)、7-氯-1-(2-二乙基氨基乙基)-5-(2-氟苯基)-1H-1,4-苯并二氮杂-2(3H)-酮(氟胺安定)、7-氯-5-苯基-1-(2,2,2-三氟乙基)-1H-1,4-苯并二氮杂-2(3H)-酮(哈拉西泮)、10-溴-11b-(2-氟苯基)-2,3,7,11b-四氢[1,3]唑[3,2-d][1,4]苯并二氮杂-6(5H)-酮(haloxazolam)、海洛因、4,5α-环氧基-3-甲氧基-17-甲基-6-吗啡喃酮(氢可酮)、4,5α-环氧基-3-甲氧基-17-甲基-6-吗啡喃酮(氢化吗啡酮)、羟基哌替啶、异美沙酮、羟甲基morphinane、11-氯-8,12b-二氢-2,8-二甲基-12b-苯基-4H-[1,3]]嗪[3,2-d][1,4]苯并二氮杂-4,7(6H)-二酮(凯他唑仑)、1-[4-(3-羟苯基-1-甲基-4-哌啶)-1-丙酮(凯托朱酮)、(3S,6S)-6-二甲基氨基-4,4-二苯基庚烷-3-基乙酸酯(levacetylmethadol(LAAM))、(-)-6-二甲基-氨基-4,4-二酚基-3-庚酮(levomethadone)、(-)-17-甲基-3-吗啡喃醇(左啡诺)、左苯甲酰基吗啡、lofentanil、6-(2-氯苯基)-2-(4-甲基-1-哌嗪亚甲基)-8-硝基-2H-咪唑并[1,2-a][1,4]-苯并二氮杂-1(4H)-酮(氯普唑仑)、7-氯-5-(2-氯苯基)-3-羟基-1H-1,4-苯并二氮杂-2(3H)-酮(lorazepam)、7-氯-5-(2-氯苯基)-3-羟基-1-甲基-1H-1,4苯并二氮杂-2(3H)酮(lormetazepam)、5-(4-氯苯基)-2,5-二氢-3H-咪唑并[2,1-a]异吲哚-5-醇(马吲哚)、7-氯-2,3-二氢-1-甲基-5-苯基-1H-1,4-苯并二氮杂(去氧安定)、N-(3-氯丙基)-α-甲基苯乙基氨基(美芬雷司)、哌替啶、2-甲基-2-丙基三亚甲基二氨基甲酸酯(异丙基眠尔通)、美普他酚、美他佐辛、甲基吗啡、N,α-二甲基苯乙胺(脱氧麻黄碱)、(±)-6-二甲基氨基-4,4-二苯基-3-庚酮(美沙酮)、2-甲基-3-O-甲苯基-4(3H)-喹唑啉酮(安眠酮)、甲基[2-苯基-2-(2-哌啶基)乙酸酯](苯哌啶醋酸甲酯)、5-乙基-1-甲基-5-苯基巴比妥酸(甲苯巴比妥)、3,3-二甲基-5-甲基-2,4-哌啶二酮(甲普龙)、美托酮、8-氯-6-(2-氟苯基)-1-甲基-4H-咪唑并[1,5-a][1,4]苯并二氮杂(咪达唑仑)、2-(二苯甲基亚硫酰基)-乙酰胺(莫达非尼)、4,5α-环氧基-17-甲基-7-吗啡喃-3,6α-二醇(吗啡)、myrophine、(±)-反-3-(1,1-二甲基庚基)-7,8,10,10α-四氢-1-羟基-6,6-二甲基-6H-二苯并[b,d]吡喃-9(6αH)-酮(nabilone)、环丁甲羟氢吗啡、烯丙吗啡、那碎因、尼可吗啡、1-甲基-7-硝基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(硝甲西泮)、7-硝基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(硝西泮)、7-氯-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(去甲西泮)、去甲左啡诺、6-二甲基氨基-4,4-二苯基-3-己酮(normethadone)、诺吗啡、诺匹哌酮、属于Papaver sommniferum(鸦片)种的植物的渗出物、7-氯-3-羟基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(奥沙西泮)、(顺-反-10,氯-2,3,7,11b-四氢-2-甲基-11b-苯唑[3,2-d][1,4]苯并二氮杂-6-(5H)-酮(oxazolam)、4,5α-环氧基-14-羟基-3-甲氧基-17-甲基-6-吗啡喃酮(羟考酮)、oxymorphone、属于Papaver sommniferum(包括setigerum亚种)种的植物和植物部分、阿片全碱、2-亚氨基-5-苯基-4-唑酮(pernoline)、1,2,3,4,5,6-六氢-6,11-二甲基-3-(3-甲基-2-丁烯基)-2,6-亚甲基-3-苯并氮杂因-8-醇(镇痛新)、5-乙基-5-(1-甲基丁基)-巴比妥酸(戊巴比妥)、乙基(1-甲基-4-苯基-4-哌啶羧酸酯)(哌替啶)、非那多松、非诺啡烷、非那唑辛、苯哌利定、去痛定、pholcodine、3-甲基-2-苯基吗啉(芬美曲嗪)、5-乙基-5-苯巴比妥酸(苯巴比妥)、α,α-二甲基苯乙胺(苯丁胺)、7-氯-5-苯基-1-(2-丙炔基)1H-1,4-苯丙二氮杂-2(3H)-酮(匹那西泮)、α-(2-哌啶)二苯甲醇(哌苯甲醇)、1’-(3-氰基-3,3-二苯基丙基)[1,4’-二哌啶]-4’-酰胺(哌嗪米特)、7-氯-1-(环丙基甲基)-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(环丙二氮杂)、普罗法朵、普罗庚嗪、二甲哌替啶、丙哌利啶、propoxyphene、N-(1-甲基-2-哌啶乙基)N-(2-吡啶)丙酰胺、甲基{3-[4-甲氧基羰基-4-(N-苯基丙氨基)哌啶]丙酸酯}(remifentanil)、5-仲-丁基-5-乙基巴比妥酸(secbuta巴比妥)、5-烯丙基-5-(1-甲基丙基)-巴比妥酸(司可巴比妥)、N-{4-甲氧基甲基-1-[2-(2-噻吩基)乙基]-4-哌啶}-N-丙酰苯胺(sufentanil)、7-氯-2-羟基-甲基-5-苯基-1H-苯并二氮杂-2(3H)-酮(羟基安定)、7-氯-5-(1-环己基)-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(tetrazepam)、乙基(2-二甲基氨基-1-苯基-3-环己烯基-1-羧酸酯)(替立定(顺式和反式))、曲蚂多、8-氯-6-(2-氯苯基)-1-甲基-4H-[1,2,4]三唑[4,3-a][1,4]苯并二氮杂(三唑苯并二氮杂)、5-(1-甲基丁基)-5-乙烯基巴比妥酸(vinylbital)、(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-酚、(1R,2R,4S)-2-(二甲基氨基)甲基-4-(对-氟苄氧基)-1-(间-甲氧基苯基)环己醇、(1R,2R)-3-(2-二甲基氨基-甲基环己基)酚、(1S,2S)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)酚、(2R,3R)-1-二甲基氨基-3(3-甲氧基苯基)-2-甲基-戊基-3-醇、(1RS,3RS,6RS)-6-二甲基氨甲基-1-(3-甲氧基苯基)-环己基-1,3-二醇,优选外消旋体、3-(2-二甲基氨甲基-1-羟基-环己基)苯基2-(4-异丙基-苯基)-丙酸酯、3-(2-二甲基氨甲基-1-羟基-环己基)2-(6-甲氧基-萘-2-基)-丙酸酯、3-(2-二甲基氨基-甲基-环己基-1-烯基)苯基2-(4-异丙基-苯基)-丙酸酯、3-(2-二甲基氨甲基-环己基-1-烯基)-苯基2-(6-甲氧基-萘基-2-基)-丙酸酯、(RR-SS)-2-乙酸基-4-三氟甲基-苯甲酸3-(2-二甲基氨甲基-1-羟基-环己基)-苯酯、(RR-SS)-2-羟基-4-三氟甲基-苯甲酸3-(2-二甲基氨甲基-1-羟基-环己基)-苯酯、(RR-SS)-4-氯-2-羟基-苯甲酸3-(2-二甲基氨甲基-1-羟基-环己基)苯酯、(RR-SS)-2-羟基-4-甲基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)苯酯、(RR-SS)-2-羟基-4-甲氧基--苯甲酸3-(2-二甲基氨甲基-1-羟基-环己基)苯酯、(RR-SS)-2-羟基-5-硝基-苯甲酸3-(2-二甲基氨甲基-1-羟基-环己基)苯酯、(RR-SS)-2’,4’-二氟-3-羟基-二苯基-4-羧酸3-(2-二甲基氨甲基-1-羟基-环己基)苯酯和对应的立体异构化合物、它们每一种对应的衍生物,特别是酰胺、酯或醚、以及它们每一种的生理上可接受的化合物、特别是它们的盐和溶剂化物,特别优选盐酸盐。
根据本发明的剂型特别适合于防止选自羟考酮、氢化吗啡酮、吗啡和曲蚂多以及它们生理上可接受的衍生物或化合物,优选它们的盐和溶剂化物,优选盐酸盐的类鸦片活性成分的滥用。
根据本发明的药剂进一步特别适合于防止选自下列类鸦片活性成分的滥用:(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-酚、(2R,3R)-1-二甲基氨基-3-甲氧基-苯基)-2-戊烷-3-醇、(1RS,3RS,6RS)-6-二甲基氨基甲基-1-(3-甲氧基-苯基)-环己基-1,3-二醇、(1R,2R)-3-(2-二甲基氨基乙基-环己基)-酚、它们生理上可接受的盐和溶剂,优选盐酸盐、生理上可接受的对映异构体、立体异构体、非对映异构体、外消旋体以及它们的生理上可接受的衍生物,优选醚、酯或酰胺。
这些化合物及其制备方法被描述在EP-A-693475或EP-A-780369中。相应的说明在这里引作参考并且被视作公开的一部分。
为了得到根据本发明的剂型的必要的断裂强度,至少要使用一种合成的或天然的聚合物(C),该聚合物具有通过使用本申请公开的方法测量的至少500N的断裂强度。为了达到这个目的,使用至少一种选自聚环氧烷,优选聚氧亚甲基、聚环氧乙烷、聚环氧丙烷;聚乙烯、聚丙烯、聚氯乙烯、聚碳酸酯、聚苯乙烯、聚丙烯酸酯及其共聚物;优选至少两种所述的共聚物的混合物。优选热塑性的高分子量的聚环氧烷。特别优选通过流变测量的具有至少0.5兆,优选至少1兆至15兆的分子量的高分子量的聚环氧乙烷。这些聚合物的粘度用型号为RVF Brookfield的粘度计(转轴2号/转速2rpm)在5重量%的含水溶液中测量,在25℃下为4500-17600cP,用所述粘度计(转轴1号或3号/转速10rpm)在2重量%的含水溶液中测量粘度为400-4000cP或用所述粘度计(转轴2号/转速10rpm)在1重量%的含水溶液中测量粘度为1650-10000cP。
聚合物优选使用粉末形式。可以将它们溶解在水中。
为了得到根据本发明的剂型的必要的断裂强度,更可能另外使用至少一种天然的或合成的蜡(D),该蜡具有通过使用本申请公开的方法测量的至少500N的断裂强度。优选具有在至少60℃的软化点的蜡。巴西棕榈蜡和蜂蜡是特别优选的。巴西棕榈是更特别优选的。巴西棕榈蜡是从巴西棕榈的叶子中获得的天然蜡,具有在至少80℃的软化点。当该蜡成分被另外使用时,它与至少一种聚合物(C)一起使用,用量使该剂型具有至少500N的断裂强度。
相对于剂型的总重量,组分(C)的使用量优选为20-99.9重量%,特别优选至少30重量%,更特别优选至少40重量%。
可被使用的辅料物质(B)是那些用于配制固体剂型的常规的已知辅料物质。这些是优选的增塑剂,如聚乙二醇、影响活性成分释放的辅料物质,优选疏水性的或亲水性的,优选亲水性的聚合物,更特别优选羟丙基纤维素、和/或抗氧化剂。合适的抗氧化剂是抗坏血酸、丁基羟基苯甲醚、丁基羟基甲苯、抗坏血酸盐、一硫代甘油、亚磷酸、维生素C、维生素E及其衍生物、亚硫酸氢钠、特别优选丁基羟基甲苯(BHT)或丁基羟基苯甲醚(BHA)和α-生育酚。
相对于剂型的总重量,抗氧化剂的使用量优选0.01-10重量%,特别优选0.03-5重量%。
根据本发明的剂型的特征在于它们的硬度,它们不能被滥用者常规使用的粉碎用具粉碎,如研钵和研杵。这样实际上排除了口服或非肠道,特别是静脉或经鼻的滥用。然而,为了防止根据本发明的剂型的任何可能的滥用,在优选实施方式中,根据本发明的剂型可以进一步包含作为辅料物质(B)的使滥用复杂化或防止滥用的的制剂。
根据本发明的防止滥用的剂型除了一种或多种滥用可能性的活性成分外,还包含至少一种硬化的聚合物(C)和任选地至少一种蜡(D),也可以相应地含有至少一种下列的作为辅料物质(B)的组分(a)-(e):
(a)至少一种刺激鼻道和/或咽的物质;
(b)至少一种增粘剂,该增粘剂借助于必需的最小量的含水液体与从该剂型获得的提取物形成一种凝胶,该凝胶优选当将其加入到更多量的含水液体时,仍然能够被直观地识别出来。
(c)至少一种具有滥用可能性的活性成分的拮抗剂;
(d)至少一种催吐剂;
(e)至少一种作为嫌恶剂的染料;
(f)至少一种苦味物质。
组分(a)-(f)每一种是单独地另外适用于根据本发明的防止滥用的剂型。相应地,组分(a)优选适于防止鼻、口服和/或非肠道优选静脉滥用的剂型。组分(b)优选适于防止,特别优选静脉和/或鼻滥用的剂型。组分(c)优选适于防止鼻和/或非肠道,特别优选静脉滥用的剂型。组分(d)优选适于防止非肠道,特别优选静脉和/或口服和/或鼻滥用的剂型。组分(e)适于作为可视的防止口服或非肠道滥用的阻滞剂。组分(f)适于防止口服或鼻的滥用的剂型。将至少上述提到的一种组分的根据本发明结合使用使更有效地防止根据本发明的剂型的滥用成为可能。
在一个实施方式中,根据本发明的剂型也可以包含组分(a)-(f)的两种或多种的组合,优选(a)、(b)和任选地(c)和/或(f)和/或(e);或(a)、(b)和任选地(d)和/或(f)和/或(e)。
在另一个实施方式中,根据本发明的剂型可以包含所有的(a)-(f)组分。
如果为防止滥用根据本发明的剂型包括组分(a),则根据本发明被视为刺激鼻道和/或咽的物质是那些当通过鼻道和/或咽给药时,引起生理反应的任何物质,所述生理反应既可以是使滥用者不愉快以致于他/她不希望或不能继续服用,如灼烧,也可以是服用了对应的活性成分的生理抵抗反应,如由此增加了鼻分泌物或打喷嚏。当这些常规刺激鼻道和/或咽的物质通过非肠道,特别是静脉给药时,可以引起非常不愉快的感觉,甚至不能忍受,使得滥用者不希望或不能继续服用该物质。
刺激鼻道和/或咽的物质特别合适的物质是那些引起灼烧、痒、想打喷嚏、增加分泌物或这些刺激中至少两种的组合的物质。常规使用的合适的物质和含量对于技术人员来说是已知的或可以通过简单初步测试鉴定的。
组分(a)的刺激鼻道和/或咽的物质优选基于一种或多种成分、或一种或多种至少一种热物质药物的植物部分。
对应的热物质药物对于本领域技术人员来说是已知的,并且在由Hildebert Wagner教授博士所著的“Pharmazeutische Biologie-Drogenund ihre Inhaltsstoffe”第二版,修订版,Gustav Fischer Verlag,Stuttgart-New York,1982,82页,et seq..中进行了描述。那里对应的描述被引作参考,并且被视为公开的一部分。
剂量单位是指分离的或可分离的给药单位,如片剂或胶囊。
可以将至少下列一种热物质药物中的一种或多种成分作为组分(a)添加到根据本发明的剂型中:Allii sativi bulbus(蒜)、Asari rhizomacum herba(细辛根和叶)、Calami rhizoma(菖蒲根)、Capsici fructus(辣椒)、Capsici fructus acer(番椒)、Curcumae longae rhizoma(郁金香根)、Curcumae xanthorrhizae rhizoma(Javanese郁金香根)、Galangae rhizoma(良姜根)、Myristicae semen(肉豆蔻)、Piperis nigrifructus(花椒)、Sinapis albae semen(白芥菜种子)、Sinapis nigri semen(黑芥菜种子)、Zedoariae rhizoma(蓬莪术根)和Zingiberis rhizoma(姜根)、特别优选选自Capsici fructus(辣椒)、Capsici fructus acer(cayenne番椒)和Piperis nigri fructus(番椒)的一种药物。
热物质药物的成分优选包括邻甲氧基(甲基)酚化合物、酰胺化合物、芥子油或硫化物或由它们衍生的化合物。
特别优选选自下列热物质药物的至少一种成分:肉豆蔻醚、榄香素、异丁香酚、β-细辛脑、黄樟脑、姜醇、黄根醇、capsaicinoids,优选辣椒碱、辣椒碱衍生物,如N-香草基-9E-十八烯酰胺、二氢辣椒碱、去甲二氢辣椒碱、高辣椒碱、去甲辣椒碱和nomor辣椒碱、胡椒碱,优选反-胡椒碱、硫代葡糖酸盐,优选基于非挥发的芥子油,特别优选基于对-羟苄基芥子油,甲基巯基芥子油或甲基磺酰芥子油和这些成分衍生的化合物。
根据本发明的剂型可以优选包含0.01-30重量%的对应的热物质药物的植物部分,特别优选包含0.1-0.5重量%,每一种相对于剂量单位的总重量。
如果使用对应的热物质药物的一种或多种成分,则在根据本发明的剂量单位中它们的含量优选为0.001-0.005重量%,相对于剂量单位的总重量。
根据本发明的防止剂型滥用的另一个方案在于将作为进一步防止滥用的组分(b)的至少一种增粘剂加入到剂型中,借助于必需的最少量的含水液体与从该剂型获得的提取物形成凝胶,该凝胶实质上不能安全服用,并且优选当将其加入到更多量的含水液体中时,可直观地识别出来。
为了达到本发明的目的,直观地识别是指将在借助于必需的最少量的含水液体所形成的含有活性成分的凝胶加入到,优选借助于皮下针在37℃下的更多量的含水液体时,该凝胶仍然基本上是不溶的,而且是粘性的,并且不能以一种可以被非肠道,特别是静脉内安全给药的方式被直接分散。这种材料优选保持至少1分钟,优选至少10分钟的直观识别。
提取物的增加的粘度使得它更难或者甚至不可能穿过针或被注射。如果凝胶是可直观识别的,这意味着将获得的凝胶加入到更多量的含水液体中,如注射到血液中时,开始它是大量的粘性的线的形式,它事实上可以被分解为更小的碎片,它不能被分散或者甚至以一种可以被非肠道,特别是静脉安全给药的方式被溶解。与至少一种任选存在的组分(a)-(e)组合,这又引起不愉快的灼烧、呕吐、口味差和/或可视的阻止。
将这样的凝胶静脉给药最可能导致血管阻塞,对滥用者的健康造成严重的伤害。
为了验证是否一种增粘剂适合用作根据本发明剂型的组分(b),将活性成分与增粘剂混合,并且悬浮在温度为25℃下的10ml的水中。如果这样形成的凝胶满足上述的条件,则对应的增粘剂适合用于防止或避免根据本发明的剂型的滥用。
如果将组分(b)添加到根据本发明的剂型中,则使用一种或多种选自下列的增粘剂:含有11重量%的羧甲基纤维素钠(AvicelRC591)的微晶纤维素、羧甲基纤维素钠(Blanose,CMC-Na C300P,Frimulsion BLC-5,Tylose C300P)、聚丙烯酸(Carbopol980NF,Carbopol981)、角豆粉(CesagumLA-200,CesagumLID/150,CesagumLN-1)、果胶,优选橘果或苹果(CesapectinHM MediumRapid Set)、蜡状的玉米淀粉(C*Gel 04201)、藻酸钠(FrimulsionALG(E401))、瓜耳胶粉(Frimulsion BM,Polygum 26/1-75)、iota角叉菜(Frimulsion D021)、刺梧桐树胶、胶凝糖树胶(KelcogelF,Kelcogel LT100)、半乳甘露聚糖(Meyprogat 150)、tara豆粉(Polygum 43/1)、丙二醇藻酸酯(Protanal-Ester SD-LB)、透明质酸钠、黄蓍胶、tara树胶(Vidogum SP 200)、发酵的多糖welan树胶(K1A96)、黄原酸胶(Xantural 180)。黄原胶是特别优选的。在括号中提及的名称是商业上已知材料的商标名。通常,0.1-20重量%,特别优选0.1-15重量%的所述的增粘剂足以满足上述的条件。
提供的组分(b)增粘剂优选以≥5mg每剂量单位,即每给药单位的数量存在于根据本发明的剂型中。
在本发明的一个特别的优选实施方式中,用作组分(b)的增粘剂是那些借助于必需的最少量的含水液体在从剂型的提取中形成的封有空气气泡的凝胶。得到的凝胶可以通过混浊现象识别,这样提供给可能的滥用者又一个视觉的警告,并且阻止他或她经过非肠道给药该凝胶。
组分(C)也可以任选地用作另一种借助于必需的最少量的含水液体形成凝胶的增粘剂。
在根据本发明的剂型中将增粘剂与其他的成分配制成在空间上排列成相互分离的方式也是可能的。
为了阻止和防止滥用,根据本发明的剂型可以更进一步地包含组分(c),即具有滥用可能性的那个或那些活性成分的一种或多种拮抗剂,其中拮抗剂优选在空间上与根据本发明的剂型的其余成分是分离的,并且当正确使用时它们不会产生任何作用。
用于防止活性成分滥用的合适的拮抗剂对于本领域技术人员本身是已知的,并且可以在根据本发明的剂型中以那样的形式存在,或以对应的衍生物,特别是酯或醚的形式、或在每种情形下以对应的生理上可接受的化合物,特别是以它们的盐或溶剂化物的形式存在。
如果存在在剂型中的活性成分是类鸦片,则所用的拮抗剂优选选自纳洛酮、纳曲酮、纳美芬、nalid、纳美酮、烯丙吗啡或naluphine,在每种情形下任选地以对应的生理上可接受的化合物形式,特别是以碱、盐或溶剂化物的形式存在。对应的拮抗剂,当提供组分(c)时,其优选用量≥1mg,特别优选3-100mg,更优选5-50mg每剂型,即每给药单位。
如果根据本发明的剂型包括作为活性成分的刺激剂,则该拮抗剂优选是安定药,优选至少一种选自氟哌啶醇、普鲁米近、氟奋乃静、奋乃静、甲氧异丁嗪、甲硫达嗪、培拉嗪、氯丙嗪、氯普噻吨、zuclopentixol、三氟噻醇、丙硫喷地、佐替平、benperidol、匹泮哌隆、美哌隆和bromperidol的化合物。
根据本发明的剂型优选包括本领域技术人员已知的常规治疗剂量的这些拮抗剂,特别优选剂量是每给药单位常规剂量的2-4倍。
用于防止活性成分滥用的合适的催吐药是本领域技术人员已知的,并且可以在根据本发明的剂型中以那样的形式存在,或以对应的衍生物,特别是酯或醚的形式、或在每种情形下以生理上可接受的化合物,特别是以它们的盐或溶剂化物的形式存在。
如果为了阻止或防止根据本发明的剂型的滥用的组合物包括组分(d),则它可以包括至少一种催吐药,它优选以与根据本发明剂型的其它成分在空间上相互分离排列的方式存在。当它们被正确使用时,在身体里不会发生作用。
基于吐根(吐根)根的一种或多种成分,优选基于成分吐根碱的催吐药可以被优选在根据本发明的剂型中考虑,如在由HildebertWagner教授博士所著的“Pharmazeutische Biologie-Drogen und ihreInhaltsstoffe”第二版,修订版,Gustav Fischer Verlag,Stuttgart-NewYork,1982,82页,et seq..中描述的那样。那里对应的描述被引作参考,并且被视为公开的一部分。
根据本发明的剂型可以优选包括作为组分(d)的吐根碱,优选含量≥3mg,特别优选≥10mg,更特别优选≥20mg每剂型,即给药单位。
阿朴吗啡也可以同样优选用作根据本发明的防止滥用的催吐药,优选含量≥3mg,特别优选≥5mg,更特别优选≥7mg每给药单位。
如果根据本发明的剂型包含作为进一步防止滥用的辅助物质的组分(e),使用这样的染料引起对应的水溶液着色很深,特别当试图为非肠道,优选静脉给药而提取活性成分时,着色可以起到阻止可能的滥用者的作用。常规以通过活性成分的水提取开始的口服滥用也可以通过这种着色被阻止。进行阻止必需的合适的染料和含量在WO03/015531中可以发现。其中对应的公开应当被视为本发明公开的一部分,并且因而被引作参考。
如果根据本发明的剂型包含作为进一步防止滥用的辅助物质的组分(f),则这种至少一种苦味物质的添加以及必然的剂型的口味的破坏也防止口服和/或经鼻的滥用。
合适的苦味物质和使用的有效剂量可以在US-2003/0064-99A1中发现,其中对应的公开应视为本申请的公开,并且因而被引作参考。合适的苦味物质优选芳香油,优选薄荷油、桉树油、苦杏仁油、薄荷醇、水果香味物质,优选香味物质选自柠檬、橘、白柠檬、葡萄或它们的混合物,和/或denatonium benzoate(Bitrex)。denatoniumbenzoate是特别优选的。
根据本发明的固体剂型适合于口服、阴道或经直肠施用,优选口服。该剂型优选不是膜形式的。
根据本发明的剂型可以采取多粒子形式,优选微片、微胶囊、微丸、颗粒、球体、滴丸,任选包裹在胶囊中或压成片剂形式,优选口服给药。多粒子形式优选大小或大小分布在0.1-3mm范围内,特别优选在0.5-2mm范围内。取决于所需要的剂型,常规的辅助物质(B)也可任选地用于该剂型的配制。
根据本发明的防止滥用的固体剂型优选是通过借助于挤压机热成型不出现可观察到的挤出物的随后脱色的现象来制备的。
为了研究由于这种热成型引起的脱色程度,组成该剂型的起始成分的混合物的颜色首先用不加入赋予颜色的成分来测定,所述成分例如染料或内在着色的组分(如α-生育酚)。然后根据本发明将这种组合物热成型,其中所有的加工步骤,包括挤出物的冷却都在惰性气体氛围中进行。将相同的组合物用相同的方法制备,但不在惰性气体氛围中进行来进行比较。对由起始组合物根据本发明制备的剂型的颜色以及通过比较制备的剂型的颜色进行测定。所述的测定借助于由Munsell Color Company Baltimore,Maryland,USA,1966版著的“Munsell Book of Color”进行的。如果根据本发明的热成型的剂型的颜色具有标号N9.5的颜色,但是至多具有标号为5Y9/1的颜色,则热成型被分类为”没有脱色”。如果所述剂型具有标号5Y9/2或更大值的颜色,如根据Munsell Book of Color测定的那样,所述的热成型被分类为“脱色”。
令人吃惊地,根据本发明的剂型按照上述的分类显示不脱色,如果整个制备过程是在惰性气体氛围中进行,优选借助于用于热成型的挤出机在氮气气氛围下进行的话。
相应地本发明也提供了一种根据本发明的防止滥用剂型的方法,该方法的特征在于:z)将组分(A)、(B)、(C)和任选存在的组分(D)混合,并且将任选存在的组分(a)-(f)共混合,或如果必要的话,将它们单独混合同时加入组分(C)和任选地(D),
y)将得到的这个混合物或这些混合物在挤压机中加热到至少达到组分(C)的软化点,并且通过施加压力通过挤压机的出口孔挤出,
x)拣选该塑性挤出物,形成所述的剂型或
w)将被冷却的及任选地再加热的经拣选的挤出物成形为所述的剂型。
其中步骤y)和x)和任选地步骤z)和w)在惰性气体氛围下进行,优选在氮气氛围中进行。
根据加工步骤c)所述组分的混合也可以在挤压机中进行。
将组分(A)、(B)、(C)、任选地(D)混合以及将任选地进一步存在的组分(a)-(f)以及任选地组分(C)和任选存在的组分(D)混合是任选地在本领域技术人员已知的混合机中进行的。混合机可以是例如滚轴混合机、摇振混合机、剪切混合机或桨式混合机。
在将其余组分混合之前,优选将组分(C)和任选存在的组分(D)与一种抗氧化剂一起提供。这个可以通过混合这两种组分(C)和抗氧化剂来进行,优选通过在高挥发性溶剂中溶解或悬浮所述抗氧化剂,并且将该溶液或悬浮液与组分(C)和任选存在的组分(D)均匀混合,并且通过干燥,优选在惰性气体氛围中干燥除去溶剂。
根据本发明的剂型也可以通过按照步骤z)的共挤出或单独挤出来制备,所述的剂型含有具有阻止或使滥用复杂化的另外辅助物质的亚单位。
在任何情况下,将优选熔融的在挤压机中已经被加热到至少组分(C)的软化点的这个混合物或这些混合物从具有至少一个孔的冲模的挤压机中挤出。
根据本发明的方法优选使用常规的挤压机进行,特别优选使用螺杆挤压机进行,该挤压机可以具有一个或两个螺杆。
所述挤压机优选包括至少两个温度区域,在第一温度区域中将混合物加热到至少组分(C)的软化点,该区域在喂料区域的下游,以及任选的混合区域。混合物的物料通量优选为2.0kg-8.0kg/小时。
在加热到至少组分(C)的软化点后,将熔融的混合物借助于螺杆运输,进一步均匀化,压缩或使之紧密以使在从挤压机冲模出来之前,它显示5巴的最小压强,优选至少10巴,并且根据冲模所包含的孔的数量通过如挤出的线的冲模被挤出。冲模的形状或孔的形状是可以自由选择的。冲模或孔可以相应地为圆形、长方形或椭圆横截面,其中圆形横截面优选直径0.1mm-15mm,并且长方形横截面优选最大纵向伸长21mm以及交叉伸长10mm。可优选地,所述冲模或孔具有圆形横截面。根据本发明使用的挤压机的汽缸可以被加热或冷却。对应的温度控制,即加热或冷却,也被设置成以使欲被挤压的混合物具有对应于组分(C)的软化点的至少平均温度(产品温度),并且不升高到使欲被加工的具有滥用可能性的活性成分可能被破坏的温度以上。优选地,欲被挤出的混合物的温度调节到低于180℃,优选低于150℃,但是至少达到组分(C)的软化温度。
将熔融混合物挤出以及任选地将挤出的线冷却后,优选将该挤出物粉碎。所述粉碎可以优选通过旋转刀或旋转小刀、水喷刀、金属丝、刀片或借助于激光刀将挤出物进行切割。
惰性气体氛围对于中间物或任选地拣选的挤出物的最终储存或根据本发明的剂型的最终形状不是必要的。
所述拣选的挤出物可以用常规的方法丸化,或为了赋予剂型最终的形状将其压模成片剂。但是,不拣选挤出的线是可能的,并且借助于在它们外套管中含有反向凹穴的反转砑辊来形成最终的形状,优选片剂,以及用常规的方法将它们进行拣选。
如果任选地不将拣选的挤出物立即成形为最终形状,而是冷却储存,在惰性气体氛下,优选氮气氛围下储存一段时间后,在将储存的挤出物加热的过程中应当提供和必须保持到塑化和确定的形状以产生所述剂型。
在挤压机中对至少塑化的混合物施加的压力可以通过控制挤压机中的运输装置的旋转速度、它们的形状以及出口孔的大小来调节,以在挤压机中建立将塑化的混合物挤出必要的压力,优选以在挤出之前的方式立即进行。对于每种特定的组成产生至少500N的断裂强度的剂型的挤出参数可以通过简单的初步测试来建立。
在进一步的优选实施方式中,根据本发明的剂型采用片剂、胶囊的形式,或以口服渗透治疗系统(OROS)的形式,优选如果也存在至少一种进一步防止滥用的组分(a)-(f)的话。
如果在根据本发明的剂型中存在组分(c)和/或(d)和/或(f),必须注意确保它们以这样的方式被配制或以这样的低剂量存在,即当正确地给药时,所述的剂型能够实质上不会损害病人或破坏活性成分的效力。
如果根据本发明的剂型包括组分(d)和/或(f),则必须对剂量进行选择,以使当正确口服给药时,不会引起负作用。但是,如果在滥用的情况下,超过剂型所需要的剂量,则引起恶心、想要呕吐或口味差。在正确的口服给药的情况下,病人仍然可以容忍的组分(d)和/或(f)的特别的含量可以由本领域技术人员通过简单的初步测试来测定。
然而,如果不考虑根据本发明的剂型实质上是不可能粉碎的事实,则含有组分(c)和/或(d)和/或(f)的剂型被提供保护,这些组分应当优选被以足够高的剂量使用,使得滥用服用时,它们给滥用者带来强烈的负作用。这个优选通过将至少一种活性成分或多种活性成分与组分(c)和/或(d)和/或(f)空间分离而获得,其中这种活性成分或这些活性成分在至少一个亚单位(X)中存在,并且组分(c)和/或(d)和/或(f)在至少一个亚单位(Y)中存在;并且当剂型被正确给药时,组分(c)、(d)和(f)在服用时和/或在身体中不会产生作用,并且制剂的其余的组分,特别是组分(C)和任选地(D)是一样的。
如果根据本发明的剂型包括组分(c)和(d)或(f)中的至少2种,则这些可以每一种在同样的或不同的亚单位(Y)中存在。可优选地,当它们存在时,所有的组分(c)和(d)和(f)在一个并且相同的亚单位(Y)中存在。
为了达到本发明的目的,亚单位是固体制剂,在每种情况下,除了本领域技术人员已知的常规辅助物质外,该固体制剂包含活性成分、至少一种聚合物(C)和任选存在的组分(D)和任选至少一种任选存在组分(a)和/或(b)和/或(e),或每种情况下,至少一种聚合物(C)和任选地(D)和拮抗剂和/或催吐剂和/或组分(e)和/或组分(f)和任选地至少一种任选存在的组分(a)和/或(b)。这里必须注意以确保每一个亚单位根据前面提及的方法进行配制。
将活性成分与在根据本发明的剂型的亚单位(X)和(Y)中的组分(c)或(d)或(f)分离配制的一个显著的优势是:当正确给药时,组分(c)和/或(d)和/或(f)在服用时或在身体里很难释放,或者释放量很小,因此,它们在通过病人身体时,不会损害病人或影响治疗效果,它们仅被释放到它们不能被大量地吸附的有效作用的位点。当这种剂型正确给药时,优选几乎没有任何的组分(c)和/或(d)和/或(f)被释放到病人的身体里,或者它们不会被病人注意到。
本领域技术人员将理解前述所述的条件可以随使用的特定的组分(c)、(d)和/或(f)的功能以及亚单位的配制或剂型的不同而变化。用于特定剂型的最佳配制可以通过简单的初步测试来测量。关键的是每个亚单位包含聚合物(C)和任选地组分(D),并且以前面所述的方式进行配制。
如果与预期相反,为了滥用活性成分,滥用者成功地将根据本发明的这样的剂型粉碎,该剂型包括在亚单位(Y)中的组分(c)和/或(e)和/或(d)和/或(f),以及获得用合适的提取剂提取的粉末,则不仅活性成分,而且特别是组分(c)和/或(e)和/或(f)和/或(d)将被以一种不容易与活性成分分离的形式被获得,这样的话,当服用已经被擅自改变的剂型时,特别是口服和/或非肠道给药时,在服用时和/或在身体里将发挥作用,并且对滥用产生对应于组分(c)和/或(d)和/或(f)的负作用,或者当试图提取活性成分时,着色将作为阻滞剂发生作用并且因此防止该剂型的滥用。
根据本发明的剂型,其中该活性成分或这些活性成分与组分(c)、(d)和/或(e)在空间上是分离的,优选配制在不同的亚单位中,该剂型可以通过不同的方式配制,其中条件是满足前面提及的释放组分(c)和/或(d)的条件,在对应的亚单位中每一种都可以以任何相对于另一个所需的空间排列方式在根据本发明的剂型中存在。
本领域技术人员将理解也是任选存在的组分(a)和/或也是优选存在的(b)可以优选配制在根据本发明的剂型中,既在特定的亚单位(X)和(Y)中也在以对应于亚单位(X)和(Y)的单独的亚单位的形式中存在,条件是防止滥用和在正确给药的情况下都不会被制剂的性质破坏,并且聚合物(C)和任选地(D)包括在制剂中,为了获得必要的硬度,该制剂根据前面提及的方法来制备。
在根据本发明剂型的一个优选的实施方式中,亚单位(X)和(Y)以多粒子形式存在,其中优选微片、微胶囊、微丸、颗粒、球体、珠或丸,并且亚单位(X)和亚单位(Y)选择相同的形式,即形状,这样通过机械选择不可能将亚单位(X)与(Y)分离。这种多粒子形式优选大小在0.1至3mm范围内,优选0.5至2mm。
在多粒子形式中的亚单位(X)和(Y)也可以优选被包装在胶囊中或压成片剂,其中在每种情况下的最终的配制是以亚单位(X)和(Y)也保留在制得的剂型中的方式进行的。
相同形状的亚单位(X)和(Y)应当也是不能彼此直观识别出来的,这样的话,滥用者不能通过简单的分类将它们彼此分离开来。这种,例如可以通过应用相同的包衣获得,所述的包衣除了具有伪装的功能外,也可以合并其它的功能,如一种或多种活性成分的控释或者提供特定的亚单位的最终抵抗胃酸的作用。
多粒子亚单位也可以制成口服剂型如淤浆或在药学上安全的悬浮介质中的悬浮液。
在本发明的又一个的优选实施方式中,亚单位(X)和(Y)在每种情况下是以相对于彼此以层进行排列的。
为了达到这个目的,层状的亚单位(X)和(Y)优选在根据本发明的剂型中的相对于彼此垂直或水平排列,其中在每种情况下,一种或多种层状的亚单位(X)和一种或多种层状的亚单位(Y)可以在剂型中以这样的形式存在,即除了优选的层顺序(X)-(Y)或(X)-(Y)-(X)外,也可以考虑任何其它需要的层顺序,任选含有组分(a)和/或(b)的组合的层。
另一个根据本发明的优选的剂型是一个其中亚单位(Y)形成了一个完全被亚单位(X)封入的芯的结构,其中分离层(Z)可以存在在所述层之间。这样的结构也优选适于前面提及的多粒子形式,其中亚单位(X)和(Y)以及任选存在的分离层(Z),它们必须满足根据本发明的硬度的要求,它们被配制在一个并且相同的多粒子形式中。在根据本发明剂型的进一步的优选实施方式中,亚单位(X)形成芯,它被亚单位(Y)封入,其中后者包括至少一种一条从该芯通向剂型表面的通道。
根据本发明的剂型可以在一层亚单位(X)和一层亚单位(Y)之间,在每种情况下,一层或多层,优选一层,任选地包括可膨胀的分离层(Z),该分离层具有将亚单位(X)与亚单位(Y)空间分离的作用。
如果根据本发明的剂型包括以至少部分垂直或水平排列的层状的亚单位(X)和(Y)以及任选存在的分离层(Z),则该剂型优选采用片剂、共挤压物或层压物形式。
在一个特别优选实施方式中,亚单位(Y)的全部游离表面和任选地至少亚单位(X)的部分游离表面以及任选地至少任选存在的分离层(Z)的部分游离表面可以用至少一层阻止组分(c)和/或(e)和/或(d)和/或(f)释放的障碍层(Z’)包衣。该障碍层(Z’)也必须满足根据本发明的硬度条件。
另一个根据本发明的剂型的特别优选的实施方式包括垂直或水平排列的亚单位层(X)和(Y)以及至少一层排列在它们之间的推进层(p)和任选地分离层(Z),其中在该剂型中向由亚单位(X)和(Y)组成的层结构的全部游离表面、推进层和任选存在的分离层(Z)提供可半渗透的包衣(E),它对于释放介质,即常规的生理液体是可渗透的,但是对于活性成分和组分(c)和/或(d)和/或(f)实质上是不能渗透的,并且其中这种包衣(E)包括至少一个用于释放在亚单位(X)区域中释放活性成分的开口。
对应的剂型是本领域技术人员已知的,例如所谓的口服渗透治疗系统(OROS)、用于制造的合适的材料和方法以及其他的内容从US4612008、US 4765989和US 4783337获知。对应的说明在此被引入作为参考,并且被视为公开的一部分。
在又一个优选实施方式中,根据本发明剂型的亚单位(X)是片剂形式,它的边缘面和任选地两个主要面的一个被含有组分(c)和/或(d)和/或(f)的障碍层(Z’)覆盖。
本领域技术人员将理解用于制备根据本发明剂型的亚单位(X)或(Y)以及任选存在的分离层(Z)和/或障碍层(Z’)的辅助物质将随在根据本发明的剂型中的排列、给药方式和任选存在的组分(a)和/或(b)和或(e)和组分(c)和/或(d)和/或(f)的特定的活性成分而变化。在每种情况下的具有必要性质的材料对于本领域技术人员是已知的。
如果组分(c)和/或(d)和/或(f)从根据本发明剂型的亚单位(Y)中释放借助于覆盖物,优选障碍层而被阻止的话,则该亚单位可以由本领域技术人员已知的常规材料组成,条件是它包括满足根据本发明剂型硬度条件的至少一种聚合物(C)和任选地(D)。
如果不提供对应的障碍层(Z’)来阻止组分(c)和/或(d)和/或(f)的释放,则亚单位的材料应当选择那些从亚单位(Y)释放特定的组分(c)和/或(d)实质上是不可能的物质。前面所述的适合于制备障碍层的材料可以优选用于实现这个目的。
优选的材料是选自下列的物质:烷基纤维素、羟烷基纤维素、葡聚糖、硬葡聚糖、甘露聚糖、黄原胶、聚[双(对-羧基苯氧基)丙烷和癸二酸的共聚物,优选摩尔比为20∶80(商购的名称Polifeprosan 20)、羧甲基纤维素、纤维素醚、纤维素酯、硝基纤维素、基于(甲)丙烯酸及其酯的聚合物、聚酰胺、聚碳酸酯、聚亚烃、聚亚烷基二醇、聚环氧烷、聚亚烷基对苯二酸酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、卤化的聚乙烯、聚乙醇酸交酯、聚硅氧烷和聚氨基甲酸酯以及它们的共聚物。
特别合适的材料可以选自:甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、乙酸纤维素、丙酸纤维素(低、中或高分子量)、乙酸丙酸纤维素、乙酸丁酸纤维素、乙酸邻苯二甲酸纤维素、羧甲基纤维素、三乙酸纤维素、硫酸钠纤维素、聚丙烯酸甲酯、聚丙烯酸乙酯、聚丙烯酸丁酯、聚丙烯酸异丁酯、聚丙烯酸己酯、聚丙烯酸异癸酯、聚丙烯酸月桂酯、聚丙烯酸苯酯、聚丙酸甲酯、聚丙酸异丙酯、聚丙酸异丁酯、聚丙酸十八烷酯、聚乙烯、低密度聚乙烯、高密度聚乙烯、聚丙烯、聚乙二醇、聚环氧乙烷、聚对苯二甲酸亚乙基酯、聚乙烯醇、聚乙烯异丁基醚、聚乙酸乙烯酯和聚氯乙烯。
特别优选的共聚物可以选自:甲基丙烯酸丁酯和甲基丙烯酸异丁酯的共聚物、甲基乙烯醚和高分子量的马来酸的共聚物、甲基乙烯醚和马来酸单乙基酯的共聚物、甲基乙烯醚和马来酸酐的共聚物和乙烯醇和乙酸乙烯酯的共聚物。
特别适合于制备障碍层的进一步的材料是淀粉填充的聚己酸内酯(WO 9820073)、脂族聚酰胺酯(DE 19753534 A1、DE 19800698 A1、EP 0820698 A1)、脂族和芳族的聚酯型氨基甲酸酯(DE 19822979)、聚羟基链烷酸酯,特别是聚羟基丁酸酯、聚羟基戊酸酯、酪蛋白(DE4309528)、聚交酯和共聚交酯(EP 0980894 A1)。对应的说明在此被引作参考并且被视为公开的一部分。
前面提及的材料可以任选地与本领域技术人员已知的常规的其他辅助物质混合,优选选自:硬脂酸甘油酯、半合成的甘油三酯衍生物、半合成的甘油酯、氢化蓖麻油、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、聚乙烯吡咯烷酮、明胶、硬脂酸镁、硬脂酸、硬脂酸钠、滑石、山嵛酸钠、硼酸、胶态二氧化硅、脂肪酸、取代的甘油三酯、甘油酯、聚氧亚烷基二醇和它们的衍生物。
如果根据本发明的剂型包括分离层(Z’),所述的层,如暴露的亚单位(Y)可以优选由前面提及的用于障碍层描述的材料组成。本领域技术人员将会理解活性成分或组分(c)和/或(d)从特定的亚单位的释放是通过分离层的厚度进行控制的。
根据本发明的剂型具有控释活性成分的作用。优选适合于每日向病人给药两次。
根据本发明的剂型可以包括至少部分以控释形式存在的一种或多种活性成分,其中控释可以借助于本领域技术人员已知的常规的材料和方法而达到。例如,将活性成分包埋在控释基质中,或应用一种或多种控释包衣。但是,活性成分的释放必须以满足前面提及的条件的方式控制,例如,在剂型的正确给药情况下,这个活性成分或这些活性成分实质上在任选存在的组分(c)和/或(d)发挥损害作用之前就完全释放了。影响控释的材料的添加必须不能破坏必要的硬度。
根据本发明剂型的控释优选通过将活性成分包埋在基质中获得。作为基质材料的辅助物质控制活性成分的释放。基质材料可以是,例如疏水性的、形成凝胶的材料,活性成分主要通过扩散从该材料中释放出来,或者疏水性的材料,活性成分主要通过基质中的孔扩散从该材料中释放出来。
本领域技术人员已知的生理上可接受的疏水材料可以用作基质材料。聚合物,特别优选纤维素醚、纤维素酯和/或丙烯酸酯优选用作亲水基质材料。乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、聚(甲)丙烯酸和/或它们的衍生物,如它们的盐、酰胺或酯更特别优选被用作基质材料。
从疏水材料制备的基质材料,如疏水聚合物、蜡、脂肪、长链脂肪酸、脂肪醇或对应的酯或醚或它们的混合物也是优选的。C12-C13脂肪酸的单或二甘油酯和/或C12-C13脂肪醇和/或蜡或它们的混合物特别优选被用作疏水材料。
使用前面提及的亲水和疏水材料用作基质材料也是可能的。
组分(C)和任选存在的组分(D)具有获得根据本发明的必要的至少500N的断裂强度的作用,也进一步任选地作为另外的基质材料而起作用。
如果根据本发明的剂型是用于口服给药,它也可以优选包括一种包衣,该包衣对胃液具有抵抗作用,并且可溶解具有调节释放环境的pH值的作用。通过该包衣,确保根据本发明的剂型穿过胃而不被溶解,并且活性成分仅释放到小肠中。抵抗胃液的包衣优选在5和7之间的pH值下溶解。
用于活性成分的控释以及用于抵抗胃液的包衣的对应的材料和方法对于本领域技术人员来说是已知的,例如由Kurt H.Bauer,K.Lehmann,Hermann P.Osterwald,Rothgang,Gerhart著的“包衣的药物剂型-原理、制造技术、生物药学、实验方法和原料”第1版,1998,Medpharm Scientific Publishers。对应的文字说明在此被引作参考,并且被视为公开的一部分。
测量断裂强度的方法
为了验证聚合物是否可以用作组分(C)或(D),将聚合物用150N的力在至少对应于该聚合物的软化点的温度下压成直径为10mm,厚为5mm的片,并且借助于聚合物的DSC图进行测定。采用这种方式制造的片剂,断裂强度是按照公开在欧洲药典1997,143-144页,第2.9.8..号方法测量片剂的断裂强度的方法使用下面描述的仪器进行测定的。使用的用于测量的仪器是“Zwick Z 2.5材料测试仪,Fmax=2.5KN最大拉伸1150mm,设定1个柱和1个轴,在100mm后间隙,并且可调节的测试速度在0.1和800mm/min之间,使用测试软件。测量使用具有螺杆插入件和气缸(直径10mm)的压力活塞,力转换器,Fmax.1kN,直径=8mm,0.5级10N,1级2N至ISO 7500-1,具有制造者测试合格证M至DIN 55350-18(Zwick总力Fmax=1.45kN)(所有的仪器购于Zwick Gmbh和KG,Ulm公司,德国)用编号为BTC-FR 2.5TH D09测试仪,编号为BTC-LC 0050N.P01的力转换器,编号为BO70000 S06的离心装置。
图1显示片剂的断裂强度的测试,特别是用于这个目的的之前和在测试中的片剂(4)的调节装置(6)。在末端,片剂(4)被放在具有两个2-部分夹子装置的力应用仪(未显示)的上压力板(1)和下压力板之间,一旦对于将要被测量的片剂的放置和离心必要的空距(5)被建立,在每种情况下它们用上下压力板紧紧地夹紧。所述的空距可以通过在放置它们的压力板上水平往外或里移动2-部分夹持装置来建立。
被视为在特定负荷下可以抵抗断裂的片剂不仅包括那些没有断裂的,也包括那些在压力作用下可以经受塑性变形的片剂。
对于根据本发明的剂型,断裂强度是根据所述的方法进行测定的。不是片剂的剂型也被测试。
下面的实施例完全是通过实例说明本发明,并且不限制本发明的一般概念。
实施例:
实施例1
组分 | 每片 | 每批 |
盐酸曲玛多 | 100.0mg | 1495.0g |
聚环氧乙烷,NF,MW 7000000(Polyox WSR 303,Dow Chemicals) | 167.8mg | 2508.6g |
羟丙基甲基纤维素100000mPa·s | 33.5mg | 500.8g |
聚乙二醇(PEG6000) | 33.5mg | 500.8g |
丁基羟基甲苯(BHT) | 0.2mg | 3.0g |
总重量 | 335.0mg | 5008.2g |
将所述量的BHT溶解在乙醇(96%)中获得7.7%(质量/质量)的乙醇溶液。开始用150g的聚环氧乙烷在高速混合机中混合30分钟,然后将其余的聚环氧乙烷加入,并且再连续搅拌30分钟。在40℃下干燥该组合物12小时。
将所有的其它组分加入,并且在自由落体混合机中混合15分钟。将该粉末混合物分配到挤压机中。用由Leistriz(Nurnberg)制造的具有18mm直径螺杆的Micro27 GL 40D型双螺杆挤压机进行挤出。使用具有钝末端的螺杆,在螺杆的末端的六角形孔用盖子封闭。使用的冲模是直径为8mm的可加热的圆形冲模。全部工序是在氮气氛围中进行的。
选择下列的参数用于挤出:
螺杆速度:100rpm
物料通过量:4kg/h
产品温度:125℃
汽缸温度:120℃
将仍然是热的挤出物在氮气氛围中冷却。该冷却的线被拣选成双平面的片剂。所述片剂当暴露在500N的力下不断裂。用锤子或用钵和研杵也不能粉碎所述片剂。
冷却的线或经拣选的10片颜色用Munsell Book of Colour在N9.5/下测定,通过根据本发明的工序制备的所述片剂由于借助于挤压机热成型而不显示任何脱色的现象。
Claims (36)
1.一种经挤出而不脱色的热成型的防止滥用的剂型,其特征在于:除了含有一种或多种具有滥用可能性的活性成分(A)以及任选地含有生理上可接受的辅助物质(B)外,它还包含至少一种合成的或天然的聚合物(C)以及任选地至少一种蜡(D),其中组分(C)和任选存在的组分(D)具有至少500N的断裂强度。
2.根据权利要求1的剂型,其特征在于:它是片剂形式的。
3.根据权利要求1的剂型,其特征在于:它是多粒子形式的,优选它是微片、微丸、颗粒、球体、珠或丸,任选地被压成片剂或包装在胶囊中。
4.根据权利要求1-3中任一项的剂型,其特征在于:它包括作为聚合物(C)的至少一种选自聚环氧乙烷、聚氧亚甲基、聚环氧丙烷、聚乙烯、聚丙烯、聚氯乙烯、聚碳酸酯、聚苯乙烯、聚丙烯酸酯、共聚物及它们的混合物的聚合物,优选聚环氧乙烷。
5.根据权利要求1-4中任一项的剂型,其特征在于:所述的聚环氧乙烷(C)的分子量至少为0.5兆。
6.根据权利要求5的剂型,其特征在于:所述的聚环氧乙烷(C)的分子量至少为1兆。
7.根据权利要求6的剂型,其特征在于:所述的聚环氧乙烷(C)的分子量至少为1-15兆。
8.根据权利要求1-7中任一项的剂型,其特征在于:它包含作为蜡(D)的至少一种具有至少60℃的软化点的天然的或半合成的或合成的蜡。
9.根据权利要求8的剂型,其特征在于:所述的蜡(D)是巴西棕榈蜡或蜂蜡。
10.根据权利要求1-9中任一项的剂型,其特征在于:组分(C)和任选地(D)的存在量使得该剂型的断裂强度至少500N。
11.根据权利要求1-10中任一项的剂型,其特征在于:所述的活性成分(A)是至少一种选自类鸦片、安定剂、刺激剂、巴比妥酸盐以及其它麻醉剂的活性成分。
12.根据权利要求1-11中任一项的剂型,其特征在于:它还另外包含至少下列组分a)-f)中的一种:
(a)至少一种刺激鼻道和/或咽的物质;
(b)至少一种增粘剂,该增粘剂借助于必需的最少量的含水液体与从该剂型获得的提取物形成凝胶,当将该凝胶加入到更多量的含水液体中时,它优选仍然是可直观地识别出来的;
(c)至少一种具有滥用可能性的活性成分的拮抗剂;
(d)至少一种催吐剂;
(e)至少一种作为嫌恶剂的染料;
(f)至少一种苦味物质。
13.根据权利要求12的剂型,其特征在于:所述的组分(a)刺激物质引起灼烧、痒、想打喷嚏、分泌物的形成增加或这些刺激中的至少两种的组合。
14.根据权利要求12或13的剂型,其特征在于:所述的组分(a)刺激物质是基于至少一种热物质药物中的一种或多种成分。
15.根据权利要求14的剂型,其特征在于:所述热物质药物是至少一种选自下列的药物:Allii sativi bulbus(蒜)、Asari rhizoma cumherba(细辛根和叶)、Calami rhizoma(菖蒲根)、Capsici fructus(辣椒)、Capsici fructus acer(番椒)、Curcumae longae rhizoma(郁金香根)、Curcumae xanthorrhizae rhizoma(Javanese郁金香根)、Galangae rhizoma(良姜根)、Myristicae semen(肉豆蔻)、Piperis nigrifructus(花椒)、Sinapis albae semen(白芥菜种子)、Sinapis nigri semen(黑芥菜种子)、Zedoariae rhizoma(蓬莪术根)和Zingiberis rhizoma(姜根),特别优选至少一种选自Capsici fructus(辣椒)、Capsici fructusacer(cayenne番椒)和Piperis nigri fructus(番椒)的药物。
16.根据权利要求14或权利要求15的剂型,其特征在于:所述的热物质药物的成分是邻甲氧基(甲基)酚化合物、酰胺化合物、芥子油或硫化物或由它们衍生的化合物。
17.根据权利要求14-16中任一项的剂型,其特征在于:所述的热物质药物的成分是至少一种选自下列的成分:肉豆蔻醚、榄香素、异丁香酚、β-细辛脑、黄樟脑、姜醇、黄根醇、capsaicinoids,优选辣椒碱、胡椒碱,优选反-胡椒碱、硫代葡糖酸盐,优选基于非挥发的芥子油,特别优选基于对-羟基苄基芥子油、甲基巯基芥子油或甲基磺酰芥子油和这些成分衍生的化合物。
18.根据权利要求12-17中任一项的剂型,其特征在于:所述的组分(b)是至少一种选自下列的增粘剂:含有11重量%的羧甲基纤维素钠(AvicelRC 591)的微晶纤维素、羧甲基纤维素钠(Blanose,CMC-Na C300P,Frimulsion BLC-5,Tylose C300P)、聚丙烯酸(Carbopol980NF,Carbopol981)、角豆粉(CesagumLA-200,CesagumLID/150,CesagumLN-1)、来自橘果或苹果的果胶(CesapectinHM Medium Rapid Set)、蜡状的玉米淀粉(C*Gel04201)、藻酸钠(Frimulsion ALG(E401))、瓜耳胶粉(FrimulsionBM,Polygum 26/1-75)、iota角叉菜(Frimulsion D021)、刺梧桐树胶、胶凝糖树胶(Kelcogel F,Kelcogel LT100)、半乳甘露聚糖(Meyprogat 150)、tara豆粉(Polygum 43/1)、丙二醇藻酸酯(Protanal-Ester SD-LB)、苹果果酸、透明质酸钠、黄蓍胶、tara树胶(Vidogum SP 200)、发酵的多糖welan树胶(K1A96)、黄原酸胶(Xantural 180)。
19.根据权利要求12-18中任一项的剂型,其特征在于:所述的组分(c)是至少一种选自下列的类鸦片拮抗剂:纳洛酮、纳曲酮、纳美芬、nalid、纳美酮、烯丙吗啡、naluphine,和对应的生理上可接受的化合物,特别是碱、盐或溶剂化物。
20.根据权利要求12-18中任一项的剂型,其特征在于:所述的使用的组分(c)是至少一种作为刺激拮抗剂的安定药,优选选自氟哌啶醇、普鲁米近、氟奋乃静、奋乃静、甲氧异丁嗪、甲硫达嗪、培拉嗪、氯丙嗪、氯普噻吨、zuclopentixol、三氟噻醇、丙硫喷地、佐替平、benperidol、匹泮哌隆、美哌隆和bromperidol。
21.根据权利要求12-20中任一项的剂型,其特征在于:所述的组分(d)基于吐根(吐根)的根的一种或多种成分,优选基于吐根碱和/或阿扑吗啡。
22.根据权利要求12-21中任一项的剂型,其特征在于:所述的组分(e)是至少一种生理上可接受的染料。
23.根据权利要求12-22中任一项的剂型,其特征在于:所述的组分(f)是至少一种选自下列的苦味物质:芳香油,优选薄荷油、桉树油、苦杏仁油、薄荷醇和它们的混合物、水果香味物质,优选来自柠檬、橘、白柠檬、葡萄和包括至少两种它们的混合物、denatoniumbenzoate和包括至少两种它们的混合物。
24.根据权利要求12-23任一项的剂型,其特征在于:所述这种活性成分或这些活性成分(A)与组分(c)和/或(d)和/或(f)在空间上是分离的,优选不直接接触,其中这种活性成分或这些活性成分(A)优选在至少一个亚单位(X)中存在,并且组分(c)和/或(d)和/或(f)在至少一个亚单位(Y)中存在,当该剂型正确给药时,来自于亚单位(Y)的组分(c)和/或(d)和/或(f)在身体里和/或服用时不起作用。
25.根据权利要求1-24中任一项的剂型,其特征在于:它包含至少一种至少部分控释形式的活性成分。
26.根据权利要求25的剂型,其特征在于:每一种具有滥用可能性的活性成分存在于控释的基质中。
27.根据权利要求26的剂型,其特征在于:组分(C)和/或任选存在的组分(D)也作为控释基质材料起作用。
28.制备根据权利要求1-27中任一项的剂型的方法,其特征在于:
z)将组分(A)、(B)、(C)和任选存在的组分(D)混合,并且将任选存在的组分(a)-(f)共混合,或如果必要的话,将它们单独混合并且添加组分(C)和任选地(D),
y)将得到的这个混合物或这些混合物在挤压机中加热到至少达到组分(C)的软化点,并且通过施加压力通过挤压机的出口孔挤出,
x)拣选该塑性挤出物,形成所述的剂型或
w)将被冷却的并且任选地再加热的被拣选的挤出物成形为所述的剂型。
其中步骤y)和x)和任选地步骤z)和w)在惰性气体氛围下进行。
29.根据权利要求28的方法,其特征在于:根据z)的组分的混合也在挤压机中在惰性气体氛围下进行。
30.根据权利要求28或权利要求29的方法,其特征在于:将根据z)的混合物共挤出或分别挤出。
31.根据权利要求28-30中任一项的方法,其特征在于:将根据z)的这个混合物或这些混合物通过具有至少一个孔的冲模挤出。
32.根据权利要求28-31中任一项的方法,其特征在于:通过切割拣选所述的挤出物。
33.根据权利要求28-32中任一项的方法,其特征在于:所述的挤出物是线的形式,并且将其成形,并且借助于在它们外套管中含有反向凹穴的反转砑辊对其进行拣选的。
34.根据权利要求28-32中任一项的方法,其特征在于:将所述的可拣选的挤出物制成丸或压成片剂。
35.根据权利要求28-34中任一项的方法,其特征在于:氮气被用作惰性气体氛围。
36.可通过权利要求28-35中任一项的方法获得的权利要求1-27的剂型。
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DE10336400A DE10336400A1 (de) | 2003-08-06 | 2003-08-06 | Gegen Missbrauch gesicherte Darreichungsform |
DE10336400.5 | 2003-08-06 | ||
DE10361596.2 | 2003-12-24 | ||
DE10361596A DE10361596A1 (de) | 2003-12-24 | 2003-12-24 | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
DE102004020220A DE102004020220A1 (de) | 2004-04-22 | 2004-04-22 | Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform |
DE102004020220.6 | 2004-04-22 | ||
DE102004032051A DE102004032051A1 (de) | 2004-07-01 | 2004-07-01 | Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform |
DE102004032051.9 | 2004-07-01 | ||
PCT/EP2004/008792 WO2005016313A1 (de) | 2003-08-06 | 2004-08-05 | Gegen missbrauch gesicherte darreichungsform |
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