CN1917862A - 防滥用给药形式的制备方法 - Google Patents
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Abstract
本发明涉及防滥用、热成型给药形式的制备方法,所述给药形式除一种或几种具有滥用潜在性的活性物质外,还含有至少一种断裂抗力至少500N的合成或天然聚合物,以及任选的生理相容辅助物质。
Description
本发明涉及具有至少降低滥用潜在性的固体药物剂型的制备方法,该方法包括
a)通过施力将制剂混合物形成成型制品,所述制剂混合物含有至少一种具有滥用潜在性的活性成分以及至少一种具有至少500N断裂强度的合成或天然聚合物(C),
b)任选将成型制品分断(singulating),并任选在各情况下将它们按尺寸分等级,和
c)在至少加热至聚合物(C)的软化点后或期间,将成型制品暴露于力下直到它们具有至少500N的裂断硬度,任选提供给它们覆盖(cover),并任选将所有成型制品再混合在一起。
许多药物活性成分,除了在其适当的应用方面具有优良的活性外,还具有滥用的潜在性,即它们可以被滥用者使用带来与预期作用不同的作用。例如阿片样物质,它们在抗严重至非常严重的疼痛时高度有效,却频繁地被滥用者用于诱导麻醉或欣快状态。
为了使得滥用成为可能,滥用者将相应的剂型例如片剂或胶囊剂粉碎,例如在研钵中研磨,用优选水性液体从所得粉末中提取活性成分,所得溶液任选经脱脂棉或纤维素填塞物过滤后,经非肠道、特别是静脉内给药。与口服给药的滥用相比,这种给药的另一种现象进一步加速提高了给滥用者带来所期望作用(即“刺激”或“快感”)的活性成分水平。如果经鼻给予(即用鼻吸入)粉末状的剂型也可获得这种刺激。
因为甚至当以滥用高剂量口服时,含有滥用潜在性活性成分的延迟释放剂型也不产生滥用者所期望的刺激,因此为了能被滥用此类剂型也被粉碎和提取。
为了防止滥用,US-A-4,070,494提出向剂型中加入膨胀剂。当加水提取活性成分时,该膨胀剂膨胀并确保从凝胶中分离的滤液中仅含少量活性成分。
WO 95/20947中公开的多层片基于类似的方法防止非肠道滥用,所述片剂含有滥用潜在性活性成分,并在不同的层中各含有至少一种胶凝剂。
WO 03/015531 A2公开了另一种防止非肠道滥用的方法。其中描述了一种含有镇痛剂阿片样物质和用作厌恶剂的染料的剂型。损坏剂型后所释放出的颜色用于阻碍滥用者使用已被损坏的剂型。
另一种已知的使滥用复杂化的方法涉及向剂型中加入活性成分的拮抗剂,例如在阿片样物质的情况下加入纳洛酮或纳曲酮,或加入能引起生理防御反应的化合物,例如吐根树(吐根)根。
然而,因为如在过去,在大多数情况下为了达到滥用的目的,必须研磨含有适合滥用活性成分的剂型,因此本发明的目的是提供防滥用剂型的制备方法,该剂型使得使用潜在滥用者可采用的常规手段在滥用之前对剂型的研磨复杂化或受到阻碍,并因此制备具有滥用潜在性活性成分的剂型,当正确给药时,该剂型能确保所期望的治疗作用,但是其中的活性成分不能简单地通过研磨转化成适于滥用的形式。
所述目的已通过根据本发明制备具有至少降低滥用潜在性的固体药物剂型的方法实现,该方法的特征在于:
a)通过施力将制剂混合物形成成型制品,所述制剂混合物含有至少一种具有滥用潜在性的活性成分、至少一种具有至少500N断裂强度的合成或天然聚合物(C)以及任选的辅助物质(B),
b)任选将成型制品分断,并任选在各情况下将其按尺寸分等级,知
c)在至少加热至聚合物(C)的软化点后或期间,将成型制品暴露于力下直到它们具有至少500N的裂断硬度,任选提供给它们覆盖,并任选将所有成型制品再混合在一起。
使用在根据本发明的方法中具有所述最小断裂强度的聚合物(C),优选以一定的量使用以便该剂型也表现出这样的最小断裂强度,意味着使用常规方法研磨该剂型在相当程度上更困难,因此在相当程度上使随后的滥用复杂化或受到阻碍。
如果粉碎不充分,经非肠道给药特别是静脉内给药就不能安全地进行,或者从中提取活性成分对滥用者而言时间太长,或由于释放不是即时的,口服时无“刺激”现象。
根据本发明,采用粉碎意味着通过用滥用者通常可采用的常规方法施力研磨剂型,例如用研棒和研钵、锤、木槌或其他常规研磨工具研磨,其中可出现的细粉(粒度等于或小于0.3mm)比例必须不超过5%重量。
根据本发明获得的剂型因此适用于防止具有滥用潜在性的药物活性成分的经非肠道、鼻和/或口滥用。
对本领域技术人员而言,具有滥用潜在性的药物活性成分的使用数量及其制备方法是已知的,并且可以根据本发明的剂型本身、以其相应的衍生物形式特别是酯或醚,或在各情况下以相应生理上可接受的化合物形式特别是以其盐或溶剂化物的形式、以外消旋体或立体异构体的形式提供。根据本发明获得的剂型也适用于大多数活性成分的给药。优选用于一种特定活性成分的给药。
根据本发明获得的剂型特别适用于防止至少一种选自以下的药物活性成分的滥用:鸦片制剂、阿片样物质、镇静剂,优选苯并二氮杂类、巴比妥类、兴奋剂和其它的麻醉剂。
根据本发明获得的剂型非常特别优选适用于防止鸦片制剂、阿片样物质、镇静剂或另外麻醉剂的滥用,它们选自:N-{{1-[2-(4-乙基-5-氧代-2-四唑啉-1-基)乙基]-4-甲氧基甲基-4-哌啶基}丙酰苯胺(阿芬太尼)、5,5-二烯丙基巴比土酸(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(阿普唑仑)、2-二乙氨基苯基乙基酮(安非拉酮)、(±)-α-甲基苯乙胺(苯丙胺)、2-(α-甲基苯乙氨基)-2-苯基乙腈(安非他尼)、5-乙基-5-异戊基巴比土酸(异戊巴比妥)、阿尼利定、阿朴可待因、5,5-二乙基巴比土酸(巴比妥)、苄基吗啡、苯腈米特、7-溴-5-(2-吡啶基)-1H-1,4-苯并二氮杂-2(3H)-酮(溴西泮)、2-溴-4-(2-氯苯基)-9-甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂(溴替唑仑)、17-环丙基甲基-4,5α-环氧-7α[(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-乙基巴比土酸(丁巴比妥)、布托啡诺、二甲基氨基甲酸(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)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(利眠宁)、7-氯-1-甲基-5-苯基-1H-1,5-苯并二氮杂-2,4(3H,5H)-二酮(氯巴占)、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-甲酸(氯氮)、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(氯噻西泮)、10-氯-11b-(2-氯苯基)-2,3,7,11b-四氢唑并[3,2-d][1,4]苯并二氮杂-6(5H)-酮(氯唑仑)、(-)-甲基-[3β-苯甲酰氧基-2β(1αH,5αH)-托烷羧酸盐](可卡因)、4,5α-环氧-3-甲氧基-17-甲基-7-吗啡烯-6α-醇(可待因)、5-(1-环己烯基)-5-乙基巴比土酸(环巴比妥)、赛克罗酚、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、(+)-(1-苄基-3-二甲氨基-2-甲基-1-苯基丙基)丙酸盐(右旋丙氧吩)、地佐辛、地恩丙胺、二醋吗啡(diamorphone)、7-氯-1-甲基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(地西泮)、4,5α-环氧基-3-甲氧基-17-甲基-6α-吗啡喃醇(二氢可待因)、4,5α-环氧基-17-甲基-3,6α-吗啡喃二醇(二氢吗啡)、地美沙朵、地美庚醇(dimephetamol)、二甲基噻吩丁烯胺、吗苯丁酯、地匹哌酮、(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(屈大麻酚)、依他佐辛、8-氯-6-苯基-4H-[1,2,4]三唑并[4,3-(a)][1,4]苯并二氮杂(艾司唑仑)、依索庚嗪、乙基甲基噻吩丁烯胺、[7-氯-5-(2-氟苯基)-2,3-二氢-2-氧代-1H-1,4-苯并二氮杂-3-甲酸]乙酯(氯氟乙酯)、4,5α-环氧基-3-乙氧基-17-甲基-7-吗啡烯-6α-醇(乙基吗啡)、依托尼秦、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(唉托啡)、N-乙基-3-苯基-8,9,10-三降冰片烷-2-基胺(芬坎法明)、7-[2-(α-甲基苯乙基氨基)乙基]-茶碱)(芬乙茶碱)、3-(α-甲基苯乙基氨基)丙腈(芬普雷司)、N-(1-苯乙基-4-哌啶基)丙酰苯胺(芬太尼)、7-氯-5-(2-氟苯基)-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(氟地西泮)、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(氟西泮)、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]唑并[3,2-d][1,4]苯并二氮杂-6(5H)-酮(卤沙唑仑)、海洛因、4,5α-环氧基-3-甲氧基-17-甲基-6-吗啡烷酮(氢可酮)、4,5α-环氧基-3-羟基-17-甲基-6-吗啡烷酮(氢吗啡酮)、羟哌替啶、异美沙酮、羟甲基吗啡喃、11-氯-8,12b-二氢-2,8-二甲基-12b-苯基-4H-[1,3]嗪并[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-哌啶基]-1-丙酮(凯托米酮)、(3S,6S)-乙酸6-二甲基氨基-4,4-二苯基庚烷-3-基酯(左醋美沙朵(LAAM))、(-)-6-二甲氨基-4,4-二苯酚-3-庚酮(左美沙酮)、(-)-17-甲基-3-吗啡喃醇(左吗啡)、左芬啡烷、洛芬太尼、6-(2-氯苯基)-2-(4-甲基-1-哌嗪基亚甲基)-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(劳拉西泮)、7-氯-5-(2-氯苯基)-3-羟基-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(氯甲西泮)、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(美达西泮)、N-(3-氯丙基)-α-甲基苯乙胺(美芬雷司)、哌替啶、二氨基甲酸2-甲基-2-丙基-1,3-丙二醇酯(安宁)、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-4,4-二苯酚-3-庚酮(美沙酮)、2-甲基-3-邻-甲苯基-4(3H)-喹唑啉酮(甲喹酮)、[2-苯基-2-(2-哌啶基)乙酸]甲酯(哌醋甲酯)、5-乙基-1-甲基-5-苯基巴比土酸(甲基苯巴比妥)、3,3-二乙基-5-甲基-2,4-哌啶二酮(甲普里隆)、美托酮、8-氯-6-(2-氟苯基)-1-甲基-4H-咪唑并[1,5a][1,4]苯并二氮杂(咪达唑仑)、2-(二苯甲基亚磺酰基)乙酰胺(莫达非尼)、4,5α-环氧基-17-甲基-7-吗啡烯-3,6α-二醇(吗啡)、麦罗啡、(±)-反式-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(大麻隆)、纳布啡(nalbuphene)、纳洛芬、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(去甲美沙酮)、去甲吗啡、诺匹哌酮、罂粟(鸦片)(Papaver somniferum)类植物的渗出物、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-苯基唑并[3,2-d][1,4]苯并二氮杂-6-(5H)-酮(奥沙唑仑)、4,5α(-环氧基-14-羟基-3-甲氧基-17-甲基-6-吗啡烷酮(羟考酮)、羟吗啡酮、罂粟(Papaver somniferum)(包括setigerum亚种)类植物和植物部分(Papaver somniferum)、阿片全碱、2-亚氨基-5-苯基-4-唑烷酮(pernoline)、1,2,3,4,5,6-六氢-6,11-二甲基-3-(3-甲基-2-丁烯基)-2,6-桥亚甲基-3-苯并氮杂辛英(benzazocin)-8-醇(喷他佐辛)、5-乙基-5-(1-甲基丁基)-巴比土酸(戊巴比妥)、(1-甲基-4-苯基-4-哌啶甲酸)乙酯(哌替啶)、非那多松、非诺啡烷、非那佐辛、苯哌利定、匹米诺定、福尔可定(pholcodeine)、3-甲基-2-苯基吗啉(芬美曲嗪)、5-乙基-5-苯基巴比土酸(苯巴比妥)、α,α-二甲基苯乙胺(芬特明)、7-氯-5-苯基-1-(2-丙炔基)-1H-1,4-苯并二氮杂-2(3H)-酮(匹那西泮)、α-(2-哌啶基)二苯甲基醇(哌苯甲醇)、1′-(3-氰基-3,3-二苯基丙基)[1,4′-联哌啶]-4′-甲酰胺(哌腈米特)、7-氯-1-(环丙基甲基)-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(普拉西泮)、普罗法多、普罗庚嗪、γ-二甲哌替啶、丙哌利定、丙氧芬、N-(1-甲基-2-哌啶子基乙基)-N-(2-吡啶基)丙酰胺、{3-[4-甲氧基羰基-4-(N-苯基丙酰胺基)哌啶子基]丙酸}甲酯(瑞芬太尼)、5-仲丁基-5-乙基巴比土酸(仲丁比妥)、5-烯丙基-5-(1-甲基丁基)-巴比土酸(司可巴比妥)、N-{4-甲氧基甲基-1-[2-(2-噻吩基)乙基]-4-哌啶基}丙酰苯胺(舒芬太尼)、7-氯-2-羟基-甲基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(替马西泮)、7-氯-5-(1-环己烯基)-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(四氢西泮)、(2-二甲氨基-1-苯基-3-环己烯-1-甲酸)乙酯(替利定(顺式和反式))、曲马朵、8-氯-6-(2-氯苯基)-1-甲基-4H-[1,2,4]三唑并[4,3-a][1,4]苯并二氮杂(三唑仑)、5-(1-甲基丁基)-5-乙烯基巴比土酸(乙烯比妥)、(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、(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)苯酚、(1S,2S)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、(2R,3R)-1-二甲基氨基-3(3-甲氧基苯基)-2-甲基-戊-3-醇、(1RS,3RS,6RS)-6-二甲基氨基甲基-1-(3-甲氧基苯基)-环己烷-1,3-二醇优选外消旋体、2-(4-异丁氧基-苯基)-丙酸3-(2-二甲基氨基甲基-1-羟基-环己基)苯基酯、2-(6-甲氧基-萘-2-基)-丙酸3-(2-二甲基氨基甲基-1-羟基-环己基)苯基酯、2-(4-异丁基-苯基)-丙酸3-(2-二甲基氨基甲基-环己-1-烯基)-苯基酯、2-(6-甲氧基-萘-2-基)-丙酸3-(2-二甲基氨基甲基-环己-1-烯基)-苯基酯、(RR,SS)-2-乙酰氧基-4-三氟甲基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR,SS)-2-羟基-4-三氟甲基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR,SS)-4-氯-2-羟基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(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)-苯基酯、(RR,SS)-2-羟基-4-甲氧基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR,SS)-2-羟基-5-硝基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR,SS)-2′,4′-二氟-3-羟基-联苯-4-甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯及相应的立体异构化合物,在各情况中其相应的衍生物,特别是酰胺、酯或醚,及在各情况中其生理上可接受的化合物,特别是其盐和溶剂化物,特别优选盐酸盐。
根据本发明的剂型特别适用于防止阿片类活性成分的滥用,这些成分选自羟考酮、氢吗啡酮、吗啡、曲马朵及其生理上可接受的衍生物或化合物,优选其盐和溶剂化物,优选其盐酸盐。
根据本发明的剂型而且特别适用于防止阿片类活性成分的滥用,这些成分选自(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、(2R,3R)-1-二甲基氨基-3-(3-甲氧基苯基)-2-甲基-戊-3-醇、(1RS,3RS,6RS)-6-二甲基氨基甲基-1-(3-甲氧基苯基)-环己烷-1,3-二醇、(1R,2R)-3-(2-二甲基氨基甲基(nethyl)-环己基)苯酚,其生理上可接受的盐优选盐酸盐,生理上可接受的对映异构体、立体异构体、非对映异构体和外消旋体及其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分别在EP-A-693475和EP-A-780369中有描述。因此相应的内容作为参考文献引入并认为是本公开的一部分。
为了达到必需的断裂强度,在根据本发明的方法中使用至少一种合成或天然聚合物(C),该聚合物具有用本专利申请中公开的方法测定的、至少500N的断裂强度。
优选,为了达到该目的,至少一种聚合物选自:聚环氧烷,优选聚甲醛、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;其共聚物;及至少两种所述聚合物类别或聚合物的混合物。这些聚合物的分子量至少为50万,由流变学测定方法测定。非常特别优选热塑性聚环氧烷例如聚环氧乙烷,具有由流变学测定方法测定的至少50万的分子量,优选至少100万至1500万。这些聚合物的粘度在25℃时,用RVF Brookfield型粘度计(转轴号2/转动速度2rpm)、在5%重量水性溶液中测定为4500-17600cP,用上述粘度计(转轴号1或3/转动速度10rpm)、在2%重量水性溶液中测定为400-4000cP,用上述粘度计(转轴号2/转动速度2rpm)、在1%重量水性溶液中测定为1650-10000cP。
聚合物优选以粉末形式使用。它们在水中可以溶解。
在根据本发明制备的制剂混合物或剂型中,聚合物(C)相对于总重量的量至少为30%重量,优选至少50%-99.9%重量。
为了达到根据本发明获得的剂型所必需的断裂强度,此外可能另外使用至少一种天然或合成的、用本专利申请中所公开的方法测定的断裂强度至少为500N的蜡(D)。
优选使用软化点至少为60℃的蜡。特别优选巴西棕榈蜡和蜂蜡。非常特别优选巴西棕榈蜡。巴西棕榈蜡是一种从巴西棕榈叶中获得的天然蜡,它的软化点至少为80℃。当另外使用蜡组分(D)时,它与至少一种聚合物(C)以使剂型表现出至少500N断裂强度的量一起使用。
可使用的辅助物质(B)为已知的固体剂型制剂常规辅助物质。它们优选塑化剂,例如聚乙二醇、影响活性成分释放的辅助物质,优选疏水性的或亲水性的,优选亲水性聚合物,非常特别优选羟丙基甲基纤维素,和/或抗氧化剂。合适的抗氧化剂有抗坏血酸、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)及α-生育酚。
抗氧化剂优选以相对于剂型总重量的0.01-10%重量、优选0.03-5%重量的量使用。
防滥用固体剂型通过以下方法制备:开始将活性成分、组分(C)、任选蜡组分(D)、任选辅助物质(B)和任选至少一种下列还任选存在的防滥用组分(a)-(f)混合,所得制剂混合物通过施力形成成型制品,优选剂型。
制剂混合物在本领域技术人员已知的混合机中制备。该混合机例如可为辊式混合机、振动式混合机、剪切式混合机或强制式混合机。
所得制剂混合物优选通过施力直接形成成型制品,优选剂型,优选不暴露在热中。制剂混合物例如可通过直接压片形成片剂。直接压片时,压片借助于压片工具,即下冲、上冲和冲模进行。
制剂混合物也可首先制粒,然后成型。
成型优选施加力进行,施加大于或等于0.5kN、优选1-100kN的力。该力优选借助于压机施加,优选具有成型辊或装备辊的成型带的压片机。制剂混合物也可借助于挤出机挤压成线料,其再分断成具有所期望尺寸的成型制品。如果在施力过程中也进行加热,加热应保持在60℃以下。
如果加工制剂混合物产生多颗粒形式的制品,例如颗粒剂、微丸,它们最小的尺寸应为0.5mm,优选尺寸为1-3.5mm。在进一步加工之前,这些成型制品,如果它们的尺寸大部分不是均匀的,优选按尺寸分等级。分等级可借助于筛分方法进行。
在再一种方法步骤c)中,再向成型制品施力,其中在施力之前或在施力过程中,加热成型制品至少至聚合物(C)的软化点,优选大于或等于60℃。施加至少0.1kN的力,优选1kN至最高达120kN,特别优选最高达100kN,非常特别优选最高达至多90kN。正如本领域技术人员所知的那样,用力处理的持续时间取决于所施力的强度,取决于在施力之前或施力期间的加热及任选取决于成型制品的尺寸,并可通过样品测试确定,以便在施力之后,成型制品表现出至少500N的、用下述方法测定的裂断硬度。
必要的加热可优选借助于温度传感器,通过测量成型制品内部温度监控。
力可借助于上述装置连续地或不连续地施加。根据本发明的整个方法可连续地和不连续地进行。
图1显示一种装置,用该装置成型的制品1(在该情况下为片剂)加热后暴露于在具有加压辊2的成型带之间的力下。这些成型带,一个在上、一个在下平行运行,从而提供容纳片剂的手段。箔/膜、优选铝箔或功能性箔/膜(图1中未显示)也可用成型带运行,以便在施力过程中,可同时提供给成型制品1(在该情况下为片剂)覆盖。以该方式覆盖的成型制品可分成所期望数目的连接的剂型,例如泡罩包装。
成型制品可以各种不同的方式加热。优选在烘箱中加热,即借助于加热的气体气氛,或借助于辐射热。加热也可通过电磁波、特别是微波进行。除了装载不连续批次的烘箱外,成型制品经过这些烘箱连续传送的隧道式烘箱也适合。在再一种优选的不同方法中,热也通过传送带输入到成型制品(1)中。
加热优选在保护性气体气氛中进行,特别优选在氮气气氛中进行。
正如已经解释的那样,力可借助于压片机施加,加热的成型制品被提供给冲模。特别是,这也可与旋转(jacketed)片剂制备相联合,其中通过压力施用的外部包封物质可由辅助物质或活性成分/辅助物质混合物组成。
特别优选其中根据c)的施力通过成型辊(见图1)进行的方法。在该方法中,向两个反向转动的、包含容纳各片剂的侧面凹口的加压辊(2)提供加热的成型制品(1)。向在辊间的加热成型制品(1)施力产生所期望的剂型断裂强度。
该方法也适用于连续操作,其中成型制品通过传送带向辊提供,通过这一方式,在向成型制品施力之前,所述制品先直接暴露于隧道式烘箱、辐射源下或通过带加热。
在再一个优选的实施方案中,成型制品(1)用载体(3)传送,该载体包含成型制品(1)的侧面,并特别优选以连续的传送带装配。该载体(3)与同样包含成型制品(1)的部分侧面的第二个成型带(5)形成排列,力施加在这些载体带的两侧。该方法在图2中显示。
在根据本发明的方法中,可最好在其中力施加于成型制品的成型侧面上采用释放剂,及施加于成型制品以使成型制品易于再次从载体带或加压辊分离。合适的释放剂为药学上常规的释放剂,例如滑石、硬脂酸镁。优选的释放剂为在加工温度下不改变其聚集状态的那些释放剂。
此外,最好可在用于施力的设备中提供机械释放助剂,该释放助剂在施力后主动地推出成型制品。例如它可通过在压力下向孔中吹气或通过机械冲进行。
根据本发明的方法可通过在按照c)施力后迅速冷却成型制品来加速和优化。例如,这可通过将成型制品传送到或通过冷却室或通过将它们输入到冷却介质中,例如输入到液态气体中进行。
根据本发明获得的剂型由于其硬度是显著的,例如它们不能通过研磨被粉碎,即使冷却到低温也不能被粉碎。这事实上排除了经口或肠胃外,特别是静脉或经鼻的滥用。
如果虽然通过施以极度的力已经粉碎和/或研碎了根据本发明获得的剂型,然而为了防止任何可能的滥用,在优选的实施方案中,根据本发明获得的剂型还可含有使滥用复杂化或防止滥用的、作为辅助物质(B)的试剂。
根据本发明获得的防滥用剂型除了一种或多种具有滥用潜在性的活性成分外,还包含至少一种硬化聚合物(C)、任选辅助物质(B)及任选至少一种蜡(D),也可相应地包含至少一种下列组分(a)-(e)作为另外任选的辅助物质(B):
(a)至少一种刺激鼻通道和/或咽的物质,
(b)至少一种粘度增加剂,借助于必需最小量的水性液体,优选为从该剂型中获得的水提取物,当输入更多量水性液体时该粘度增加剂形成优选保持视觉可区别的凝胶,
(c)至少一种具有滥用潜在性的各活性成分的拮抗剂,
(d)至少一种催吐剂,
(e)至少一种作为厌恶剂的染料,
(f)至少一种苦味物质。
组分(a)-(f)另外各自单独地适用于根据本发明的防滥用剂型。因此,组分(a)优选适用于防止经鼻、口和/或肠胃外优选静脉滥用的剂型;组分(b)优选适用于防止肠胃外,特别优选静脉内和/或经鼻滥用;组分(C)优选适用于防止经鼻和/或肠胃外滥用,特别优选防止静脉内滥用;组分(D)优选适用于防止肠胃外,特别优选静脉内和/或经口和/或经鼻滥用;组分(e)适合用作防止经口或肠胃外滥用的视觉制止物;而组分(f)适用于防止经口或鼻的滥用。根据本发明联合使用至少一种上述组分,使得仍然更有效地使滥用根据本发明获得的剂型复杂化成为可能。
在一个实施方案中,根据本发明的剂型也可包含两种或多种组分(a)-(f)的组合,优选(a)、(b)及任选(c)和/或(f)和/或(e)或(a)、(b)及任选(d)和/或(f)和/或(e)。
在另一个实施方案中,根据本发明获得的剂型可包含所有组分(a)-(f)。
如果根据本发明获得的剂型包含防滥用组分(a),根据本发明可被认为是刺激鼻通道和/或咽的物质是任何这样的物质:当其相应地通过鼻通道和/或咽给药时,产生身体反应,这种反应对滥用者而言或者非常不愉快以致他/她不愿意或不能继续服用,例如灼烧感,或者生理上抵抗服用相应的活性成分,例如由于鼻分泌物或喷嚏增加。当肠胃外给药特别是静脉内给药时,这些常规刺激鼻通道和/或咽的物质也可产生非常不愉快的感觉或者甚至无法忍受的痛苦,因此滥用者不愿意或不能继续服用该物质。
特别合适的刺激鼻通道和/或咽的物质为引起灼烧感、痒、打喷嚏的冲动、分泌物形成的增加或至少两种这些刺激的组合的物质。适当的物质及其常规使用的量对本领域技术人员而言,本身是已知的或可通过简单的初步试验鉴别。
组分(a)的刺激鼻通道和/或因的物质优选基于至少一种辛辣物质药物的一种或多种成分或一种或多种植物部分。
相应的辛辣物质药物对本领域技术人员而言本身是已知的,并且在例如“Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe”中描述,该书作者Hildebert Wagner教授,第二修订版,Gustav FischerVerlag,Stuttgart-New York,1982,第82页等。相应的内容因此作为参考文献引用并认为是本公开的一部分。
剂量单位表示单独的或可分开给药的单位,例如片剂或胶囊剂。
至少一种辛辣物质药物的一种或多种成分优选可作为组分(a)加入到根据本发明方法获得的剂型中,这些辛辣物质药物选自:大蒜(Alliisativi bulbus)(大蒜)、细辛(Asari rhizoma cum herba)(细辛根和叶)、菖蒲(Calami rhizoma)(菖蒲根)、辣椒(Capsici fructus)(辣椒)、卡宴辣椒(Capsici fructus acer)(卡宴辣椒)、姜黄(Curcumae longae rhizoma)(姜黄根)、爪哇姜黄(Curcumae xanthorrhizae rhizoma)(爪哇姜黄根)、高良姜(Galangae rhizoma)(高良姜根)、肉豆蔻(Myristicae semen)(肉豆蔻)、胡椒(Piperis nigri fructus)(胡椒)、白芥子(Sinapis albae semen/Erucaesemen)(白芥末种子)、黑芥子(Sinapis nigri semen)(黑芥末种子)、莪术(Zedoariae rhizoma)(莪术根)及姜(Zingiberis rhizoma)(姜根),特别优选选自辣椒(Capsici fructus)(辣椒)、卡宴辣椒(Capsici fructus acer)(卡宴辣椒)及胡椒(Piperis nigri fructus)(胡椒)。
辛辣物质药物的成分优选包含邻-甲氧基(甲基)苯酚化合物、酸的酰胺化合物、芥末油或硫化物化合物或由其衍生的化合物。
特别优选,至少一种辛辣物质药物成分选自:肉豆蔻油醚、榄香素、异丁子香酚、β-细辛脑、黄樟脑、姜醇、xanthorrhizol、辣椒素,优选辣椒碱、辣椒碱衍生物,例如N-香兰基-9E-十八烯酰胺、二氢辣椒碱、去甲二氢辣椒碱、高辣椒碱、去甲辣椒碱及nomorcapsaicin,胡椒碱优选反式-胡椒碱,芥子油苷,优选基于非挥发性的芥末油,特别优选基于对-羟基苄基芥末油、甲硫基芥末油或甲磺酰基芥末油,及由这些成分衍生的化合物。
在各情况下相对于该剂量单位总重量,根据本发明获得的剂型优选可含有量为0.01-30%重量,特别优选0.1-0.5%重量的相应辛辣物质药物的植物部分。
如果使用一种或多种相应的辛辣物质药物成分,其在根据本发明的剂量单位中的量优选为相对于该剂量单位总重量的0.001-0.005%重量。
另一个根据本发明获得的防止滥用剂型的选项包括向该剂型中加入至少一种作为另外的防滥用组分(b)的粘度增加剂,借助于必需最小量的水性液体,该粘度增加剂与从该剂型获得的提取物形成凝胶,该凝胶事实上使得安全给药不可能,并且当输入更多量水性液体时优选保持在视觉上是可辨别的。
对本发明的目的而言,视觉上可辨别表示借助于必需最小量的水性液体形成的含活性成分凝胶,当优选借助于皮下注射针、于37℃输入更多量水性液体时,基本上保持不溶并粘合在一起,并且不能直接地以能安全地肠胃外给药,特别是静脉内给药的方式分散。该物质优选保持视觉上可辨别至少一分钟,优选至少10分钟。
提取物粘度的增加使得通过针或注射更困难或者甚至不可能。如果凝胶保持视觉上可辨别,这意味着输入更多量水性液体所获得的凝胶,例如经注射进入血液,最初保持大量粘在一起的线的形式,该线状物虽然确实可以机械地粉碎成更小的片段,但不能以能安全地肠胃外给药,特别是静脉内给药的方式分散或甚至溶解。与至少一种任选存在的组分(a)-(e)组合,这另外导致不愉快的灼烧、呕吐、不良味道和/或视觉上的制止。
该凝胶的静脉内给药最可能导致血管堵塞,这与滥用者健康的严重损害相关。
为了检验粘度增加剂是否适合作为组分(b)用于根据本发明获得的剂型,将活性成分与粘度增加剂混合,并在25℃的温度下悬浮于10ml水中。如果这导致满足上述条件的凝胶形成,则相应的粘度增加剂适用于防止或避免根据本发明的剂型的滥用。
如果将组分(b)加入到根据本发明获得的剂型中,可使用选自以下的一种或多种粘度增加剂:含11%重量羧甲基纤维素钠的微晶纤维素(AvicelRC 591)、羧甲基纤维素钠(Blanose,CMC-Na C300P,Frimulsion BLC-5,Tylose C300P)、聚丙烯酸(Carbopol980 NF,Carbopol981)、刺槐豆粉(CesagumLA-200,CesagumLID/150,CesagumLN-1)、果胶优选产自柠檬果或苹果(CesapectinHM MediumRapid Set)、蜡状玉米淀粉(C*Gel 04201)、藻酸钠(Frimulsion ALG(E401))、瓜儿豆粉(Frimulsion BM,Polygum 26/1-75)、ι-角叉菜胶(Frimulsion D021)、刺梧桐胶、结冷胶(gellan gum)(Kelcogel F,Kelcogel LT100)、半乳甘露聚糖(Meyprogat 150)、他拉(tara)石粉(Polygum 43/1)、丙二醇藻酸酯(Protanal-Ester SD-LB)、透明质酸钠、黄芪胶、他拉胶(Vidogum SP 200)、发酵多糖文莱(welan)胶(K1A96)、黄原胶(Xantural 180)。特别优选黄原胶。括号中所述的名称为这些物质商业上已知的商品名。一般而言,相对于剂型总重量,0.1-20%重量、特别优选0.1-15%重量的所述一种或多种粘度增加剂足够满足上述条件。
其中提供的组分(b)粘度增加剂在根据本发明的剂型中存在的量优选每剂量单位大于或等于5mg,即每给药单位5mg。
在本发明特别优选的实施方案中,用作组分(b)的粘度增加剂为那些在用必需的最小量水性液体从剂型中提取时,形成包裹空气气泡的凝胶的组分。所得凝胶可由浑浊的外观辨别,它向潜在的滥用者提出了另外的视觉警告并阻碍他/她经肠胃外给予该凝胶。
组分(C)也可任选用作另外的粘度增加剂,该粘度增加剂借助于必需的最小量水性液体形成凝胶。
也可以在空间上相互分离的排列方式,将粘度增加剂和其它成分配制成根据本发明获得的剂型。
为了阻碍和防止滥用,根据本发明获得的剂型此外可包含组分(c),即一种或多种具有滥用潜在性的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获得的剂型的其余成分分离,并且当正确使用时,不发挥任何作用。
合适的防止活性成分滥用的拮抗剂对本领域技术人员而言是已知的,可在根据本发明获得的剂型中照此存在,或以相应衍生物的形式存在,特别是以酯或醚的形式存在,或者在各情况中以相应的生理上可接受的化合物形式、特别是以其盐或溶剂化物的形式存在。
如果在剂型中的活性成分是鸦片剂或阿片样物质,所使用的拮抗剂优选选自以下的拮抗剂:纳洛酮、纳曲酮、纳美芬、nalid、纳美酮、烯丙吗啡或naluphine,在各情况下任选以相应的生理上可接受的化合物,特别是以碱、盐或溶剂化物的形式存在。其中提供组分(c)的相应的拮抗剂,优选每剂量单位,即每给药单位以大于或等于1mg的量,特别优选以3-100mg的量,非常特别优选以5-50mg的量使用。
如果根据本发明获得的剂型包含兴奋剂作为活性成分,拮抗剂优选为精神安定药,优选至少一种选自以下的化合物:氟哌啶醇、异丙嗪、氟奋乃静、奋乃静、左美丙嗪、硫利达嗪、培拉嗪、氯丙嗪、氯普噻吨、珠氯噻醇、氟哌噻吨、丙硫喷地、佐替平、苯哌利多、匹泮哌隆、美哌隆及溴哌利多。
根据本发明获得的剂型优选包含那些本领域技术人员已知的常规治疗剂量的拮抗剂,特别优选每给药单位两倍或三倍于常规剂量的量。
如果阻碍和防止根据本发明获得的剂型滥用的组合包含组分(d),它可包含至少一种催吐剂,该催吐剂优选与根据本发明的剂型的其它组分在空间上分离排列,在正确使用时,在体内不发挥其作用。
合适的防止活性成分滥用的催吐剂本身对本领域技术人员而言是已知的,并且可如此存在于根据本发明获得的剂型中,或以相应的衍生物的形式、特别是酯或醚,或在各情况下以相应的生理上可接受的化合物的形式、特别是以其盐或溶剂化物的形式存在。
在根据本发明获得的剂型中,优选可考虑基于一种或多种吐根树(吐根)根成分,优选基于吐根碱成分的催吐剂,例如在“PharmazeutischeBiologie-Drogen und ihre Inhaltsstoffe”中所描述,该书作者为HildebertWagner教授,第二修订版,Gustav Fischer Verlag,Stuttgart,New York,1982。相应的文献内容因此作为参考文献引用,并且认为是本公开的一部分。
根据本发明获得的剂型优选可包含催吐剂吐根碱作为组分(d),优选其在每剂型,即每给药单位的量大于或等于3mg,特别优选大于或等于10mg,并且非常特别优选大于或等于20mg。
同样可优选阿朴吗啡在根据本发明的防滥用剂型中用作催吐剂,优选其在每给药单位的量≥3mg,特别优选≥5mg,并且非常特别优选≥7mg。
如果根据本发明获得的剂型含有作为另外的防滥用辅助物质的组分(e),该染料的使用使相应的水溶液产生很深的颜色,特别是当试图提取活性成分用于经肠胃外、优选静脉内给予时,对潜在的滥用者而言此颜色可用作制止物。口服滥用,通常通过用水提取活性成分开始,也可被此颜色防止。合适的染料和必需的制止所需要的量可在WO 03/015531中查到,其中相应的公开内容应被认为是本公开的一部分并且作为参考文献引用。
如果根据本发明获得的剂型含有组分(f)作为进一步防滥用辅助物质,则加入至少一种苦味物质,该剂型味道破坏的结果又防止了经口和/或经鼻的滥用。
合适的苦味物质及使用的有效量可在US-2003/0064099 A1中查到,其相应的公开应被认为是本申请的公开,并且因此作为参考文献引用。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、水果香气物质,优选来自柠檬、橙、酸橙、葡萄或其混合物的香气物质,和/或地那铵苯甲酸盐。特别优选地那铵苯甲酸盐。
根据本发明获得的固体剂型适用于人和动物经口、阴道或直肠给药,优选口服给药。该剂型优选不是膜形式。根据本发明的可口服给药剂型可假定为多颗粒形式,优选微片剂、微囊剂、微丸剂、颗粒剂、球、珠或丸形式,任选装在胶囊中或压成片。多颗粒形式的最小尺寸优选为0.5mm,特别优选在1-3.5mm范围内。根据所期望的剂型,常规辅助物质(B)也任选用于剂型的形成。
在进一步优选的实施方案中,根据本发明的剂型假定为片剂、胶囊剂形式,或如果也还存在至少一种防滥用组分(a)-(f),优选为口服渗透治疗系统(OROS)形式。
如果在根据本发明获得的剂型中有组分(c)和/或(d)和/或(f),必须小心以确保它们以该方式配制或以此低剂量存在:即当正确给药时,该剂型事实上不能够产生损害患者的作用或产生活性成分的效力。
如果根据本发明制备的剂型含有组分(d)和/或(f),必须选择剂量,使得正确口服给药时不产生副作用。然而,如果该剂型预定的剂量非故意地过量,特别是对儿童而言过量,或如果滥用,可产生恶心或呕吐的倾向或不良的气味。如果患者正确口服给药仍然可忍受的组分(d)和/或(f)的特定量,可由本领域技术人员通过简单的初步试验确定。
然而,如果不顾根据本发明制备的剂型实际上不可能被研碎的事实,而为含有组分(c)和/或(d)和/或(f)的剂型提供保护,这些组分优选应以足够高的剂量使用,使当滥用给药时,它们能对滥用者产生强烈的副作用。这优选通过至少活性成分或来自组分(c)和/或(d)和/或(f)的活性成分的空间分离实现,其中活性成分或那些活性成分以至少一个亚单位(X)存在,而组分(c)和/或(d)和/或(f)以至少一个亚单位(Y)存在,并且其中当该剂型正确给药时,组分(c)、(d)和(f)对服用和/或在体内不发挥其作用,并且该制剂的其余组分,特别是组分(C)是相同的。
如果根据本发明的剂型包含组分(c)和(d)或(f)中的至少2种,这些组分可各自以相同或不同的亚单位(Y)存在。优选,当存在时,所有组分(c)和(d)和(f)以一种且相同的亚单位(Y)存在。
对本发明的目的而言,亚单位为固体制剂,在每种情况中,除了本领域技术人员已知的常规辅助物质外,它还含有一种或多种活性成分,优选也含至少一种聚合物(C)并任选存在组分(D)及任选至少一种任选存在组分(a)和/或(b)和/或(e),或优选在各种情况中含有至少一种聚合物(C)和任选(D)和一种或多种拮抗剂和/或一种或多种催吐剂和/或组分(e)和/或组分(f)及任选至少一种任选存在组分(a)和/或(b)。在此必须注意确保各亚单位按照根据本发明的上述方法配制,如果期望或需要机械技能的话。
根据本发明制备的剂型的活性成分与亚单位(X)和(Y)中组分(c)或(d)或(f)分别配制的一个重大优势是,当正确给药时,组分(c)和/或(d)和/或(f)在服用时和/或在体内几乎不被释放,或者仅释放很少的量使其不能发挥有损患者或有损治疗成功的作用,或者在从患者体内经过时,它们仅在它们不能足够被吸收而有效的部位释放。当剂型正确给药时,优选任一组分(c)和/或(d)和/或(f)几乎不在患者体内释放,或它们不被患者注意而消失。
本领域技术人员将理解:上述条件可随所用的特定组分(c)、(d)和/或(f)的功能及亚单位或剂型制剂的功能而变化。特定剂型的最佳配制可通过简单的初步试验确定。如果有必要预防滥用,各亚单位含有聚合物(C)并已经按所述方式配制及根据本发明制备是重要的。
如果与期待的相反,滥用者为了滥用活性成分的目的成功地粉碎了根据本发明的剂型,该剂型在亚单位(Y)中包含组分(c)和/或(e)和/或(d)和/或(f),并且获得了用合适的提取剂提取的粉末,不仅活性成分而且特定的组分(c)和/或(e)和/或(f)和/或(d)将以不能容易地与该活性成分分离的形式获得,使得当给予该已经被损坏的剂型时,特别是经口和/或肠胃外给药时,它将对服用和/或在体内发挥其作用,并对滥用者具有相应于组分(c)和/或(d)和/或(f)的另外副作用,或者当试图提取活性成分时,颜色将起制止剂的作用并因此防止该剂型的滥用。
根据本发明的剂型,其中活性成分或那些活性成分优选通过配制成不同的亚单位在空间上与组分(c)、(d)和/或(e)分离,可以许多不同的方式配制,其中相应的亚单位可各自以相对于彼此的任何所期望空间排列存在于根据本发明的剂型中,条件是满足上述释放组分(c)和/或(d)的条件。
本领域技术人员将理解:任选也存在的一种或多种组分(a)和/或(b)可优选以特定的亚单位(X)和(Y)以及相应于亚单位(X)和(Y)的独立亚单位形式,配制成根据本发明制备的剂型,条件是如果正确给药,既无防滥用又无活性成分释放,则被制剂的性质破坏,及聚合物(C)优选包括在该制剂中,并且配制优选按照根据本发明的方法进行。
在优选的根据本发明制备的剂型实施方案中,亚单位(X)和(Y)以多颗粒形式存在,其中优选颗粒、球、珠或丸,亚单位(X)和亚单位(Y)选择相同的形式,即形状,使得不可能由机械选择将亚单位(X)与(Y)分离。多颗粒形式的尺寸优选在0.5-3.5mm,优选0.5-2mm范围内。
多颗粒形式的亚单位(X)和(Y)优选也可包装在胶囊中或模压成片剂,其中在各情况中的最终配制以亚单位(X)和(Y)也保留在所得剂型中的方式进行。
相同形状的多颗粒亚单位(X)和(Y)也应彼此在视觉上不可分辨,因此滥用者不能由简单的挑选将它们相互分离。例如,这可通过采用相同的包衣实现,该包衣除了这种伪装功能,也可具有其他功能,例如,延缓一种或多种活性成分的释放或为特定的亚单位提供对胃液的最终抵抗。
多颗粒亚单位也可配制成如浆或在药学上安全的悬浮介质中的悬浮液的口服剂型。
在进一步优选的本发明实施方案中,亚单位(X)和(Y)在各情况中相互以层形式排列。
层状的亚单位(X)和(Y)优选为此目的在根据本发明制备的剂型中相互垂直或平行地排列,其中在各情况中一个或多个层状的亚单位(X)和一个或多个层状的亚单位(Y)也可在剂型中存在,使得除了优选的层顺序(X)-(Y)或(X)-(Y)-(X)外,也可考虑任何期望的其他层顺序,任选与含组分(a)和/或(b)的层组合。
另一个优选的根据本发明制备的剂型为其中的亚单位(Y)形成完全由亚单位(X)包裹的核,其中在所述层之间可存在分隔层(Z)。该结构优选也适用于上述多颗粒形式,其中亚单位(X)和(Y)及任选存在分隔层(Z),其应优选满足根据本发明的硬度要求,然后使用根据本发明的方法配制成一种并且相同的多颗粒形式。
在进一步优选的根据本发明制备的剂型实施方案中,亚单位(X)形成被亚单位(Y)包裹的核,其中后者包含至少一个从核通向该剂型表面的通道。
在各情况中,根据本发明制备的剂型可在一层亚单位(X)和一层亚单位(Y)之间包括一层或多层,优选一层任选可吞服的分隔层(Z),分隔层(Z)用于在空间上分离亚单位(X)和(Y)。
如果根据本发明制备的剂型包含至少部分垂直或水平安排的层状亚单位(X)和(Y)及任选存在分隔层(Z),该剂型优选采取用根据本发明的方法已经制备的片、共挤出或层压形式。
在一个特别优选的实施方案中,亚单位(Y)的自由表面全部、任选至少一个或多个亚单位(X)自由表面的一部分和任选至少部分任选存在的一个或多个分隔层(Z)的自由表面,可用至少一个防止组分(c)和/或(e)和/或(d)和/或(f)释放的隔离层(Z′)涂覆。隔离层(Z′)应优选也满足根据本发明的硬度条件。
另一个特别优选的根据本发明制备的剂型实施方案包括垂直或水平排列的亚单位(X)和(Y)的层及至少一个排列在其间的推压层(p),及任选分隔层(Z),在该剂型中,由亚单位(X)和(Y)组成的层结构的自由表面全部、推压层及任选存在的分隔层(Z)涂覆有半透的涂层(E),该涂层对释放介质即常规上的生理液体可渗透,但是对活性成分及对组分(c)和/或(d)和/或(f)基本上不渗透,并且其中该涂层(E)在亚单位(X)区域包含至少一个用于释放活性成分的孔。
对本领域技术人员而言相应的剂型是已知的,例如名叫口服渗透治疗系统(OROS)的剂型,其用于制备的合适物质和方法在US4,612,008,US 4,765,989及US 4,783,337中可以找到。因此相应的内容作为参考引用并被认为是本公开的一部分。
在进一步优选的实施方案中,根据本发明制备的剂型的亚单位(X)为片形式,其边缘面及任选两个主要面之一用含有组分(c)和/或(d)和/或(f)的隔离层(Z′)覆盖。
本领域技术人员将理解:用于根据本发明制备各剂型的一个或多个亚单位(X)或(Y)及任选存在的一个或多个分隔层(Z)和/或一个或多个隔离层(Z′)的辅助物质,将随其在剂型中的排列功能、给药方式而变化,并随任选存在的组分(a)和/或(b)和/或(e)及组分(c)和/或(d)和/或(f)的特定活性成分的功能而变化。在各情况中,具有必要性质的物质本身对本领域技术人员而言是已知的。
如果组分(c)和/或(d)和/或(f)从根据本发明制备的剂型的亚单位(Y)中的释放被借助于覆盖、优选隔离层防止,该亚单位可由本领域技术人员已知的常规物质组成,条件是它们含有至少一种聚合物(C)和任选(D),及优选根据本发明已经制备出。
如果相应的隔离层(Z′)不提供防止组分(c)和/或(d)和/或(f)的释放,应选择该亚单位的物质使得特定组分(c)和/或(d)从亚单位(Y)中的释放事实上被排除。
为此目的,可优选使用下述适用于隔离层制备的物质。
优选的物质为选自以下的物质:烷基纤维素、羟烷基纤维素、葡聚糖、硬化葡聚糖、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20∶80的共聚物(商业上以Polifeprosan20出售);羧甲基纤维素、纤维素醚、纤维素酯、硝化纤维素、基于(甲基)丙烯酸及其酯的聚合物、聚酰胺、聚碳酸酯、聚烯(polyalkylenes)、聚烷二醇、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、卤化聚乙烯、聚乙交酯、聚硅氧烷及聚氨酯及其共聚物。
特别合适的物质可选自: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、纤维素硫酸钠、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸丁酯、聚甲基丙烯酸异丁基酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸基酯、聚甲基丙烯酸月桂基酯、聚甲基丙烯酸苯基酯、聚丙烯酸甲酯、聚丙烯酸异丙基酯、聚丙烯酸异丁基酯、聚丙烯酸十八烷基酯、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1,2-乙二醇酯、聚乙烯醇、聚乙烯异丁基醚、聚乙酸乙烯酯及聚氯乙烯。
特别合适的共聚物可选自:甲基丙烯酸丁酯与甲基丙烯酸异丁酯的共聚物、甲基乙烯基醚与马来酸的高分子量共聚物、甲基乙烯基醚与马来酸单乙酯的共聚物、甲基乙烯基醚与马来酸酐的共聚物及乙烯基醇与乙酸乙烯酯的共聚物。
再一些特别适用于配制隔离层的物质有淀粉填充的聚己内酯(WO98/20073)、脂族聚酯酰胺(DE 19 753 534 A1,DE 19 800 698 A1,EP 0 820 698 A1)、脂族和芳族聚酯尿烷(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(DE 4 309 528)、聚交酯和共聚交酯(DE 0 980 894 A1)。因此相应的描述作为参考文献引用并认为是本公开的一部分。
上述物质可任选与另外的、本领域技术人员已知的常规辅助物质共混,这些辅助物质优选选自:甘油单硬脂酸酯、半合成甘油三酯衍生物、半合成甘油酯、氢化蓖麻油、棕榈酰硬脂酸甘油酯、甘油二十二烷酸酯、聚乙烯吡咯烷酮、明胶、硬脂酸镁、硬脂酸、硬脂酸钠、滑石、苯甲酸钠、硼酸和胶体二氧化硅、脂肪酸、取代的甘油三酯、甘油酯、聚氧烷二醇及其衍生物。
如果根据本发明制备的剂型包含分隔层(Z′),所述层,同未覆盖的亚单位(Y)一样,优选可由上述描述用于隔离层的物质组成。本领域技术人员将理解:活性成分或组分(c)和/或(d)从特定的亚单位中释放可通过该分隔层的厚度控制。
根据本发明制备的剂型表现出活性成分的控制释放。对于患者的日重复给药,它优选适合,例如用于抗人患者的疼痛。
根据本发明制备的剂型可包含一种或多种活性成分,至少部分为进一步延缓释放形式,其中延缓释放可借助于本领域技术人员已知的常规物质和方法实现,例如通过将活性成分置入延缓释放骨架中或通过采用一种或多种延缓释放包衣。然而,必须控制活性成分的释放使得在各情况中满足上述条件,例如,如果正确给予该剂型,活性成分或那些活性成分事实上在任选存在的组分(c)和/或(d)能发挥破坏作用之前完全释放。
此外,加入影响控制释放的物质必须不损害必要的硬度。
根据本发明制备的剂型的控制释放优选通过将活性成分置于骨架中实现。起骨架材料作用的辅助物质控制活性成分的释放。例如,骨架材料可为亲水性、形成凝胶的物质,其中活性成分的释放主要通过扩散进行;或为疏水性物质,其中活性成分的释放主要通过骨架中小孔的扩散进行。
本领域技术人员已知的、生理上可接受的疏水性物质可用作骨架材料。聚合物,特别优选纤维素醚、纤维素酯和/或丙烯酸树脂优选用作亲水性骨架材料。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(甲基)丙烯酸和/或其衍生物例如其盐、酰胺或酯非常特别优选用作骨架材料。
也优选由疏水性物质,例如疏水性聚合物、蜡、脂肪、长链脂肪酸、脂肪醇或相应的酯或醚或其混合物制备的骨架材料。C12-C30脂肪酸和/或C12-C30脂肪醇的单-或二甘油酯和/或蜡或其混合物特别优选用作疏水性物质。
也可使用上述亲水性和疏水性物质的混合物作为骨架材料。
此外,根据本发明获得的用于实现至少500N断裂强度的组分(C)和任选存在的组分(D),其本身可用作另外的骨架材料。
如果根据本发明制备的剂型将用于口服给药,它优选也可包含能抵抗胃液并随释放环境pH值的函数溶出的包衣。
通过该包衣,可确保根据本发明制备的剂型经过胃不溶出,并且活性成分仅在肠道释放。抵抗胃液的包衣优选于pH值在5-7.5之间溶解。
控制活性成分释放和采用抵抗胃液包衣的相应物质和方法对本领域技术人员而言是已知的,例如在“Coated Pharmaceutical DosageForms-Fundamentals,Manufacturing Techniques,BiopharmaceuticalAspects,Test Methods and Raw Materials”,Kurt H.Bauer,K.Lehmann,Hermann P.Osterwald,Rothgang,Gerhart,第一版,1998,MedpharmScientific Publishers中描述的。相应的文献内容因此作为参考引用并且认为是本公开的一部分。
测定断裂强度的方法
A)为了确证聚合物是否可用作组分(C)或(D),使用150N的力,在至少相应于聚合物软化点并借助于该聚合物的DSC图测定的温度下,将该聚合物压成直径10mm、高5mm的片。用以该方式制备的片剂,按照欧洲药典1997年版,143、144页,方法no.2.9.8中公布的测定片剂断裂强度的方法,采用下述仪器测定断裂强度。用于测定的仪器是Zwick GmbH & Co.KG,UIm,Germany的“TMTC-FR2.5TH.D09”型号的单柱台式材料测试仪,Fmax=2.5kN,最大拉伸1150mm,该仪器应装备一个柱和一个转轴,在100mm之后的间隙及可在0.1-800mm/分钟之间调节的测试速度以及测试控制软件。测定使用压力活塞进行,该压力活塞具有旋入式嵌件及汽缸(直径10mm)、力传感器、Fmax 1kN、直径=8mm,等级0.5从10N、等级1从2N至ISO7500-1,具有生产商的测试证明M-DIN 55350-18(Zwick gross forceFmax=1.45kN)(所有仪器均来自Zwick GmbH & Co.KG,UIm,Germany),测试仪的订货号为BTC-FR 2.5TH.D09,力传感器的订货号为BTC-LC 0050N.P01,定心装置的订货号为BO 70000 S06。
图3显示片剂的断裂强度测定,特别是在测定之前和测定期间,用于该目的的片(4)调节装置(6)。为了达到该目的,片(4)借助于两个2-部分夹钳装置置于施力装置(未显示)的上压力板(1)和下压力板(3)之间,一旦确立了待测定片剂的调节和定心必要的间隙(5),在各情况下该2-部分夹钳装置用上下压力板牢固地扣紧(未显示)。在各情况下,在它们被安放的压力板上,间隙(5)可通过水平地向外或向内移动该2-部分夹钳装置确立。
被认为抗特殊负载断裂的片剂不仅包括那些未断裂的而且也包括在力的作用下可能遭受可塑性变形的那些片剂。
根据本发明获得的剂型的断裂强度通过所述测定方法测定,并且也测试了不是片剂的剂型。
下面结合实施例解释本发明。这些解释仅通过实施例的方式给出,并不限制本发明的整体概念。
实施例:
在一系列实施例中,曲马朵盐酸盐用作活性成分。尽管曲马朵不是通常的具有滥用潜在性的活性成分,因为它不由德国麻醉剂法规管理,而且曲马朵是具有良好水溶性的阿片样物质类成员,所以为了简化试验工作,还是使用曲马朵盐酸盐。
实施例1:
组分 | 每片 | 整批 |
曲马朵HCl | 100.0mg | 60.0g |
聚环氧乙烷,NF,MFI(190℃,21.6kg/10min)MW 7,000,000(PolyoxWSR 303,Dow Chemicals) | 221.0mg | 132.6g |
羟丙基甲基纤维素100,000cP(Metholose 90SH 100,000) | 20.0mg | 12.0g |
硬脂酸镁 | 9.0mg | 54g |
总重量 | 350.0mg | 210.0g |
将曲马朵盐酸盐和聚环氧乙烷粉末及羟丙基甲基纤维素在自由沉降混合机中混合。然后将硬脂酸镁粉末混入其中。在Korsch EK0偏心压片机上将该粉末混合物压成片。压片工具的直径为10mm、曲率半径为8mm。借助于实验室热封仪(Kopp实验室密封仪SPGE 20,Kopp的Hot & Cold tack热-封缝接强度(seam strength)测试仪)进一步加工这些片剂。热封条替换成两个金属横杆,其中各金属横杆磨有直径10mm及半径8mm的凹面。凹面的表面用聚四氟乙烯涂覆。一旦热封条被置于热封仪上,两个补充的凹面产生片剂在各情况下被放置其中的镜片形状。热封条预先加热至130℃,放入片剂,然后施以750N的力,保持2.5分钟。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
活性成分曲马朵从片剂中的体外释放按照欧洲药典,用带沉降篮桨式搅拌装置测定。释放介质的温度为37℃,搅拌桨的转动速率为75min-1。所用的释放介质为pH 6.8的肠液。在各情况下、在任一时间,活性成分释放至溶出介质的量用分光光度法测定。
时间 | 释放的活性成分的量 |
30分钟 | 21% |
240分钟 | 70% |
480分钟 | 94% |
720分钟 | 100% |
实施例2:
组分 | 每片 | 整批 |
曲马朵HCl | 100.0mg | 60.0g |
聚环氧乙烷,NF,MFI(190℃,21.6kg/10min)MW 5,000,000(PolyoxWSR Coagulant,Dow Chemicals) | 221.0mg | 132.6g |
羟丙基甲基纤维素100,000cP(Metholose 90 SH 100,000) | 20.0mg | 12.0g |
硬脂酸镁 | 9.0mg | 5.4g |
总重量 | 350.0mg | 210.0g |
按实施例1所述,制备直径为10mm及曲率半径为8mm的片。
除了密封条加热到100℃外,片剂也按实施例1进一步加工。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
活性成分从制剂中的体外释放按照欧洲药典,用带沉降篮桨式搅拌装置测定。释放介质的温度为37℃,搅拌桨的转动速率为75min-1。所用的释放介质为pH 6.8的肠液。在各情况下、在任一时间,活性成分释放至溶出介质的量用分光光度法测定。
时间 | 释放的活性成分的量 |
30分钟 | 17% |
240分钟 | 60% |
480分钟 | 84% |
720分钟 | 95% |
实施例3:
组分 | 每片 | 整批 |
曲马朵HCl | 100.0mg | 60.0g |
聚环氧乙烷,NF,MFI(190℃,21.6kg/10min)MW 7,000,000,细粉末(Polyox WSR 303 FP,Dow Chemicals) | 221.0mg | 132.6g |
羟丙基甲基纤维素100,000cP(Metholose 90 SH 100,000) | 20.0mg | 12.0g |
硬脂酸镁 | 9.0mg | 5.4g |
总重量 | 350.0mg | 210.0g |
片剂按实施例1所述制备。片剂也按实施例1所述进一步加工。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
活性成分从制剂中的体外释放按照欧洲药典,用带沉降篮桨式搅拌装置测定。释放介质的温度为37℃,搅拌桨的转动速率为75min-1。所用的释放介质为pH 6.8的肠液。在各情况下、在任一时间,活性成分释放至溶出介质的量用分光光度法测定。
时间 | 释放的活性成分的量 |
30分钟 | 21% |
240分钟 | 69% |
480分钟 | 93% |
720分钟 | 100% |
实施例4:
组分 | 每片 | 整批 |
曲马朵HCl | 100.0mg | 60.0g |
聚环氧乙烷,NF,MFI(190℃,21.6kg/10min)MW 7,000,000(Polyox WSR 303,DowChemicals) | 221.0mg | 132.6g |
羟丙基甲基纤维素100,000cP(Metholose 90SH 100,000) | 20.0mg | 12.0g |
硬脂酸镁 | 9.0mg | 5.4g |
总重量 | 350.0mg | 210.0g |
片剂按实施例1所述制备。
然后片剂在微波炉中、于700瓦特加热10分钟。再按实施例1所述进行加工,不同之处在于使用各包括5个凹面的2个热封条,并使用加热到100℃的密封条,在各情况下将5个加热的片剂暴露在1000N的力中,保持30秒。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
实施例5:
组分 | 每片 | 整批 |
曲马朵HCl | 100.0mg | 60.0g |
聚环氧乙烷,NF,MFI(190℃,21.6kg/10min)MW 7,000,000(Polyox WSR 303,Dow Chemicals) | 221.0mg | 132.6g |
羟丙基甲基纤维素100,000cP(Metholose 90 SH 100,000) | 20.0mg | 12.0g |
硬脂酸镁 | 9.0mg | 5.4g |
总重量 | 350.0mg | 210.0g |
片剂按实施例1所述制备。
然后片剂在N2气氛中、于110℃下,在循环空气室中加热45分钟。片剂按实施例4所述进一步加工,不同之处在于密封条加热到130℃。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
实施例6:
组分 | 每片 | 整批 |
曲马朵HCl | 100.0mg | 60.0g |
聚环氧乙烷,NF,MFI(190℃,21.6kg/10min)MW 7,000,000(Polyox WSR 303,Dow Chemicals) | 221.0mg | 132.6g |
羟丙基甲基纤维素100,000cP(Metholose 90 SH 100,000) | 20.0mg | 12.0g |
硬脂酸镁 | 9.0mg | 5.4g |
总重量 | 350.0mg | 210.0g |
片剂按实施例1所述制备。
按实施例1所述进行进一步加工,不同之处在于密封条加热到130℃,并且当置于10N的力时片剂在下条预加热2分钟。然后片剂在压缩后于130℃施以1000N的力,保持20秒。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
实施例7:
组分 | 每片 | 整批 |
曲马朵HCl | 100mg | 18.2g |
聚环氧乙烷,NF,MW 7,000,000(Polyox WSR 303,FP,Dow Chemicals) | 165mg | 30.0g |
聚乙二醇6000 | 7mg | 1.3g |
丁基羟基甲苯 | 0.3mg | 0.1g |
硬脂酸镁 | 2.7mg | 0.5g |
总重量 | 274.8mg | 50.0g |
将上述量的丁基羟基甲苯溶解于0.6g乙醇(96%)中。将该溶液与聚乙二醇6000混合,然后于40℃干燥12小时。将除了硬脂酸镁外所有另外的组分加入,并在自由沉降混合机中混合15分钟。然后将硬脂酸镁混入其中。该混合物过0.8mm筛。
使用Korsch EK0偏心压片机,用过筛的混合物制备片剂(直径:10mm,曲率半径:8mm)。然后在干燥室中,在N2气氛中加热这些片剂至80℃,保持15分钟。
热片在偏心压片机(Kilian/IMA,型号SP 300)上,用80kN的力再压。所用工具是直径为11mm及曲率半径为8mm的压片冲。
用上述方法测定片剂的断裂强度。当施以500N的力时,未出现断裂。片剂不能用锤粉碎,也不能借助于槌和研钵粉碎。
活性成分从制剂中的体外释放按照欧洲药典,用带沉降篮桨式搅拌装置测定。释放介质的温度为37℃,搅拌桨的转动速率为75min-1。所用的释放介质为pH 6.8的肠液。在各情况下、在任一时间,活性成分释放至溶出介质的量用分光光度法测定。
时间 | 释放的活性成分的量 |
30分钟 | 17% |
240分钟 | 65% |
480分钟 | 87% |
720分钟 | 95% |
Claims (10)
1.一种具有至少降低滥用潜在性的固体药物剂型的制备方法,其特征在于:
a)通过施力将制剂混合物形成成型制品,所述制剂混合物含有至少一种具有滥用潜在性的活性成分、至少一种具有至少500N断裂强度的合成或天然聚合物(C)以及任选的辅助物质(B),
b)任选将所成型制品分断,并任选在各情况下按尺寸分等级,和
c)在至少加热至聚合物(C)的软化点后或期间,将所成型制品暴露于力下直到它们具有至少500N的裂断硬度,任选提供给它们覆盖,并任选将所有成型制品再混合在一起。
2.权利要求1的方法,其特征在于所述方法连续或不连续进行。
3.权利要求1或权利要求2的方法,其特征在于所述制剂混合物包含至少30%重量限度的组分(C)。
4.权利要求1-3中任一项的方法,其特征在于所述制剂混合物包含至少50%重量限度的组分(C)。
5.权利要求1-4中任一项的方法,其特征在于:a)所述制剂混合物的成型在施用至少0.5kN的力并任选加热至小于60℃进行。
6.权利要求1-5中任一项的方法,其特征在于:根据c),在施用至少0.1kN的力、优选1kN-120kN前或期间,所述成型制品被加热至至少60℃。
7.权利要求1-6中任一项的方法,其特征在于根据a)或c)的施力借助于压机进行,优选压片机、成型辊或装备辊的成型带。
8.权利要求1-7中任一项的方法,其特征在于根据a)的成型得到片剂。
9.权利要求1-7中任一项的方法,其特征在于根据a)的成型得到最小尺寸为0.5mm、优选1-3.5mm的多颗粒剂型。
10.权利要求1-9中任一项的方法,其特征在于阿片类活性成分用作活性成分。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE10361596.2 | 2003-12-24 | ||
DE10361596A DE10361596A1 (de) | 2003-12-24 | 2003-12-24 | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
PCT/EP2004/014679 WO2005063214A1 (de) | 2003-12-24 | 2004-12-23 | Verfahren zur herstellung einer gegen missbrauch gesicherten darreichungsform |
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-
2003
- 2003-12-24 DE DE10361596A patent/DE10361596A1/de not_active Withdrawn
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2004
- 2004-12-22 AR ARP040104887A patent/AR046994A1/es not_active Application Discontinuation
- 2004-12-23 WO PCT/EP2004/014679 patent/WO2005063214A1/de active Application Filing
- 2004-12-23 AU AU2004308653A patent/AU2004308653B2/en not_active Ceased
- 2004-12-23 PL PL04804271T patent/PL1699440T3/pl unknown
- 2004-12-23 DE DE502004010368T patent/DE502004010368D1/de active Active
- 2004-12-23 CN CN2004800418549A patent/CN1917862B/zh not_active Expired - Fee Related
- 2004-12-23 PT PT04804271T patent/PT1699440E/pt unknown
- 2004-12-23 JP JP2006546080A patent/JP4895821B2/ja not_active Expired - Fee Related
- 2004-12-23 DK DK04804271.7T patent/DK1699440T3/da active
- 2004-12-23 ES ES04804271T patent/ES2336571T3/es active Active
- 2004-12-23 AT AT04804271T patent/ATE447942T1/de active
- 2004-12-23 CA CA002551231A patent/CA2551231A1/en not_active Abandoned
- 2004-12-23 EP EP04804271A patent/EP1699440B1/de active Active
- 2004-12-23 SI SI200431334T patent/SI1699440T1/sl unknown
-
2005
- 2005-01-03 PE PE2005000026A patent/PE20050814A1/es not_active Application Discontinuation
-
2006
- 2006-06-14 IL IL176296A patent/IL176296A0/en active IP Right Grant
- 2006-06-20 US US11/471,438 patent/US20070003616A1/en not_active Abandoned
-
2007
- 2007-03-13 HK HK07102732.2A patent/HK1099511A1/xx not_active IP Right Cessation
-
2008
- 2008-06-17 US US12/140,718 patent/US20090005408A1/en not_active Abandoned
-
2010
- 2010-02-11 CY CY20101100142T patent/CY1110609T1/el unknown
-
2013
- 2013-08-08 US US13/962,098 patent/US20130320592A1/en not_active Abandoned
-
2014
- 2014-12-23 US US14/580,578 patent/US20150164811A1/en not_active Abandoned
-
2016
- 2016-09-02 US US15/255,441 patent/US20170049706A1/en not_active Abandoned
- 2016-09-06 US US15/257,079 patent/US11224576B2/en active Active
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US9675610B2 (en) | 2002-06-17 | 2017-06-13 | Grünenthal GmbH | Abuse-proofed dosage form |
US10369109B2 (en) | 2002-06-17 | 2019-08-06 | Grünenthal GmbH | Abuse-proofed dosage form |
US10058548B2 (en) | 2003-08-06 | 2018-08-28 | Grünenthal GmbH | Abuse-proofed dosage form |
US10130591B2 (en) | 2003-08-06 | 2018-11-20 | Grünenthal GmbH | Abuse-proofed dosage form |
US9629807B2 (en) | 2003-08-06 | 2017-04-25 | Grünenthal GmbH | Abuse-proofed dosage form |
US11224576B2 (en) | 2003-12-24 | 2022-01-18 | Grünenthal GmbH | Process for the production of an abuse-proofed dosage form |
US11844865B2 (en) | 2004-07-01 | 2023-12-19 | Grünenthal GmbH | Abuse-proofed oral dosage form |
US10729658B2 (en) | 2005-02-04 | 2020-08-04 | Grünenthal GmbH | Process for the production of an abuse-proofed dosage form |
US10675278B2 (en) | 2005-02-04 | 2020-06-09 | Grünenthal GmbH | Crush resistant delayed-release dosage forms |
US9750701B2 (en) | 2008-01-25 | 2017-09-05 | Grünenthal GmbH | Pharmaceutical dosage form |
US10493033B2 (en) | 2009-07-22 | 2019-12-03 | Grünenthal GmbH | Oxidation-stabilized tamper-resistant dosage form |
US9925146B2 (en) | 2009-07-22 | 2018-03-27 | Grünenthal GmbH | Oxidation-stabilized tamper-resistant dosage form |
US9636303B2 (en) | 2010-09-02 | 2017-05-02 | Gruenenthal Gmbh | Tamper resistant dosage form comprising an anionic polymer |
US10300141B2 (en) | 2010-09-02 | 2019-05-28 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
US10201502B2 (en) | 2011-07-29 | 2019-02-12 | Gruenenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
US10864164B2 (en) | 2011-07-29 | 2020-12-15 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
US10695297B2 (en) | 2011-07-29 | 2020-06-30 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
US9655853B2 (en) | 2012-02-28 | 2017-05-23 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
US10335373B2 (en) | 2012-04-18 | 2019-07-02 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
US10154966B2 (en) | 2013-05-29 | 2018-12-18 | Grünenthal GmbH | Tamper-resistant dosage form containing one or more particles |
US9737490B2 (en) | 2013-05-29 | 2017-08-22 | Grünenthal GmbH | Tamper resistant dosage form with bimodal release profile |
US10624862B2 (en) | 2013-07-12 | 2020-04-21 | Grünenthal GmbH | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
US10449547B2 (en) | 2013-11-26 | 2019-10-22 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
US9913814B2 (en) | 2014-05-12 | 2018-03-13 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
US9872835B2 (en) | 2014-05-26 | 2018-01-23 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
US9855263B2 (en) | 2015-04-24 | 2018-01-02 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
US10842750B2 (en) | 2015-09-10 | 2020-11-24 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
Also Published As
Publication number | Publication date |
---|---|
US20160367487A1 (en) | 2016-12-22 |
SI1699440T1 (sl) | 2010-03-31 |
PT1699440E (pt) | 2010-02-17 |
US20070003616A1 (en) | 2007-01-04 |
IL176296A0 (en) | 2006-10-05 |
ATE447942T1 (de) | 2009-11-15 |
DE502004010368D1 (de) | 2009-12-24 |
EP1699440B1 (de) | 2009-11-11 |
AU2004308653A1 (en) | 2005-07-14 |
CN1917862B (zh) | 2011-08-03 |
DK1699440T3 (da) | 2010-03-29 |
JP2007516998A (ja) | 2007-06-28 |
WO2005063214A1 (de) | 2005-07-14 |
HK1099511A1 (en) | 2007-08-17 |
US20150164811A1 (en) | 2015-06-18 |
ES2336571T3 (es) | 2010-04-14 |
US20130320592A1 (en) | 2013-12-05 |
EP1699440A1 (de) | 2006-09-13 |
US11224576B2 (en) | 2022-01-18 |
CY1110609T1 (el) | 2015-04-29 |
AR046994A1 (es) | 2006-01-04 |
PE20050814A1 (es) | 2005-11-10 |
AU2004308653B2 (en) | 2009-09-03 |
US20170049706A1 (en) | 2017-02-23 |
CA2551231A1 (en) | 2005-07-14 |
PL1699440T3 (pl) | 2010-04-30 |
JP4895821B2 (ja) | 2012-03-14 |
DE10361596A1 (de) | 2005-09-29 |
US20090005408A1 (en) | 2009-01-01 |
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