CN101111232B - 防止滥用的给药剂型的制备方法 - Google Patents

防止滥用的给药剂型的制备方法 Download PDF

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CN101111232B
CN101111232B CN2006800038549A CN200680003854A CN101111232B CN 101111232 B CN101111232 B CN 101111232B CN 2006800038549 A CN2006800038549 A CN 2006800038549A CN 200680003854 A CN200680003854 A CN 200680003854A CN 101111232 B CN101111232 B CN 101111232B
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E·阿克诺-马里克
J·巴索洛莫斯
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Abstract

本发明涉及用于制备防滥用的给药剂型的方法,所述剂型除了含有一种或多种有滥用倾向的试剂以及任选的生理可接受助剂之外,还含有至少一种最低断裂强度为500N的合成或者天然聚合物(C)。向该制剂混合物中加入针对聚合物(C)的溶剂,加入量使得所述制剂混合物被至少均匀润湿,所述至少被润湿的物质任选被分成部分物质,干燥,并成形为给药剂型。

Description

防止滥用的给药剂型的制备方法
本发明涉及用于制备防止滥用的固态剂型的方法,其中向除了一种或多种具有滥用可能性的活性成分(A)和任选的生理可接受辅助物质(B)之外还含有至少一种合成或者天然聚合物(C)(所述聚合物的断裂强度为至少500N)的制剂混合物中加入
a)针对聚合物(C)的溶剂,其量至少使得所述制剂混合物被均匀润湿,
b)已经被以此方式至少润湿的所述组合物被任选地分成亚部分,
c)所述部分(一个或多个)被干燥,并
d)成形以获得所述剂型。
许多药用活性成分除了在其合适应用中具有优异的活性之外,还具有被滥用的可能性,即,它们可以被滥用者使用,以带来除了预期效果以外的那些影响。
例如,鸦片剂(opiate)在对抗严重疼痛到极严重疼痛上高度有效,但常常被滥用者使用来诱发麻醉或者陶醉感。
为了能够滥用,相应的剂型,比如片剂或者胶囊,被滥用者粉碎,例如在研钵中研磨,采用优选的水性液体将活性成分从所得粉末中提取出来,得到的溶液任选在通过脱脂棉或者纤维素填絮过滤后肠胃外给药,尤其是静脉给药。和滥用性的口服给药相比,这种给药的另外现象是活性成分水平进一步加速增加,从而赋予滥用者所需的效果,即“兴奋(kick)”或者“激动(rush)”。如果粉末化的剂型经鼻给药,即用鼻子吸入,则也会产生兴奋感。
由于含有具有滥用可能性的活性成分的延迟释放性口服剂型即使在以滥用性大量口服时,通常也不会产生滥用者所需要的兴奋感,所以这种剂型也经过粉碎和提取。
US-A-4070494提出为了防止滥用在剂型中加入膨胀剂。当加入水来提取活性成分时,膨胀剂膨胀,确保和凝胶分离的滤液仅仅含有少量活性成分。
WO95/20947中描述的多层片剂基于和防止肠胃外滥用相似的方法,所述片剂含有具有滥用可能性的活性成分和至少一种凝胶形成物,其中所述活性成分和所述凝胶形成物各自在不同的层中。
WO03/015531A2公开了另一种防止肠胃外滥用的方法。其中描述了含有止痛药阿片样物质和作为厌恶剂的染料的剂型。破坏剂型时释放的颜色旨在使滥用者放弃使用已经被破坏的剂型。
另一种使滥用变得不容易的选择包括向剂型加入针对活性成分的拮抗剂,例如对于阿片样物质而言是纳洛酮或者纳屈酮,或者导致生理防御性响应的化合物,比如例如吐根树(吐根)的根。
但是,如同在过去一样,由于在大多数情况下,为了滥用需要使剂型粉碎,所以本发明的目标是提供制备下述剂型的方法:该剂型含有具有滥用可能性的活性成分,当该剂型被正确给药时确保产生所需的、优选的治疗作用,而且通过该剂型活性成分不会被仅仅通过粉碎而转变成适合滥用的形式。
通过提供用于制备具有至少降低了的滥用可能性的固态剂型的本发明方法,实现了所述目标,所述方法的特征在于:
a)向含有至少一种具有滥用可能性的活性成分(A)和至少一种合成或天然的聚合物(C)的制剂混合物中加入用于聚合物(C)的溶剂,加入量是至少使得所述制剂混合物被均匀润湿的量:所述聚合物的断裂强度为至少500N,
b)已经被以此方式至少润湿的组合物任选地被分成亚部分,
c)所述(一个或多个)部分被干燥,并
d)成形以获得所述剂型。
通过使用具有上述最小断裂强度(测量方法如同在本申请中所述)的聚合物,优选加入量使得该剂型也具有至少为500N,优选至少为1000N的所述最小断裂强度,则可以防止通过常规手段使该剂型粉碎,从而使任何后续滥用变得显著地复杂化或者被防止。
如果粉碎不充分,那么肠胃外给药,尤其是静脉给药,实际上不能安全进行,或者从中提取活性成分将花费滥用者太长时间,或者当口服滥用时由于不是即刻释放地所以不产生“兴奋”效果。
根据本发明,粉碎是指通过通常而言滥用者易得的常规手段施加力来破碎剂型,所述手段比如例如研钵和研杵、锤子、棒槌或者其它通常用于粉碎的装置,其中可以形成的细粉(颗粒尺寸等于或者小于0.3mm)的百分比不得超过5%。
根据本发明制备的剂型在低温下,例如低于-25℃、-40℃或者甚至在液氮中,也不能通过这些方法粉碎。
根据本发明制备的剂型优选是药用剂型,因此适于防止具有滥用可能性的活性成分,优选药用活性成分,的肠胃外、经鼻和/或经口滥用。
具有滥用可能性的活性成分,优选药用活性成分,是本领域技术人员公知的,其用量和制备方法同样是公知的,并且在根据本发明制备的剂型中以如下形式存在:比如,其相应的衍生物形式,尤其是酯类、醚类或酰胺类,或者在每种情况下以相应的生理可接受化合物的形式,尤其是其相应的盐或溶剂化物的形式,作为外消旋物或者立体异构体形式。根据本发明制备的剂型可以含有两种或多种药用活性成分。根据本发明制备的剂型优选含有仅仅一种特异性活性成分。
根据本发明的剂型尤其适于防止选自下述的至少一种药用活性成分的滥用:阿片样物质、安定剂(tranquilliser),优选苯(并)二氮
Figure G06803854920070806D000031
类、巴比妥酸盐、刺激剂和其它麻醉药。
本发明的剂型特别适于防止滥用阿片类物质、安定剂或者选自下列的另一种麻醉药: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}-N-丙酰苯胺(阿芬太尼)、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]三唑并[4,3-a][1,4]-苯并二氮杂
Figure G06803854920070806D000032
(阿普唑仑)、2-乙基氨基苯基·乙基(甲)酮(安非拉酮)、(±)-α-甲基苯乙基胺(苯丙胺)、2-(α-甲基苯乙基氨基)-2-苯基乙腈(苯丙胺苄氰)、5-乙基-5-异戊基巴比妥酸(异戊巴比妥)、阿尼利定、阿朴可待因、5,5-二乙基巴比妥酸(巴比妥)、苄基吗啡、氰苯咪呱啶、7-溴-5-(2-吡啶基)-1H-1,4-苯并二氮杂
Figure G06803854920070806D000033
-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
Figure G06803854920070806D000034
(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-桥亚乙基吗啡烷-3-醇(丁丙诺啡)、5-丁基-5-乙基巴比妥酸(丁巴比妥)、布托啡诺、(7-氯-1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂
Figure G06803854920070806D000035
-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
Figure G06803854920070806D000036
-2-基胺4-氧化物(氯氮卓)、7-氯-1-甲基-5-苯基-1H-1,5-苯并二氮杂
Figure G06803854920070806D000037
-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
Figure G06803854920070806D000041
-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
Figure G06803854920070806D000042
-3-羧酸(氯氮卓)、5-(2-氯苯基)-7-乙基-1-甲基-1H-噻吩并[2,3-e][1,4]二氮杂
Figure G06803854920070806D000043
2(3H)-酮(氯噻西泮)、10-氯-11b-(2-氯苯基)-2,3,7,11b-四氢噁唑并[3,2-d][1,4]苯并二氮杂
Figure G06803854920070806D000044
-6(5H)-酮(氯噁唑仑)、(-)-甲基-[3β-苯甲酰基氧基-2β(1αH,5αH)-托烷羧酸酯](可卡因)、4,5α-环氧基-3-甲氧基-17-甲基-7-吗啡烷-6α-醇(可待因)、5-(1-环己烯基)-5-乙基巴比妥酸(环巴比妥)、环丙甲吗喃醇、环丙诺啡、7-氯-5-(2-氯苯基)-1H-1,4-苯并二氮杂
Figure G06803854920070806D000045
-2(3H)-酮(地洛西泮)、地索吗啡、右吗拉胺、(+)-(1-苄基-3-二甲基氨基-2-甲基-1-苯基丙基)丙酸酯(右丙氧芬)、地佐辛、地恩丙胺、海洛因(diamorphone)、7-氯-1-甲基-5-苯基-1H-1,4-苯并二氮杂
Figure G06803854920070806D000046
-2(3H)-酮(地西泮)、4,5α-环氧基-3-甲氧基-17-甲基-6α-吗啡烷醇(双氢可待因)、4,5α-环氧基-17-甲基-3,6a-吗啡烷二醇(二氢吗啡)、苯醋胺乙酯、美沙醇(dimephetamo1)、二甲噻丁、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]色原烯-1-醇(屈大麻酚)、氢溴酸依他佐辛、8-氯-6-苯基-4H-[1,2,4]三唑并[4,3-(a)][1,4]二氮杂
Figure G06803854920070806D000047
(三唑氯安定)、氢氮革乙酯、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
Figure G06803854920070806D000048
-3-羧酸]乙酯(西泮酸乙酯)、4,5α-环氧基-3-乙氧基-17-甲基-7-吗啡烷-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-吗啡烷-3-醇(埃托芬)、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)(苯丙胺乙茶碱)、3-(α-甲基苯乙基氨基)丙腈(美芬雷司)、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
Figure G06803854920070806D000049
-2(3H)-酮(氟安定)、5-(2-氟苯基)-1-甲基-7-硝基-1H-1,4-苯并二氮杂-2(3H)-酮(氟硝基安定)、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
Figure G06803854920070806D0000412
-2(3H)-酮(哈拉西泮)、10-溴-11b-(2-氟苯基)-2,3,7,11b-四氢[1,3]噁唑并[3,2-d][1,4]苯并二氮杂
Figure G06803854920070806D0000413
-6(5H)-酮(溴氟唑仑)、海洛因、4,5α-环氧基-3-甲氧基-17-甲基-6-吗啡烷酮(二氢可待因酮)、4,5α-环氧基-3-羟基-17-甲基-6-吗啡烷酮(氢吗啡酮)、羟基哌替啶、异美沙酮、羟基甲基吗啡烷、11-氯-8,12b-二氢-2,8-二甲基-12b-苯基-4H-[1,3]噁嗪并[3,2-d][1,4]二氮杂
Figure G06803854920070806D000051
-4,7(6H)-二酮(凯他唑仑)、1-[4-(3-羟基苯基)-1-甲基-4-哌啶基]-1-丙酮(酚哌丙酮)、(3S,6S)-6-二甲基氨基-4,4-二苯基庚烷-3-基乙酸酯(左旋醋美沙朵(LAAM))、(-)-6-二甲基氨基-4,4-二苯酚-3-庚酮(左旋美沙酮)、(-)-17-甲基-3-吗啡烷醇(左啡诺)、苯左啡烷、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
Figure G06803854920070806D000052
-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
Figure G06803854920070806D000054
-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(氯苯咪吲哚)、7-氯-2,3-二氢-1-甲基-5-苯基-1H-1,4-二氮杂
Figure G06803854920070806D000055
(去氧安定)、N-(3-氯丙基)-α-甲基苯乙基胺(氯丙苯丙胺)、麦啶、2-甲基-2-丙基三亚甲基二氨基甲酸酯(甲丙氨酯)、甲氮草酚、间唑辛、甲基吗啡、N,α-二甲基苯乙基胺(甲基苯(异)丙胺)、(±)-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(苯哌啶醋酸甲酯)、5-乙基-1-甲基-5-苯基巴比妥酸(甲苯比妥)、3,3-二乙基-5-甲基-2,4-哌啶二酮(甲乙哌酮)、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
Figure G06803854920070806D000056
(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(morphinen)-3,6α-二醇(吗啡)、苄吗啡十四酸酯、(±)-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、烯丙吗啡、罂粟碱、二烟酰吗啡、1-甲基-7-硝基-5-苯基-1H-1,4-苯并二氮杂
Figure G06803854920070806D000057
-2(3H)-酮(硝基去氯安定)、7-硝基-5-苯基-1H-1,4-苯并二氮杂
Figure G06803854920070806D000058
-2(3H)-酮(硝西泮)、7-氯-5-苯基-1H-1,4-苯并二氮杂
Figure G06803854920070806D000059
-2(3H)-酮(去甲安定)、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、二苯哌己酮、从属于罂粟物种的植物中渗出物(鸦片)、7-氯-3-羟基-5-苯基-1H-1,4-苯并二氮杂
Figure G06803854920070806D0000510
-2(3H)-酮(奥沙西泮)、(顺-反)-10-氯-2,3,7,11b-四氢-2-甲基-11b-苯基噁唑并[3,2-d][1,4]苯并二氮杂
Figure G06803854920070806D0000511
6-(5H)-酮(甲噁安定)、4,5α-环氧基-14-羟基-3-甲氧基-17-甲基-6-吗啡烷酮(羟氢可待酮)、氧吗啡酮、属于罂粟物种(包括亚物种汤饭子(setigerum))的植物和植物部分(罂粟)、阿片金碱、2-亚氨基-5-苯基-4-噁唑啉酮(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-苯并吖辛因(benzazocin)-8-醇(戊唑星)、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)、苯吗庚酮、苄啡烷、非那佐辛、苯哌利定、匹米诺定、福尔可定、3-甲基-2-苯吗啡啉(苯甲吗啉)、5-乙基-5-苯基巴比妥酸(苯巴比妥)、α,α-二甲基苯乙基胺(苯(叔)丁胺)、7-氯-5-苯基-1-(2-丙炔基)-1H-1,4-苯并二氮杂
Figure G06803854920070806D000061
-2(3H)-酮(丙炔安定)、α-(2-哌啶基)二苯甲醇(哌苯甲醇)、1′-(3-氰基-3,3-二苯基丙基)[1,4′-联哌啶]-4′-甲酰胺(氰苯双哌酰胺)、7-氯-1-(环丙基甲基)-5-苯基-1H-1,4-苯并二氮杂
Figure G06803854920070806D000062
-2(3H)-酮(普拉西泮)、普罗法朵、丙庚嗪、二甲哌替啶、异丙哌替啶、丙氧吩、N-(1-甲基-2-哌啶并乙基)-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(雷米芬太尼)、5-仲丁基-5-乙基巴比妥酸(仲丁比妥)、5-烯丙基-5-(1-甲基丁基)-巴比妥酸(司可巴比妥)、N-{4-甲氧基甲基-1-[2-(2-噻酚基)乙基]-4-哌啶基}-N-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
Figure G06803854920070806D000063
-2(3H)-酮(羟基安定)、7-氯-5-(1-环己烯基)-1-甲基-1H-1,4-苯并二氮杂
Figure G06803854920070806D000064
-2(3H)-酮(四氢安定)、(2-二甲基氨基-1-苯基-3-环己烯-1-羧酸)乙酯(替利定(顺式和反式))、曲马多、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
Figure G06803854920070806D000065
(三唑仑)、5-(1-甲基丁基)-5-乙烯基巴比妥酸(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-氟苄基氧基)-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、优选作为外消旋化合物、3-(2-二甲基氨基甲基-1-羟基-环己基)苯基·2-(4-异丁氧基-苯基)-丙酸酯、3-(2-二甲基氨基甲基-1-羟基-环己基)苯基·2-(6-甲氧基-萘-2-基)-丙酸酯、3-(2-二甲基氨基甲基-环己-1-烯基)-苯基·2-(4-异丁基-苯基)-丙酸酯、3-(2-二甲基氨基甲基-环己-1-烯基)-苯基·2-(6-甲氧基-萘-2-基)-丙酸酯、(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-联苯基-4-羧酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯,以及相应的立体异构化合物,在每种情况下其相应的衍生物,尤其是酰胺、酯或者醚,以及在每种情况下其生理上可接受的化合物,尤其是其盐和溶剂化物,特别优选氢氯化物。
根据本发明制备的剂型特别适于选自下列的阿片样活性成分被滥用:羟氢可待酮、氢吗啡酮、吗啡、曲马多和其生理可接受的衍生物或者化合物,优选其盐和溶剂化物,优选其氢氯化物。
根据本发明制备的剂型另外特别适用于防止选自下列的阿片样活性成分被滥用:(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-(2-二甲基氨基乙基-环己基)苯酚、其生理上可接受的盐,优选氢氯化物、生理上可接受的对映体、立体异构体、非对映体和外消旋化合物,及其生理上可接受的衍生物,优选醚、酯或者酰胺。
这些化合物及其制备方法分别在EP-A-693475和EP-A-780369中进行了描述。相应的描述在此引入作为参考,并认定为本公开的一部分。
为了获得所需的断裂强度,在本发明的方法中采用了至少一种断裂强度为至少500N的合成或天然聚合物(C),所述断裂强度采用本申请公开的方法测量。优选至少一种选自下列的聚合物用于此目的: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、以及所述聚合物的至少两种的混合物。优选高分子量的热塑性聚环氧烷。特别优选分子量为至少50万,优选至少100万-1500万的高分子量聚环氧乙烷,所述分子量通过流变学测量方法来确定。这些聚合物在25℃的粘度当采用RVF Brookfield粘度计(2号心轴/转速为2rpm)对5重量%的水溶液进行测量时为4500-17600cP,当采用所述粘度计(1号心轴或者3号心轴/转速10rpm)对2重量%水溶液进行测量时是400-4000cP,当采用所述粘度计(2号心轴/转速2rpm)对1重量%水溶液进行测量时是1650-10000cP。
所述聚合物优选以粉末形式使用。它们应该溶于水。
为了利用本发明的方法获得必须的断裂强度,进一步可能的是另外使用至少一种断裂强度至少500N的天然或合成蜡(D),所述断裂强度采用本申请公开的方法测量。优选软化点为至少60℃的蜡。特别优选棕榈蜡和蜂蜡。极其优选棕榈蜡。棕榈蜡是得自棕榈树叶、软化点至少80℃的天然蜡。当另外使用蜡组分时,它和至少一种聚合物(C)一起使用,用量使得根据本发明制备的剂型的断裂强度至少为500N。
组分(C)的用量优选是20-99.9重量%,特别优选至少30重量%,及其优选至少40重量%,相对于剂型的总重量而言。
可以使用的辅助物质(B)是那些公知的对于固态剂型制剂而言常规的辅助物质。优选是增塑剂,比如甘油三乙酸酯和聚乙二醇、影响活性成分释放的辅助物质,优选疏水性的或者亲水性的,优选亲水性聚合物,特别优选羟丙基甲基纤维素或者羟丙基纤维素和/或抗氧化剂。聚合物,特别优选纤维素醚、纤维素酯和/或丙烯酸树脂被优选用作亲水性基质材料。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(甲基)丙烯酸和/或其衍生物,比如其盐、酰胺或者酯被特别优选用作基质材料。合适的抗氧化剂是抗坏血酸、丁基羟基茴香醚、丁基羟基甲苯、抗坏血酸的盐、单硫代丙三醇、磷酸、维生素C、维生素E和其衍生物、亚硫酸氢钠、特别优选丁基羟基甲苯(BHT)或者丁基羟基茴香醚(BHA)和α-生育酚。
抗氧化剂的优选用量是0.01-10重量%,优选0.03-5重量%,相对于剂型的总重量而言。
为了执行本发明的方法,对至少一种具有滥用可能性的活性成分(A)、至少一种聚合物(C)和任选的蜡(D)、任选的至少一种下面列出的其它任选存在的防滥用组分(a)-(f)、以及任选存在的辅助物质(B)比如抗氧化剂、增塑剂和/或延迟释放辅助物质,通过加入针对聚合物(C)的溶剂进行处理,以形成所述剂型。
为此,将组分(A)、(B)、(C)和任选存在的组分(D)和任选至少一种任选存在的另外的防滥用组分(a)-(f)混合,或者需要时分开混合同时加入组分(C)和任选的组分(D),所得的制剂混合物(一种或多种)在加入溶剂并任选在造粒后,经过成形以获得所述剂型。
组分(A)、(B)、(C)和任选的(D)以及任选存在的其它组分(a)-(f)和组分(C)与任选存在的组分(D)的混合,任选在每种情况下都在本领域技术人员公知的混炼机中进行。所述混炼机可以例如是辊式混炼机、振动式混炼机、剪切式混炼机或者桨叶式混炼机。
针对聚合物(C)的溶剂的加入量至少使得所述制剂混合物被均匀润湿。
适于作为针对聚合物(C)的溶剂的溶剂优选是水性溶剂,比如水、水和脂族醇,优选C1-C6的醇的混合物、酯、醚、烃,特别优选单独蒸馏水或者蒸馏水和短链醇比如甲醇、乙醇、异丙醇、丁醇的混合物以形成水性醇溶液。
溶剂优选通过搅拌加入。然后,干燥该均匀润湿的组合物。干燥优选通过于能够防止组合物出现任何脱色的温度暴露到热量下进行。所述温度可以通过简单的初步测试来建立。
在干燥前或后,组合物可以分成亚部分,其在每种情况下优选和单位剂型的质量相相应。然后,将相应干燥后的部分成形以形成剂型。
这优选通过采用压片机来进行。
制剂混合物可以以如下方式润湿:即,在加入溶剂之前,制剂混合物被划分,优选在模具中划分成亚部分,搅拌分散在液体分散剂中,然后加入溶剂。聚合物组分(C)不溶于所述分散剂,所述分散剂必须与溶剂混溶。
合适的分散剂优选是亲水性分散剂,比如脂族醇、酮、酯。优选使用短链醇。
或者,制剂混合物可以以溶剂可以以泡沫形式结合到制剂混合物中的方式被润湿。所述溶剂泡沫优选通过高速混炼机制备,优选加入常规泡沫稳定剂。合适的稳定剂是例如亲水性聚合物,比如例如羟丙基甲基纤维素。
泡沫也优选在搅拌下结合到制剂混合物中,这样优选获得颗粒化的组合物。
在被分成亚部分之前或者之后,颗粒化的组合物被干燥然后成形成剂型,其中所述亚部分优选和单位剂型质量相对应。
干燥和成形可以优选如上所述进行。
根据本发明的方法也可以以如下方式进行,即溶剂在制剂混合物中的加入量使得获得了可成形的糊。
在干燥(可以如前所述那样进行)之前或之后,所述糊可以划分成亚部分,所述干燥的部分在每种情况下在进一步划分成和单位剂型质量相应的部分之后,经过成形或转变以获得所述剂型。
在此,可以形成条状的亚部分,其可以通过筛子或者条形成器的辅助来制备。干燥的条状物优选经过单分(singulate)和成形,以获得剂型。这种成形优选在压片机的辅助下进行,采用成形辊或者配有辊的成形带。
也可以将糊转变成平板结构,并在其一旦干燥后从中冲压出所述剂型。
所述糊有利地通过挤出机进行处理,其中,取决于挤出模头的构造,制备出条状或者板状结构制品,所述制品通过砍、切或者冲压被单分。单分的亚部分可以如上所述进行成形或者成型,以获得所述剂型。相应的装置是本领域技术人员所公知的。
在此,本发明的方法可以连续或者不连续进行。
也可以在制剂混合物中加入至少溶解聚合物组分(C)的量的溶剂。所述溶液或者分散体/悬浮液优选转变成板状结构,优选使用具有扁平模头的挤出机,或者溶液被流延到平板支撑体上。
如上所述,在干燥后,可以通过冲压或者压延由所述平面结构获得剂型。也可以如上所述将溶液转变成条状物,并优选在其干燥后进行单分和成形,以获得所述剂型。
或者,也可以利用模具将溶液分成部分,使得在干燥后所述部分每个都对应于单位剂型的质量,其中,为此目的优选采用已经和单位剂型的形状相应的模具。
如果溶液被分成任何所需的部分,则所述部分可以在干燥后任选被再次组合,并经过成形以形成所述剂型,所述剂型例如被包装在胶囊里或者经过压模形成片剂。
结合有溶剂的制剂混合物优选在20℃-40℃的温度下处理,其中,除了在用于去除溶剂和任选存在的分散剂的干燥期间以外,没有使用更高的温度。在成形以获得剂型后,可以任选地进行进一步地和上述干燥相应的干燥。
如同已经解释的,根据本发明制备的剂型可以采取多颗粒形式,优选微片剂、微胶囊、微丸粒、颗粒、球状体、珠子或者丸粒形式,任选包装在胶囊中或者经压模形成片剂,优选用于经口给药。多颗粒形式优选的尺寸或者尺寸分布为0.1-3mm,特别优选为0.5-2mm。取决于所需的剂型,所述剂型的制剂也任选使用常规辅助物质(B)。
根据本发明方法获得的剂型的不同之处在于:由于其至少500N的硬度,它们不能通过滥用者可以获得的常规粉碎装置,比如研钵和研杵,来粉碎。这实质上排除了经口、肠胃外,尤其是静脉、或者经鼻滥用。但是,为了防止本发明制备的剂型的任何可能的滥用,在优选实施方案中,本发明的剂型可以进一步含有使滥用不容易或者防止滥用的试剂作为辅助物质(B)。
根据本发明制备的防滥用剂型除了包含一种或多种具有滥用可能性的活性成分(A)、至少一种硬化聚合物(C)和任选的至少一种蜡(D)之外,还可以相应地包含至少一种下列组分(a)-(e)作为辅助物质(B):
(a)至少一种刺激鼻通道和/或咽腔的物质,
(b)至少一种增加粘度的试剂,其在必需的最少量水性液体,优选是从该剂型获得的水性提取物,的帮助下,形成凝胶,所述凝胶在引入到另外量的水性液体中时优选保持视觉上可区分,
(c)至少一种针对每一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)至少一种染料作为厌恶剂,
(f)至少一种苦味物质。
组分(a)-(f)是另外的、均独立地适于防止滥用根据本发明获得的剂型的物质。相应地,组分(a)优选适于防止剂型经鼻、经口和/或肠胃外,优选经静脉滥用,组分(b)优选适于防止肠胃外滥用,特别优选防止经静脉和/或经鼻滥用,组分(c)优选适于防止经鼻和/或肠胃外滥用,特别优选适于防止经静脉滥用,组分(d)优选适于防止肠胃外滥用,特别优选防止经静脉滥用,和/或经口和/或经鼻滥用,组分(e)适于作为抵抗经口或肠胃外滥用的视觉上的阻止物,组分(f)适于防止经口或经鼻滥用。根据本发明将至少一种上述组分组合使用使其可以更有效地防止滥用根据本发明方法制备的剂型。
例如,根据本发明制备的剂型也可以组合包含两种或多种组分(a)-(f),优选(a)、(b)和任选的(c)和/或(f)和/或(e),或者(a)、(b)和任选的(d)和/或(f)和/或(e)。
在另一实施方案中,根据本发明制备的剂型可以包含所有组分(a)-(f)。
如果根据本发明制备的剂型包含防滥用组分(a),那么根据本发明可以考虑的、刺激鼻通道和/或咽腔的物质,是当经由鼻腔通道和/或咽腔相应给药时带来如下物理反应的物质:所述物理反应或者对滥用者而言是不受欢迎的以至于滥用者不愿意或者不能继续给药,例如,烧灼感,或者例如由于增加鼻腔分泌或者打喷嚏而从生理上抵制摄入相应的活性成分。常规刺激鼻腔通道和/或咽腔的这些物质,当肠胃外给药尤其是静脉给药时,也可能带来非常不受欢迎的感觉或者甚至不能承受的疼痛,使得滥用者不愿意或者不能继续摄入所述物质。
特别合适的刺激鼻腔通道和/或咽腔的物质,是导致烧灼感、刺痛感、刺激打喷嚏、分泌物形成增加、或者至少两种所述刺激的组合的物质。常规使用的合适物质及其用量是本领域普通技术人员公知的,或者可以通过简单的初步试验来确定。
组分(a)的刺激鼻腔通道和/或咽腔的物质优选基于至少一种辣物质药物的一种或多种组分或者一种或多种植物部分。
相应的辣物质药物是本领域技术人员公知的,在例如“Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe″,Prof.Dr.Hildebert Wagner,第二版,修订版,Gustav Fischer Verlag,Stuttgart-New York,1982,第82页起”中进行了描述。该相应的描述在此引入作为参考,并被认定是本公开的一部分。
剂量单位是指分开的或者可分开的给药单位,比如例如片剂或者胶囊。
在本发明的剂型中,可以优选加入至少一种选自下列辣物质药物的一种或多种组分作为组分(a):Allii sativi bulbus(大蒜)、Asarirhizoma cum herba(细辛根和叶)、Calami rhizoma(菖蒲根)、Capsicifructus(辣椒)、Capsici fructus acer(番椒)、Curcumae longae rhizoma(姜黄根)、Curcumae xanthorrhizae rhizoma(爪哇姜黄根)、Galangaerhizoma(高良姜根)、Myristicae semen(肉豆蔻)、Piperis nigri fructus(胡椒)、Sinapis albae semen(白芥菜籽)、Sinapis nigri semen(黑芥菜籽)、Zedoariae rhizoma(片姜黄根)和Zingiberis rhizoma(生姜根),特别优选选自Capsici fructus(辣椒)、Capsici fructus acer(番椒)和Piperis nigri fructus(胡椒)。
辣物质药物的组分优选包含邻甲氧基(甲基)苯酚化合物、酰胺化合物、芥菜油、或者由其衍生的一种或多种硫化物。
特别优选的,辣物质药物的至少一种组分选自肉豆蔻醚、榄香素、异丁子香酚、α-细辛醚、黄樟油精、姜醇、黄根醇(xanthorrhizol)、辣椒素生物碱,优选辣椒素、辣椒素衍生物,比如N-香草基-9E-十八烯酰胺、二氢辣椒素、去甲二氢辣椒素、高辣椒素(homocapsaicin)、去甲辣椒素(norcapsaicin)和nomorcapsaicin、胡椒碱,优选反式-胡椒碱、硫代葡萄糖酸盐,优选基于非挥发性芥菜油,特别优选基于对-羟基苄基芥菜油、甲基巯基芥菜油或者甲基硫酰基芥菜油,以及源自这些组分的化合物。
根据本发明获得的剂型可以优选含有相应辣物质药物的植物部分,在每种情况下基于剂型单位的总重量含量为0.01-30重量%,特别优选0.1-0.5重量%。
如果使用相应辣物质药物的一种或多种组分,其在本发明制备的剂型单位中的量优选是0.001-0.005重量%,相对于剂型单位的总重量。
防止滥用本发明制备的剂型的另一选项是在剂型中加入至少一种增加粘度的试剂作为另外的防滥用组分(b),其在必需的最小量水性液体,优选作为得自该剂型的水性提取物,的辅助下形成凝胶,所述凝胶实质上不能安全地给药,优选当引入到另外量的水性液体中时保持视觉上可以区分。
对于本发明而言,视觉上可区分是指在必需的最小量水性液体的辅助下形成的含活性成分的凝胶,当引入(优选在皮下注射针的辅助下)到另外量的处于37℃的水性液体中时,保持基本不溶的和内聚的,并且不能以直接以如下方式分散:所述方式使得其可以安全地、肠胃外给药,尤其是经静脉给药。所述材料优选保持视觉上可区分至少1分钟,优选至少10分钟。
提取物的增加的粘度使其更难以或者甚至不可能通过针头或者被注射。如果凝胶保持视觉上可区分的,那么这意味着所得的凝胶到引入到另外量的水性液体中时,例如通过注入到血液中引入时,首先保持为主要是内聚性的细线的形式,所述细线尽管实际上可以经机械方式破碎成更小的片段,但是不能以如下方式粉碎或者甚至溶解:所述方式使其可以安全地肠胃外给药,尤其是经静脉给药。当与至少一种任选存在的组分(a)-(e)组合时,这另外增加了不受欢迎的烧灼感、呕吐感、臭味和/或视觉上的阻碍。
静脉给药所述凝胶很有可能导致堵塞血管,伴随着严重损坏滥用者的健康。
为了验证提高粘度的试剂是否适合作为用于本发明制备的剂型中的组分(b),将活性成分和所述提高粘度的试剂混合,并悬浮在25℃的10ml水中。如果这导致形成满足上述条件的凝胶,那么相应的提高粘度的试剂适于另外防止或者避免根据本发明制备的剂型的滥用。
如果组分(b)加入到根据本发明制备的剂型中,那么使用一种或多种选自下列的提高粘度的试剂:具有11重量%羧甲基纤维素钠的微晶纤维素(
Figure G06803854920070806D000141
RC 591)、羧甲基纤维素钠(
Figure G06803854920070806D000142
、CMC-Na
Figure G06803854920070806D000143
、Frimulsion
Figure G06803854920070806D000144
,、Tylose
Figure G06803854920070806D000145
)、聚丙烯酸(
Figure G06803854920070806D000146
980NF、
Figure G06803854920070806D000147
981)、槐豆粉(
Figure G06803854920070806D000148
LA-200、LID/150、
Figure G06803854920070806D0001410
LN-1)、果胶,优选源自含果胶的水果和苹果(
Figure G06803854920070806D0001411
HM Medium Rapid Set)、蜡状玉米淀粉(C*Gel
Figure G06803854920070806D0001412
)、海藻酸钠(Frimulsion ALG
Figure G06803854920070806D0001413
)、瓜儿豆粉(Frimulsion
Figure G06803854920070806D0001414
Polygum
Figure G06803854920070806D0001415
)、阿尔塔角叉菜胶(Frimulsion
Figure G06803854920070806D0001416
)、刺梧桐树胶、胶凝糖胶(Kelcogel
Figure G06803854920070806D0001417
、Kelcogel)、半乳甘露聚糖(Meyprogat
Figure G06803854920070806D0001419
)、tara stone粉(Polygum
Figure G06803854920070806D0001420
)、丙二醇海藻酸酯(Protanal-Ester
Figure G06803854920070806D0001421
)、透明质酸钠、黄蓍胶、tara胶(Vidogum SP)、发酵的多糖威兰(welan)胶(K1A96)、黄原胶(Xantural
Figure G06803854920070806D0001423
)。特别优选黄原胶。括号中给出的名称是材料市售的商品名。通常,相对于剂型的总重量,0.1-20重量%,特别优选0.1-15重量%的所述提高粘度的试剂(一种或多种)就足以满足上述条件。
组分(b),即提高粘度的试剂,当提供时,在本发明制备的剂型中优选存在的量是≥5mg每剂量单位,即,每给药单位。
在本发明的特别优选的实施方案中,用作组分(b)的提高粘度的试剂是在用必需的最少量水性液体从剂型中提取时,形成封闭气泡的凝胶。所得的凝胶通过混浊外观进行区分,这为潜在的滥用者提供了另外的视觉警告并使其放弃肠胃外给药所述凝胶。
组分(C)也可以任选地作为另外的提高粘度的试剂,其在必需的最小量水性液体的辅助下形成凝胶。
也可以以在空间上相互分开的排列形式,来在根据本发明制备的剂型中配制所述提高粘度的试剂和其它组分。
为了放弃和防止滥用,根据本发明制备的剂型可以进一步包括组分(c),即一种或多种针对(一种或多种)具有滥用可能性的活性成分的拮抗剂,其中所述拮抗剂优选和根据本发明制备的剂型的剩余组分在空间上分开,并且当正确使用时不产生任何影响。
用于防止活性成分滥用的合适拮抗剂是本领域技术人员公知的,可以就这样或者以相应衍生物的形式,尤其是酯或者醚,或者在每种情况下以相应生理上可接受的化合物形式,尤其是其盐或者溶剂化物的形式,存在于本发明的剂型中。
如果剂型中存在的活性成分是阿片样物质,那么所用的拮抗剂优选是选自下列的拮抗剂:纳洛酮、纳曲酮、纳美芬、nalid、纳美酮、烯丙吗啡或者naluphine,在每种情况下任选地以其相应生理可接受化合物的形式,尤其是碱、盐或溶剂化物的形式。相应的拮抗剂(在提供组分(c)的情况下),优选用量是每剂型,即每给药单位≥1mg,特别优选3-100mg,极其特别优选5-50mg。
如果根据本发明制备的剂型包括刺激剂作为活性成分,那么拮抗剂优选是精神抑制药,优选是至少一种选自下列的化合物:氟哌啶醇、异丙嗪、羟哌氟丙嗪、奋乃静、甲氧异丁嗪、甲硫达嗪、丙拉嗪、氯丙嗪、氯丙硫蒽、珠氯噻醇、三氟噻吨、氮丙嗪、佐替平、苯哌唑酮、匹泮哌隆、甲哌酮和溴哌利多。
根据本发明制备的剂型优选以本领域技术人员公知的常规治疗剂量,特别优选以每给药单位2倍-3倍的所述常规剂量的量包含这些拮抗剂。
如果所述用以进一步放弃和防止滥用根据本发明制备的剂型的组合也包含组分(d),那么它可以包含至少一种催吐剂,所述催吐剂优选以和根据本发明制备的剂型的其它组分在空间上分开的排列方式存在,并且当正确使用时不会试图对身体产生影响。
用于另外防止滥用活性成分的合适催吐剂是本领域技术人员公知的,可以以原样或者以相应衍生物的形式,尤其是酯或者醚,或者在每种情况下以相应生理上可接受的化合物形式,尤其是其盐或者溶剂化物的形式,存在于根据本发明获得的剂型中。
在根据本发明制备的剂型中可以优选考虑基于吐根树(吐根)根的一种或多种组分,更优选基于组分依米丁的催吐剂,例如在“Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe″,Prof.Dr.Hildebert Wagner,第二版,修订版,Gustav Fischer Verlag,Stuttgart-New York,1982中进行了描述。该相应的描述在此引入作为参考,并被认定是本公开的一部分。
根据本发明制备的剂型可以优选含有催吐性的依米丁作为组分(d),优选每剂型,即给药单位的含量≥3mg,特别优选≥10mg,极其优选≥20mg。
阿朴吗啡同样可以优选用作催吐剂用于另外防止滥用,优选的用量优选≥3mg,特别优选≥5mg,极其特别优选≥7mg每给药单位。
如果根据本发明制备的剂型包含组分(e)作为另外的防止滥用的辅助物质,那么使用所述染料使相应的水性溶液具有强烈的着色作用,尤其是当试图提取活性成分供肠胃外给药,优选静脉给药时,所述着色可以充当对潜在滥用者的阻止物。经口滥用通常通过水性提取活性成分开始,也可以通过这种着色来防止。所述必需的阻止物所需的合适染料和量可以参见WO03/015531,其中所述相应公开应该视为本公开的一部分,在此引入作为参考。
如果根据本发明制备的剂型含有组分(f)作为另外的防止滥用的辅助物质,那么加入至少一种苦味物质和最终对剂型味道的损害,会另外防止经口和/或经鼻滥用。
合适的苦味物质及其使用有效量可以参见US2003/0064099A1,其相应的公开应该认为是本申请公开的一部分,在此引入作为参考。合适的苦味物质优选是芳族油,优选薄荷油、桉树油、苦杏仁油、薄荷醇、水果芳香物质,优选来自柠檬、桔子、酸橙、葡萄柚的芳香物质,或者其混合物,和/或苯甲酸地那铵(
Figure G06803854920070806D000161
)。苯甲酸地那铵是特别优选地。
根据本发明制备的固态剂型不仅仅适于经口给药,而且适于阴道或直肠给药,但是优选经口摄入。剂型优选不是薄膜形式。根据本发明的剂型可以采用多颗粒形式,优选圆柱形式、微片剂、微胶囊、微丸粒、颗粒、球状体、珠子或者丸粒形式,任选的包装在胶囊中或者压模成片剂,优选用于经口给药。多颗粒形式优选的尺寸或者尺寸分布是0.1-3mm,特别优选0.5-2mm。取决于所需的剂型,常规辅助物质(B)任选也用于配制所述剂型。
在进一步优选的实施方案中,根据本发明制备的剂型采用片剂、胶囊形式,或者是经口渗透治疗系统(OROS)的形式,优选也存在至少一种另外的防滥用组分(a)-(f)。
如果组分(c)和/或(d)和/或(f)存在于根据本发明制备的剂型中,则必须小心确保它们以如下方式配制或者以如下低剂量存在:即,所述方式或者所述剂量使得当正确给药时,所述剂型能够实质上不产生会损坏病人或者活性成分效率的影响。
如果根据本发明制备的剂型含有组分(d)和/或(f),那么剂量必须经选择使得当正确经口给药时,不产生负面影响。但是,如果在滥用情况下超过目标剂量,那么会产生恶心或者想呕吐或者臭味。在正确经口给药的情况下病人可以容忍的组分(d)和/或(f)的具体量可以由本领域技术人员通过简单的初步试验来确定。
但是,如果不考虑根据本发明制备的进一步剂型实质上不可能被粉碎这个事实,而采用组分(c)和/或(d)和/或(f)来保护所述剂型,那么这些组分应该优选以足够高的剂量使用,使得当被滥用性给药时,它们对滥用者产生强烈的负面影响。这优选通过将至少所述活性成分(一种或多种)和组分(c)和/或(d)和/或(f)在空间上分开来实现,其中所述活性成分(一种或多种)存在于至少一个亚单位(X)中,而组分(c)和/或(d)和/或(f)存在于至少一个亚单位(Y)中,以及其中,当剂型被正确给药时,组分(c)、(d)和(f)对摄入和/或在体内不产生影响,所述制剂的其余组分,尤其是组分(C)和任选的(D),是相同的。
如果根据本发明制备的剂型包含组分(c)和(d)或者(f)的至少2种,那么它们每个都可以存在于相同或者不同亚单位(Y)中。优选地,当存在时,所有组分(c)和(d)和(f)都存在于同一个亚单位(Y)中。
对于本发明而言,亚单位是固态制剂,其中在每种情况下,除了本领域技术人员知道的辅助物质以外,含有活性成分(一种或多种)、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的组分(a)和/或(b)和/或(e),或者在每种情况下,至少一种聚合物(C)和任选的(D)和拮抗剂(一种或多种)和/或催吐剂(一种或多种)和/或组分(e)和/或组分(f)以及任选的至少一种任选存在的组分(a)和/或组分(b)。必须小心确保每个上述亚单位都根据本发明的上述方法制备。
将活性成分和组分(c)或者(d)或者(f)在根据本发明制备的剂型的亚单位(X)和(Y)中分开配制的一个显著优点在于,当正确给药时,组分(c)和/或(d)和/或(f)在摄入时和/或在体内时几乎不释放,或者释放小量以至于不会产生损害病人或者治疗成功性的效果,或者,在通过病人身体时,它们仅仅在不能被充分吸收以至于有效的位置处释放。当剂型被正确给药时,优选几乎没有组分(c)和/或(d)和/或(f)被释放到病人身体内,或者不会被病人注意到。
本领域技术人员将理解,上述条件可以随着所用的具体组分(c)、(d)和/或(f)以及亚单位或者剂型的配制而变。特殊剂型的最优配制可以由简单的初步测试来确定。重要的是每个亚单位包含聚合物(C)和任选的组分(D),并且是根据上述方式配制和根据本发明制备。
如果和预期的相反,滥用者为了滥用活性成分而成功粉碎了根据本发明制备的剂型,所述剂型在亚单位(Y)中含有组分(c)和/或(e)和/或(d)和/或(f),并获得了通过合适提取剂提取的粉末,那么不仅活性成分而且特殊组分(c)和/或(e)和/或(f)和/或(d)将以如下形式获得:在该形式中,它不能容易地和活性成分分离,使得当所述已经被改动的剂型在被给药时,尤其是通过经口和/或肠胃外给药时,它将对摄入产生影响和/或在身体内产生影响,并且和对滥用者产生的、与组分(c)和/或(d)和/或(f)相应的负面影响相结合,或者,当试图提取活性成分时,着色充当阻止物并因而防止滥用剂型。
其中活性成分(一种或多种)和组分(c)、(d)和/或(e)在空间上分离(优选通过在不同亚单位中配制)的剂型,可以根据本发明以许多不同方式配制,其中在剂型中的相应亚单位各自可以互相以任何所需的空间排列形式存在,前提是满足用于释放组分(c)和/或(d)的上述条件。
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)优选可以在根据本发明制备的剂型中在特殊亚单位(X)和(Y)中存在,以及以和亚单位(X)和(Y)相应的独立亚单位的形式存在,前提是防止滥用或者在正确给药的情况下活性成分的释放都不会受到制剂本质的损害,聚合物(C)和任选的(D)优选包括在制剂中,并且所述配制是根据上述方法进行的以便获得所需的硬度。
在根据本发明制备的剂型的优选实施方案中,亚单位(X)和(Y)以多颗粒形式存在,其中优选微片剂、微胶囊、微丸粒、颗粒、球形体、珠子或者丸粒,对亚单位(X)和亚单位(Y)选择同样的形式,即形状,以使不可能例如通过机械选择将亚单位(X)和亚单位(Y)分离。优选多颗粒形式的尺寸为0.1-3mm,优选0.5-2mm。
多颗粒形式中的亚单位(X)和(Y)也可以优选包装在胶囊中或者压模成片剂,其中在每种情况下最终配制都以亚单位(X)和(Y)也都保留在最终剂型中的方式进行。
形状相同的多颗粒亚单位(X)和(Y)也不应互相在视觉上可以区分开,从而使得滥用者不能通过简单分拣而将它们彼此分离。这可以例如通过施加相同的涂层来实现,所述涂层除了这个伪装功能以外,也还可以结合其它的功能,比如例如,延迟释放一种或多种活性成分,或者为胃液对颗粒亚单位的作用提供最后一道屏障。
多颗粒亚单位也可以配制成如同在药用安全的悬浮介质中的浆料或者悬浮液一样的经口剂型。
在本发明的进一步优选实施方案中,在每种情况下亚单位(X)和(Y)互相成层排列。
为此,层状的亚单位(X)和(Y)优选在根据本发明制备的剂型中互相成水平或者垂直排列,其中在每种情况下,一种或多个层状亚单位(X)和一个或多个层状亚单位(Y)可以存在于剂型中,从而除了优选的层顺序(X)-(Y)或者(X)-(Y)-(X)外,可以考虑任何所需的其它层顺序,并任选的和含有组分(a)和/或(b)的层组合。
根据本发明制备的另一种优选剂型是其中亚单位(Y)形成完全被亚单位(X)封闭的芯的剂型,其中在所述层之间可以存在分隔层(Z)。所述结构也优选适用于上述多颗粒形式,其中亚单位(X)和(Y)以及任选存在的分隔层(Z)被配制在同一多颗粒形式中,其中所述分隔层(Z)必须满足本发明的硬度要求。
在根据本发明制备的剂型的进一步优选实施方案中,亚单位(X)形成芯,所述芯被亚单位(Y)封闭,其中后者包含至少一条从芯导向剂型表面的通道。
根据本发明制备的剂型在每种情况下在一层亚单位(X)和一层亚单位(Y)之间可以包含一个或者多个,优选一个,任选的可溶胀分隔层(Z),所述分隔层起到将亚单位(X)和(Y)在空间上分隔的作用。
如果根据本发明制备的剂型包含至少部分垂直或者水平排列形式的层状亚单位(X)和(Y)以及任选存在的分隔层(Z),那么该剂型优选采用片剂或者层压体的形式。
在一个特别优选的实施方案中,亚单位(Y)的全部自由表面、任选的亚单位(X)(一个或多个)的至少部分自由表面以及任选的任选存在的分隔层(Z)(一个或多个)的至少部分自由表面,可以涂有至少一个阻挡层(Z’),以防组分(c)和/或(e)和/或(d)和/或(f)的释放。阻挡层(Z’)也必须满足本发明的硬度条件。
根据本发明制备的剂型的另一特别优选的实施方案包含呈水平或者垂直排列的亚单位(X)和(Y)的层以及至少一个设置在其间的推进层(push layer)(p)以及任选的分隔层(Z),在所述剂型中,由亚单位(X)和(Y)、推进层和任选存在的分隔层(Z)的全部自由表面被设置有半渗透性的涂层(E),所述涂层对于释放介质,即,常规生理液体,是可渗透的,但是对于活性成分和组分(c)和/或(d)和/或(f)而言基本不可渗透,而且其中所述涂层(E)包含至少一个在亚单位(X)区域中的用于释放活性成分的开口。
相应的剂型是本领域技术人员公知的,例如以经口渗透性治疗系统(OROS)的名义,用于制备所述剂型的合适材料和方法等等同样也是公知的,请参见US4612008、US4765989和US4783337。相应的描述在此引入作为参考并认定为本公开的一部分。
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)是片剂形式,其边缘面和任选的两个主表面之一覆盖有含有组分(c)和/或(d)和/或(f)的阻挡层(Z’)。
本领域技术人员会理解,在根据本发明剂型配制中所用的(一个或多个)亚单位(X)或者(Y)以及任选存在的分隔层(一个或多个)(Z)和/或阻挡层(一个或多个)(Z’)的辅助物质,将随着其在剂型中排列的功能、给药模式、以及任选存在的组分(a)和/或(b)和/或(e)的特定活性成分以及组分(c)和/或(d)和/或(f)的特定活性成分而变。具有所需性质的材料在每种情况下对于本领域技术人员而言本身都是公知的。
如果通过该覆盖层,优选阻挡层,的作用,阻止了组分(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,那么该亚单位可以由本领域公知的常规材料制备,前提是它含有至少一个聚合物(C)和任选(D)以满足硬度条件,并且已经根据本发明制备。
如果没有提供相应的阻挡层(Z’)来在阻止组分(c)和/或(d)和/或(f)的释放,那么亚单位的材料应该经过选择以使实质上消除了特定组分组分(c)和/或(d)从亚单位(Y)的释放。下述适于制备阻挡层的材料可以优选用于本目的。
优选的材料是选自下列的材料:烷基纤维素、羟基烷基纤维素、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,市售名称为Polifeprosan20
Figure G06803854920070806D000211
)、羧甲基纤维素、纤维素醚、纤维素酯、硝基纤维素、基于(甲基)丙烯酸和其酯的聚合物、聚酰胺、聚碳酸酯、聚亚烷基、聚(氧化亚烷基二醇)、聚环氧烷、聚对苯二甲酸亚烷基酯、聚乙烯基醇、聚乙烯基醚、聚乙烯基酯、卤化聚乙烯基、聚乙醇酸交酯、聚硅氧烷和聚氨酯及其共聚物。
特别合适的材料可以选自下列: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、中或者高分子量)、纤维素乙酸丙酸酯、纤维素乙酸丁酸酯、纤维素乙酸邻苯二甲酸酯、羧甲基纤维素、纤维素三乙酸酯、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、聚甲基丙烯酸异丁酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸酯、聚甲基丙烯酸月桂酯、聚甲基丙烯酸苯基酯、聚丙烯酸甲酯、聚丙烯酸异丙酯、聚丙烯酸异丁酯、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、聚对苯二甲酸乙二醇酯、聚乙烯醇、聚乙烯基异丁基醚、聚乙酸乙烯酯和聚氯乙烯。
特别合适的共聚物可以选自下列:甲基丙烯酸丁酯和甲基丙烯酸异丁酯的共聚物、大分子量的甲基乙烯基醚和马来酸的共聚物、甲基乙烯基醚和马来酸单乙酯的共聚物、甲基乙烯基醚和马来酸酐的共聚物、以及乙烯醇和乙酸乙烯酯的共聚物。
特别适于配制阻挡层的其它材料是淀粉填充的聚己内酯(WO98/20073)、脂族聚酯酰胺(DE19753534A1、DE19800698A1、EP0820698A1)、脂族和芳香族聚酯尿烷(DE19822979)、聚羟基烷羧酸酯,尤其是聚羟基丁酸酯、聚羟基戊酸酯、酪蛋白(DE4309528)、聚丙交酯和共聚丙交酯(EP0980894A1)。相应的描述在此引入作为参考并认定为本公开的一部分。
上述材料可以任选地与本领域公知的其它常规辅助物质掺混,所述辅助物质优选选自下列:单硬脂酸甘油酯、半合成甘油三酸酯衍生物、半合成甘油酯、氢化的蓖麻油、棕榈硬脂酸甘油酯、二十二烷酸甘油酯、聚乙烯基吡咯烷酮、白明胶、硬脂酸镁、硬脂酸、硬脂酸钠、滑石、苯甲酸钠、硼酸和胶态氧化硅、脂肪酸、取代的三甘油酯、甘油酯、聚亚烷基二醇、和其衍生物。
如果根据本发明制备的剂型包括分隔层(Z’),那么所述层和未覆盖的亚单位(Y)一样,优选可以由上述针对阻挡层描述的材料组成。本领域技术人员可以理解可以通过分隔层的厚度来控制活性成分或者组分(c)和/或(d)从特定亚单位的释放。
根据本发明制备的剂型显示出对活性成分的受控释放。优选适于每日两次给药给病人。
根据本发明制备的剂型可以含有一种或多种至少部分处于其它延迟释放形式的、具有滥用可能性的活性成分,其中延迟释放可以通过本领域普通技术人员公知的常规材料和方法来实现,例如通过将活性成分嵌入在延迟释放基质中,或者通过施加一个或多个延迟释放涂层。但是,活性成分释放必须受控,以使在每种情况下上述条件得以满足,例如,在正确给药所述剂型的情况下,在任选存在的组分(c)和/或(d)可以产生损害效果之前,一种或多种活性成分实质上完全释放。而且,能对受控释放有影响的材料的加入也必须不损害所需的硬度。
优选,通过将活性成分嵌入在基质中,实现从根据本发明制备的剂型中的受控释放。充当基质材料的辅助物质控制着活性成分的释放。基质材料可以例如是亲水性的凝胶形成材料,活性成分通过所述材料的释放主要是通过扩散进行;或者,是疏水性材料,活性成分通过所述材料的释放主要是通过从基质中的孔扩散来进行。
本领域公知的、生理上可接受的疏水性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/或丙烯酸树脂,优选用作亲水性基质材料。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(甲基)丙烯酸和/或其衍生物,比如其盐、酰胺或酯,特别优选用作基质材料。
也优选由疏水性材料,比如疏水性聚合物、蜡、脂肪、长链脂肪酸、脂肪醇或者其相应的酯或醚或混合物,制备的基质材料。特别优选C12-C30脂肪酸的单或者二甘油酯和/或C12-C30脂肪醇和/或蜡或者其混合物用作疏水性材料。
也可以采用上述亲水性和疏水性材料的混合物作为基质材料。
用于获得根据本发明必须的至少500N的断裂强度的组分(C)和任选存在的组分(D),可以进一步自身作为另外的基质材料。
如果根据本发明制备的剂型打算用于经口给药,那么也可以优选包含抗胃液的、并且随着释放环境pH值的变化而溶解的涂层。由于所述涂层,可以确保根据本发明制备的剂型不溶解地通过胃,活性成分仅仅在肠中释放。抗胃液的涂层优选在pH为5-7.5之间时溶解。
用于延迟释放活性材料以及用于实现抗胃液涂层的相应材料和方法,是本领域技术人员公知的,例如,参见“Coated PharmaceuticalDosage Forms-Fundamentals,Manufacturing Techniques,Biopharmaceutical Aspects,Test Methods and Raw Materials”,KurtH.Bauer,K.Lehmann,Hermann P.Osterwald,Rothgang,Gerhart,第一版,1998,MedpharmScientific Publishers。相应的文献描述在此引入作为参考,并认定为本公开的一部分。
确定断裂强度的方法
为了验证材料是否可以用作组分(C)或者(D),在片剂模具中利用针对组分(C)或者(D)的溶剂将该材料溶解,一旦在低于该材料软化点的温度将溶剂去除后,采用150N的力将该材料压成直径10mm、高度5mm的片剂。
采用以此方式制备的片剂,利用下述装置根据EuropeanPharmacopoeia 1997,第143,144,方法no.2.9.8公布的确定片剂断裂强度的方法来确定断裂强度。用于该测量的装置是“Zwick Z 2.5”材料测试机,Fmax=2.5kN,最大拉伸距离为1150mm,该测试机应该配有1个柱和1个心轴,后间隙(clearance behind)为100mm,测试速度在0.1-800mm/min之间可调,以及配有testControl软件。采用具有拧入式插件和汽缸(直径10mm)的压力活塞、力传感器(Fmax为1kN,直径=8mm,根据ISO 7500-1,从10N开始为0.5级,从2N开始为1级)进行测量,所述装置具有根据DIN 55350-18的制造商测试证书M(Zwick的力总量Fmax=1.45kN)(所有装置来自Zwick GmbH&Co.KG,Ulm,Germany),其中测试机的型号为BTC-FR 2.5TH.D09,力传感器的型号为BTC-LC 0050N.P01,对中设备的型号为BO70000S06。
图1示出了片剂的断裂强度测量,具体而言,在测量前和测量中为此目的采用了片剂(4)调整设备(6)。为此,在两个2-部分夹持设备的帮助下,将片剂(4)保持在施力装置(未示出)的上压板(1)和下压板(3)之间,一旦已经建立了需要容纳待测量片剂并将所述片剂居中设置所需的间隔(5)时,则在每种情况下将所述夹持设备用上压板和下压板牢固地固定(未示出)。可以通过在每种情况下将所述2-部分夹持设备在安装它的压力板上向内或向外水平移动,来建立所述间隔(5)。
被认定在特定载荷下能抵抗断裂的片剂,不仅仅包括那些没有破裂的片剂,也包括那些在力用作可能已经发生塑性变形的片剂。
根据本发明制备的制剂的断裂强度通过用于确定断裂强度的所述测量方法来确定,还测量了除了片剂以外的剂型。
下面将参考实施例描述本发明。这些解释仅仅通过实施例来给出,不是限制本发明的范围。
实施例
实施例1
  每片剂   全批次
 盐酸曲马多   100.0mg   1495.0g
 聚环氧乙烷MW7000000(来自Dow的Polyox WSR 303)   167.8mg   2508.6g
 羟丙基甲基纤维素(羟丙甲纤维素100000mPa)   33.5mg   500.8g
 丁基羟基甲苯(BHT)   0.2mg   3.0g
 总质量   300.5mg   4507.4g
将所述量的BHT溶解在乙醇(96%)中,从而得到7.7%(质量/质量)的乙醇溶液。该溶液首先和150g聚环氧乙烷在高速混合机中混合30分钟,然后,加入剩余量的聚环氧乙烷,继续搅拌30分钟。将组合物在40℃干燥12小时。
在自由下落式混合机中加入所有其它组分,并混合15分钟。将粉末混合物在模具之间分配,每个模具的直径为13mm,深度为6mm。采用具有套管的注射器,将混合物在每种情况下悬浮在0.5ml的96%乙醇中,然后在每种情况下与0.5ml蒸馏水合并。在24小时溶胀之后,将溶胀的组合物在40℃干燥24小时。
采用型号为EK0的偏心压床,将分配好的、干燥的部分各自压模形成片剂。制造片剂的工具的直径是10mm,曲率半径是8mm。
采用上述方法确定片剂的断裂强度。当施加500N力时,没有发生破裂。片剂不能用锤子粉碎,也不能用研钵和研杵粉碎。
根据Pharm.Eur.在具有冲钻(sinker)的桨式搅拌装置中,确定在体外活性成分从片剂的释放。释放介质温度是37℃,搅拌器的旋转速度是75min-1。所用释放介质是600ml的肠液,pH为6.8。在每种情况下在任何一次释放到溶解介质中的活性成分量通过光谱法确定。
 时间   释放的活性成分量
 30分   20%
 240分   43%
 480分   83%
 720分   90%
实施例2
 粉末混合物   全批次   每片剂
 盐酸曲马多   100.1g   100mg
 聚环氧乙烷MW5000000(来自Dow的Polyox WSR促凝剂)   300.0g   299.7mg
 羟丙基甲基纤维素(羟丙甲纤维素100000mPa)   50.05g   50.0mg
 丁基羟基甲苯(BHT)   0.25g   0.25mg
 泡沫羟丙基甲基纤维(羟丙甲纤维素100000mPa)   0.250g   0.25mg
 蒸馏水   49.8g
首先如实施例1所述制备粉末混合物。
通过将所述量的羟丙甲纤维素溶解在蒸馏水中制备泡沫。然后,采用高性能均化器(IKA Ultraturrax25Basic)通过首先在水平1搅拌2分钟,然后在水平2用混合机/造粒机搅拌2分钟,最后在水平3搅拌3分钟,制备泡沫。在混合机(Kenwood Major Classic25Basic)中,将粉末混合物缓慢加入到泡沫中,并一直搅拌。
然后,将颗粒化的混合物在40℃干燥24小时,在通过孔隙为1mm的筛子(得自Frewitt,型号GLA-A-ORV)后,以450.2mg的重量将其压模成片剂。为此目的,采用了具有圆形的、制备片剂的工具的EKO型偏心压床,其中所述制备片剂的工具直径为10mm,曲率半径为8mm。将这些片剂在70℃干燥1小时。
采用上述方法确定片剂的断裂强度。当施加500N力时,没有发生破裂。片剂不能用锤子粉碎,也不能用研钵和研杵粉碎。
根据Pharm.Eur.在具有冲钻的桨式搅拌装置中,确定在体外活性成分从片剂的释放。释放介质温度是37℃,搅拌器的旋转速度是75min-1。所用释放介质是600ml的肠液,pH为6.8。在每种情况下在任何一次释放到溶解介质中的活性成分量通过光谱法确定。
 时间   释放的活性成分量
 30分   12%
 240分   47%
 480分   71%
 720分   84%

Claims (9)

1.用于制备具有至少降低的滥用可能性的固态剂型的方法,特征在于
a)向含有至少一种具有滥用可能性的活性成分A和至少一种合成或天然聚合物C的制剂混合物中,加入针对所述聚合物C的溶剂,加入量是至少使得所述制剂混合物被均匀润湿的量,其中所述聚合物C为具有分子量为至少100万-1500万的高分子量的热塑性聚环氧乙烷,
c)将经均匀润湿的混合物干燥,和
d)经成形以获得所述剂型,
聚合物C的用量使得所述剂型具有至少500N的最低断裂强度。
2.权利要求1的方法,特征在于在加入溶剂之前,所述制剂混合物已经分散在液体分散剂中,所述聚合物组分C不溶于所述液体分散剂。
3.权利要求2的方法,特征在于在所述制剂组合物分散之前或者之后,在每种情况下它都已经被分成和单位所述剂型的质量相一致的亚部分。
4.权利要求2的方法,特征在于所述溶剂和所述分散剂互相混溶。
5.权利要求1的方法,特征在于所述溶剂作为泡沫引入到所述制剂混合物中。
6.权利要求5的方法,特征在于所述泡沫在泡沫稳定剂的辅助下得以稳定。
7.权利要求5或6的方法,特征在于用所述溶剂泡沫颗粒化的组合物被干燥。
8.权利要求7的方法,特征在于所述干燥的、颗粒化的组合物被分成亚部分,并成形以获得所述剂型,其中所述亚部分在每种情况下和单位所述剂型的质量相一致。
9.权利要求1的方法,特征在于所述溶剂以使得得到可成形糊的量加入到制剂混合物中。 
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US20060188447A1 (en) 2006-08-24
EP1845955A1 (de) 2007-10-24
JP5265201B2 (ja) 2013-08-14
US20160367485A1 (en) 2016-12-22
EP1845955B1 (de) 2015-05-27
AR054222A1 (es) 2007-06-13
HK1108370A1 (zh) 2008-05-09
PE20061204A1 (es) 2006-12-15
US20150283086A1 (en) 2015-10-08
WO2006082097A1 (de) 2006-08-10
TW200640500A (en) 2006-12-01
US20080311197A1 (en) 2008-12-18
IL185017A (en) 2016-05-31
US20150091201A1 (en) 2015-04-02
CN101111232A (zh) 2008-01-23
US10729658B2 (en) 2020-08-04
JP2008528653A (ja) 2008-07-31
CA2595979A1 (en) 2006-08-10
IL185017A0 (en) 2007-12-03
TWI449540B (en) 2014-08-21
DE102005005449A1 (de) 2006-08-10

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