CN101027044B - 避免滥用的口服剂型 - Google Patents
避免滥用的口服剂型 Download PDFInfo
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- CN101027044B CN101027044B CN2005800292367A CN200580029236A CN101027044B CN 101027044 B CN101027044 B CN 101027044B CN 2005800292367 A CN2005800292367 A CN 2005800292367A CN 200580029236 A CN200580029236 A CN 200580029236A CN 101027044 B CN101027044 B CN 101027044B
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Abstract
本发明涉及一种口服剂型,该剂型防止滥用并且对于每日一次给药控制鸦片样物质的释放。本发明的特征在于,所述口服剂型包含至少一种具有滥用可能性的鸦片样物质(A)、至少一种合成和/或天然聚合物(C)、任选包含延迟基质材料、生理学上相容的辅助剂(B)、任选包含蜡(D),和任选包含至少一种延迟包衣。组分(C)或者(D)各自的断裂阻力至少为500N,优选至少750N。
Description
技术领域
本发明涉及一种防滥用口服剂型,其对于每日一次给药,控制鸦片样物质(opioid)释放其包含至少一种可能滥用的鸦片样物质(A),至少一种合成或者天然聚合物(C),任选延迟释放的基质材料、任选至少一种延迟释放包衣、任选生理学上可接受的辅助性物质(B),任选的蜡(D),在各种情形中组分(C)或者(D)的断裂强度至少为500N,优选750N。
根据本发明,名称“鸦片样物质”是指与至少一种鸦片样物质受体相互作用的化合物。特别是,除(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、其生理学上可接受的盐和/或衍生物以及其相应的立体异构体和/或药学上可接受的化合物或者衍生物之外,鸦片样物质意指那些表现出滥用可能性的鸦片样物质化合物。
优选鸦片样物质用于抗疼痛。基于此目的,通常将镇痛药用于长期治疗中,例如在慢性疼痛或者由肿瘤引起的疼痛情形中使用。特别地,在长期治疗中,使患者能够享受较高生活质量是非常重要的。改善患者生活质量的措施包括提供允许每日给药一次的剂型。然而,由于鸦片样物质的量相对较大,因此提供活性成分延迟释放的上述剂型对于期望尽快诱导期望的麻醉或者陶醉状态的滥用者是特别具有吸引力。
背景技术
然而,迄今为止,含有可能滥用鸦片样物质的延迟释放剂型即使在高滥用剂量口服时通常都不能产生期望的突跳(kick)效果,基于滥用的目的,还将这些剂型(例如,片剂或者胶囊)粉碎(例如,研磨)和由滥用者吸入,或者通过含水液体从按照上述方式得到的粉末中提取活性成分和任选在使其滤过棉絮或者纤维素填絮之后对所得溶液进行胃肠外给药,特别是静脉内给药。同口服或者鼻滥用相比,这种类型的给药可以使得鸦片样物质的水平甚至更加速地升高,同时会产生滥用者期望的结果,即“突跳”或者“急冲”(rush)。
为了防止滥用,US-A-4,070,494提出将可膨胀试剂加入到所述剂型中。当加入水以提取鸦片样物质时,该可膨胀试剂膨胀并且确保从凝胶分离的滤液中仅仅含有少量活性成分。
公开于WO 95/20947中的多层片剂基于类似的方法,以防止胃肠外滥用,所述片剂在各个不同层中含有可能滥用的鸦片样物质和至少一种凝胶靠模。
WO 03/015531A2公开了另一种方法,以防止胃肠外滥用。其中所述的剂型含有止痛鸦片样物质和作为厌恶剂的染料。由于剂型受到损害(tamper)而释放出的颜色用于防止滥用者使用已经受到损害的剂型。
为了使滥用复杂化,另一已知的可选方案是将鸦片样物质的拮抗剂加入到剂型中的所述拮抗剂为比如,例如纳洛酮或者naltexone或者产生生理防护反应的化合物,比如,例如为吐根(吐根树)根或者苦素。
然而,由于在绝大多数鸦片样物质延迟释放的剂型滥用中,仍然需要粉碎该剂型。因此,本发明的目的是进行复杂化或者防止在剂型滥用之前进行粉碎,包含常规可以用于可能滥用的装置,据此提供在每日一次正确给药时,确保期望治疗学效果的控制释放可能滥用的鸦片样物质的剂型,但是所述鸦片样物质不能仅仅通过粉碎即可转化为适于滥用的形式。
发明内容
根据本发明,上述目的通过制备对于每日一次给药,控制释放至少一种鸦片样物质的防滥用口服剂型得到了实现,所述剂型包含,除了至少一种可能滥用的鸦片样物质和/或至少一种其生理学上可接受的化合物(优选其盐或者溶剂化物或者衍生物(优选酰胺、酯或者醚)),和/或至少一种相应的立体异构化合物(优选其相应的对映异构体、立体异构体、非对映异构体或者外消旋物)和/或其生理学上可接受的化合物(比如盐或者溶剂化合物或者衍生物,比如酰胺、醚或者酯)(A)之外,还包含至少一种合成和/或天然聚合物(C),任选至少一种延迟释放的基质材料、任选至少一种延迟释放的包衣、任选生理学上可接受的辅助性物质(B),任选至少一种蜡(D),在各种情形中组分(C)或者(D)的断裂强度为至少500N,优选至少750N。
通过应用具有所述最低断裂强度(如本申请中所公开进行测量)的组分(C)和任选(D),优选其以使得剂型还显示出最低断裂强度为至少500N,优选至少750N的量应用,通过常规方法进行的剂型的粉碎以及由此随后进行的滥用(优选经鼻或者胃肠外滥用)可以得到显著复杂化或者得到防止。
由于不存在自发释放,因此如果剂型没有得到充分粉碎,那么通过滥用口服给药,无风险胃肠外给药,特别是静脉内或者经鼻给药是不可能的,或者提取活性成分花费滥用者太长时间,或者不能或者不能充分获得药物突跳。
根据本发明,粉碎是指利用滥用者可以获得的常规方法粉碎剂型,比如,例如为杵棒和研钵、锤、短锤或者其它通过常用的通过施加压力进行粉碎的装置。
由此,根据本发明的剂型适用于预防胃肠外、经鼻和/或口服滥用可能滥用的鸦片样物质。
可能滥用的鸦片样物质是本领域熟练技术人员所已知的,其使用剂量以及用于生产它的方法也是同样如此,其可以就这样以其相应的衍生物(特别是酰胺、酯或者醚)形式存在于根据本发明的剂型中,或者在各种情形中以相应的生理学上可接受的化合物形式(特别是以其盐或者溶剂化物的形式)存在,作为外消旋物或者立体异构体存在。根据本发明的剂型还适于给药许多种鸦片样物质。优选其用于给药人类或者哺乳动物(优选人类)抗疼痛的特定鸦片样物质,持续时间为至少24小时。
属于鸦片样的物质种类的物质是本领域熟练技术人员所熟知的,例如,公开于Alan F.Casy等人的“Opioid Analgesic’s”,1986版,特别是第508~518页,Plenum Publishing Corporation,H.Buschmann的“Analgesics”,2002版,第171~245页,WILEY-CHF和ElmarFiedrics等人的“Ullmann′s Encyclopedia of Industrial Chemistry”,第6版,第1~53页,WILEY-VCH中的那些物质。特别优选其中所列的鸦片样物质及其代谢产物。其对应的说明在此引入本文作为参考并且认为其属于公开内容的一部分。
根据本发明的剂型非常特别适用于防止选自以下的鸦片样物质的滥用: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}丙酰替苯胺(propionanilide)(阿芬太尼)、烯丙罗定、阿法罗定、安那里丁、羟基派替啶、下吗啡、苯腈米特、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-内型-桥亚乙基吗啡喃-3-醇(丁丙诺啡)、布托啡诺、卡芬太尼、氯尼他秦、(-)-甲基-[3β-苯甲酰氧基-2β(1αH,5αH)-托烷羧酸酯](可卡因)、4,5α-环氧-3-甲氧基-17-甲基-7-吗啡(morphinen)-6α-醇(可待因)、二氢脱氧吗啡、右旋吗酰胺、(+)-(1-苄基-3-二甲基氨基-2-甲基-1-苯丙基)丙酸酯(右旋丙氧吩)、地佐辛、地恩丙胺、二吗啡酮(diamorphone)、4,5α-环氧-3-甲氧基-17-甲基-6α-吗喃醇(二氢可待因)、4,5α-环氧-17-甲基-3,6α-吗喃二醇(二氢吗啡)、地美沙多、dimephetamol、二甲噻丁、吗苯丁酯、地匹哌酮、二氢吗啡酮、依他佐辛、乙庚嗪、乙甲噻丁、4,5α-环氧-3-乙氧基-17-甲基-7-吗啡-6α-醇(乙基吗啡)、依托尼秦、4,5α-环氧-7α-(1-羟基-1-甲基丁基)-6-甲氧基-17-甲基-6,14-内型-亚乙烯基-吗啡喃-3-醇(羟戊甲吗啡)、苯哌酰胺、N-(1-苯乙基-4-哌啶基)丙酰替苯胺(芬太尼)、海洛因、4,5α-环氧-3-甲氧基-17-甲基-6-吗啡烷酮(氢可酮)、4,5α-环氧-3-羟基-17-甲基-6-吗啡烷酮(氢化吗啡酮)、羟哌替啶、异美沙酮、羟基甲基吗啡喃、1-[4-(3-羟基苯基)-1-甲基-4-哌啶基]-1-丙酮(凯托米酮)、(3S,6S)-6-二甲基氨基-4,4-二苯基庚-3-基乙酸酯(左旋乙酰美沙醇)、(-)-6-二甲基氨基-4,4-联苯酚-3-庚酮(左美沙酮)、(-)-17-甲基-3-吗啡喃醇(利富吩)、左芬啡烷、levoxemacin、洛芬太尼、派替啶、2-甲基-2-丙基三亚甲基二氨基甲酸酯、美普他酚、美他佐辛、美沙酮、甲基吗啡、metapon、3-甲基芬太尼、4-甲基芬太尼、4,5α-环氧-17-甲基-7-吗啡-3,6α-二醇(吗啡)、吗啡-6-葡萄糖醛酸、麦罗啡、nalbuphene、烯丙吗啡、那碎因、尼可吗啡、6-二甲基氨基-4,4-二苯基-3-己酮(去甲美沙酮)、降吗啡、诺匹哌酮、属于罂粟种植物的渗出物(鸦片)、4,5α-环氧-14-羟基-3-甲氧基-17-甲基-6-吗啡烷酮(氧可酮)、氧吗啡酮、属于罂粟种(包括亚种岩黄耆属)的植物和植物部分(罂粟)、阿片全碱、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-8-醇(镇痛新)、乙基-(1-甲基-4-苯基-4-哌啶羧酸酯)(哌替啶)、非那多栓、phenomorphane、非那佐辛、苯哌利定、去痛定、福尔可定、1’-(3-氰基-3,3-二苯基丙基)[1,4’-联哌啶]-4’-羧酰胺(哌腈米特)、普罗庚嗪、二甲哌替啶、异丙哌替啶、达尔丰、甲基{3-[4-甲氧羰基-4-(N-苯基丙酰氨基)哌啶子基]丙酸酯}(瑞芬太尼)、N-{4-甲氧基甲基-1-[2-(2-噻吩基)乙基]-4-哌啶基}丙酰替苯胺(舒芬太尼)、乙基(2-二甲基氨基-1-苯基-3-环己烯-1-羧酸酯)(痛立停,顺式和反式)、蒂巴因、反胺苯环醇、(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、(优选为外消旋物)、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-(2-二甲基氨基甲基-1-羟基-环己基)-苯酯、(RR-SS)-2-羟基-5-硝基-苯甲酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯酯、(RR-SS)-2’,4’-二氟-3-羟基-联苯-4-羧酸3-(2-二甲基氨基甲基-1-羟基-环己基)-苯酯以及相应的立体异构化合物,在各种情形中,其相应的衍生物,特别是酰胺、酯或者醚,并且在各种情形中其生理学上可接受的化合物,特别是其盐和溶剂化物,特别优选盐酸盐、硫酸盐、糖精酸盐(saccharinates)、活性代谢产物、地芬诺酯、左美沙酮、nortilidine、哌腈米特和维米醇。
根据本发明的剂型特别适用于防止选自以下的鸦片样物质活性成分的滥用:氧可酮、氢化吗啡酮、吗啡、氧吗啡酮、反胺苯环醇及其生理学上可接受的衍生物或者化合物,优选其盐和溶剂化物,优选其盐酸盐、硫酸盐和糖精酸盐,和/或其立体异构体或者相应的化合物和/或衍生物。
此外,根据本发明的剂型特别适用于防止选自以下的鸦片样物质活性成分的滥用:(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-环己基)苯酚,其生理学上可接受的盐(优选盐酸盐、硫酸盐、糖精酸盐),生理学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物以及其生理学上可接受的衍生物,优选醚、酯或者酰胺。
这些化合物及其生产方法分别描述于EP-A-693475和EP-A-780369中。其对应的说明在此引入本文作为参考并且认为其属于公开内容的一部分。
对延迟释放剂型中的剂量进行选择,从而使得每日给药一次可以得到确保。其相应的剂量是本领域熟练技术人员所熟知的。
优选活性成分在根据本发明的剂型中的含量为0.05~80wt.%,特别优选为0.05~60wt.%,并且非常特别优选为0.05~40wt.%。
为了使根据本发明的剂型具有必需的断裂强度,应用至少一种合成、半合成或者天然聚合物(C),其断裂强度,利用在本申请中公开的方法测量为至少500N,优选750N。优选,基于此目的的至少一种聚合物选自聚氧化烯烃(优选聚氧化甲烯、聚氧化乙烯、聚氧化丙烯)、聚烯烃(优选聚乙烯、聚丙烯、聚氯乙烯、聚碳酸酯、聚苯乙烯、聚(甲基)丙烯酸酯及其共聚物)和至少两种所述聚合物或聚合物种类的混合物。特别优选使用水溶性或者可水膨胀的聚合物。优选高分子量、热塑性聚氧化烯烃。特别优选通过流变性测定确定,分子量为至少0.5百万的聚氧化乙烯,优选为1百万~15百万。这些聚氧化乙烯在25℃下,使用RVF Brookfield型号粘度计(2号轴/转速2rpm)在5wt.%水溶液上测定的粘度为4500~17600cP,使用所述粘度计(使用1号或者3号轴/转速10rpm)在2wt.%水溶液上测定的粘度为400~4000cP,或者使用所述粘度计(但是使用2号轴/转速2rpm),在1wt.%水溶液上测定的粘度为1650~10000cP(c.f.Handbook of PharmaceuticalExcipients by Raymond C.Rowe等人,第4版,2003,page 460)
优选所述聚合物作为粉末使用以生产根据本发明的剂型。它们可以是水溶性或者可水膨胀的。
相对于剂型的总重量,优选组分(C)以20~99.9wt.%的量进行使用,特别优选为至少35wt.%,非常特别优选为至少50wt.%。
可以使用的辅助性物质(B)是配制固体剂型所熟知的常规辅助性物质。优选组分(B)为增塑剂,比如以0.01~20wt.%的量使用的聚乙二醇,特别优选最高达15wt.%,并且非常特别优选最高达10wt.%,影响活性成分释放的辅助性物质如下所述,优选为疏水或者亲水性聚合物(优选为亲水性聚合物,非常特别优选为羟基丙基甲基纤维素或者羟基丙基纤维素)和/或抗氧化剂。适宜的抗氧化剂为抗坏血酸、丁基羟基苯甲醚、丁基羟基甲苯、抗坏血酸盐、单硫代丙三醇的盐、亚磷酸的盐、维生素C的盐、维生素E的盐及其衍生物、亚硫酸氢钠,特别优选丁基羟基甲苯(BHT)或者丁基羟基苯甲醚(BHA)和α-生育酚。
相对于所述剂型的总重量,优选所述抗氧化剂以0.01~10wt.%的量使用,优选0.03~5wt.%。
此外,除了上述聚合物之外,还可以另外使用至少一种利用本申请公开方法测量的断裂强度为至少500N(优选750N)的天然、半合成或者合成蜡(D),以获得根据本发明剂型所需要的断裂强度。优选蜡的软化点至少为60℃。特别优选巴西棕榈蜡和蜂蜡。非常特别优选巴西棕榈蜡。巴西棕榈蜡是从巴西棕榈树叶得到的天然蜡,其软化点最高为90℃。当另外使用蜡组分时,将后者与至少一种聚合物(C)(优选为聚氧化乙烯)以使得剂型表现出断裂强度至少为500N(优选至少750N)的量一起使用,所述断裂强度利用本申请所述方法进行测定。
根据本发明的剂型的区别在于它们不能利用常规的粉碎工具(比如研钵和杵棒)进行粉碎,因为它们是坚硬的。从而,口服、胃肠外(特别是静脉内)或者经鼻滥用实际上是被排除在外的。然而,为了防止根据本发明的剂型的任何可能滥用,在优选的实施方案中,根据本发明的剂型可以含有作为辅助性物质(B)的其它滥用-复杂化或者防止滥用试剂。
由此,根据本发明的防滥用剂型可以包含,除了至少一种可能滥用的鸦片样物质之外,含有至少一种聚合物(C)和任选至少一种蜡(D)、至少一种作为辅助性物质(B)的以下组分(a)~(f):
(a)至少一种刺激鼻通道和/或咽的物质,
(b)至少一种粘度增强试剂,其在必需的最低量含水液体的辅助下(优选作为由所述剂型获得的含水提取物)形成凝胶,优选所述凝胶在被引入到进一步量含水液体中时仍然在视觉上是可区分的,
(c)至少一种本发明可能滥用的鸦片样物质的拮抗剂,
(d)至少一种催吐剂,
(e)至少一种作为厌恶剂的染料,
(f)至少一种苦素。
所述组分(a)~(f)各自自身适宜于作为防止滥用的根据发明剂型的附加保护。据此,优选组分(a)适用于防止剂型经鼻、口服和/或胃肠外(优选静脉内)滥用,优选组分(b)适用于防止胃肠外(特别优选静脉内)和/或经鼻滥用,优选组分(c)适用于防止经鼻和/或胃肠外滥用,特别优选防止静脉内滥用,优选组分(d)适用于防止胃肠外(特别优选静脉内)和/或口服和/或经鼻滥用,组分(e)适于作为防止口服或者胃肠外滥用的视觉制止剂和组分(f)适用于防止口服或者经鼻滥用。通过共同使用至少一种上述组分,可以使根据本发明的剂型更有效地使滥用复杂化。
在一种实施方案中,根据本发明的剂型还可以联合含有两种或者多种组分(a)~(f),优选联合(a)、(b)和任选(c)和/或(f)和/或(e)或者(a)、(b)和任选(d)和/或(f)和/或(e)。
在另一实施方案中,根据本发明的剂型可以含有所有组分(a)~(f)。
如果根据本发明的剂型含有组分(a)作为防止滥用的附加保护,那么可以根据本发明设想的刺激鼻通道和/或咽的物质为任何经鼻通道和/或咽给药时产生身体反应的物质,所述身体反应或者是使滥用者产生他/她不期望或者不能继续给药的不舒适(例如灼烧)或者与摄取相应鸦片样物质和/或鸦片剂生理学上对抗作用(例如,由于增强的鼻分泌或者打喷嚏而产生的生理学对抗作用)。这些通常刺激鼻通道和/或咽的物质在胃肠外给药(特别是静脉内给药)时还可能会产生非常不舒适的感觉或者甚至无法忍受的疼痛,从而使得滥用者不希望或者不能继续摄取该物质。
特别适宜的刺激鼻通道和/或咽的物质是产生灼烧、痒、想打喷嚏、增强分泌物形成或者至少两种上述刺激组合的那些物质。通常应用的适当物质及其量是本身为所述技术领域熟练技术人员所熟知或者可以通过简单初步试验得到确认。
优选组分(a)的刺激鼻通道和/或咽的物质以至少一种辣(hot)物质药物的一种或多种组分或者一种或多种植物部分为基础。
相应的辣物质药物本身是本领域熟练技术人员所已知的,并且其描述于例如Prof.Dr.Hildebert Wagner的“Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe”,修订版第2版,Gustav FischerVerlag,Stuttgart-New York,1982,82页及以下等等之中。其对应的说明在此引入本文作为参考并且认为其属于公开内容的一部分。
至少一种辣物质药物的一种或者多种组分选自大蒜(大蒜)、Asari根茎附带草(细辛根和叶)、菖蒲根茎(菖蒲根)、辣椒果实(辣椒)、辣椒果实槭属(尖辣椒)、姜黄根茎(姜黄根)、爪哇姜黄根茎(爪哇姜黄根)、高良姜根茎(高良姜根)、肉豆蔻籽(肉豆蔻)、黑胡椒果实(胡椒)、白芥籽(白芥子)、黑芥籽(黑芥子)、莪术根茎(莪木根)和姜根茎(姜根),特别优选选自辣椒果实(辣椒)、辣椒果实槭属(尖辣椒)和黑胡椒果实(胡椒)的辣物质药物可以作为组分(a)加入到根据本发明的剂型中。
优选所述辣物质药物的组分含有o-甲氧基(甲基)-苯酚化合物、酰胺化合物、芥子油或者硫醚化合物或者由此衍生得到的化合物。
特别优选至少一种所述辣物质药物的组分选自肉豆蔻醚、榄香素、异丁香酚、α-细辛醚、黄樟素、姜辣素、甜没药萜烯型倍半萜烯(xanthorrhizol)、辣椒碱,优选辣椒素、辣椒素衍生物(比如N-香草基-9E-十八碳烯酰胺、二氢辣椒素、降二氢辣素、高辣素、norcapsaicin和降二氢辣椒碱)、胡椒碱(优选反式-胡椒碱)、葡糖异硫氰酸盐(优选基于非挥发性芥子油,特别优选基于对-羟基苄基芥子油、甲基巯基芥子油或者甲磺酰芥子油)和由这些组分衍生得到的化合物。
在各种情形中,相对于所述剂量单位的总重量,优选根据本发明的剂型可以以0.01~30wt.%的量含有相应辣物质药物的植物部分,特别优选0.1~0.5wt.%。
如果应用相应辣物质药物的一种或者多种组分,那么相对于剂量单位的总重量,优选其在根据本发明的剂量单位中的量合计为0.001~0.005wt.%。
另一种防止根据本发明的剂型滥用的任选项在于将至少一种粘度增强剂作为另外的防滥用组分(b)加入到所述剂型中,优选所述粘度增强剂在必需的最低量含水液体(优选作为从所述剂型中获得的含水提取物)的辅助下形成凝胶,所述凝胶实际上不可能进行安全给药和优选当将其引入到进一步量含水液体中时仍然在视觉上是可区分的。
基于本申请的目的,视觉上可区分的是指在必需的最低量含水液体的辅助下形成的含鸦片样物质凝胶或者含鸦片剂凝胶,优选在皮下注射针的辅助下,在37℃下被引入到进一步量的含水液体中时,仍然基本上不溶的和粘合在一起,不能以使其安全地进行胃肠外给药(特别是静脉内给药)地方式得到直接分散。优选所述材料可以保持视觉上可区分至少一分钟,优选保持至少10分钟。
增加凝胶的粘度将使得它更加难于或者甚至不可能通过针或者进行注射。如果所述凝胶保持视觉上可区分的,这意味着通过引入到进一步量含水液体中(例如,通过注射引入到血液中)而得到的凝胶开始仍然为大量粘结性胶丝的形式,虽然当然可以将其机械破碎成较小碎片,但是它们不能以使得其可以安全地进行胃肠外给药(特别是静脉内给药)的方式得到分散或者甚至溶解。与至少一种另外存在的组分(a)、(d)~(f)联合使用,这会进一步引起令人不舒适的灼烧、呕吐、不良气味和/或视觉制止物。
静脉内给药所述凝胶将非常可能导致血管阻塞,这与滥用者的健康严重受损相联系。
为了验证粘度增强剂是否适宜作为用于根据本发明剂型中的组分(b),将鸦片样物质和/或鸦片剂与粘度增强剂混合并且在25℃下,将其悬浮在10ml水中。如果这导致满足上述状况的凝胶形成,那么对应的粘度增强剂适用于进一步预防或者防止根据本发明的剂型的滥用。
如果将组分(b)加入到根据本发明方法获得剂型中,那么优选使用一种或者多种粘度增强剂,所述粘度增强剂选自:含有11wt.%羧甲基纤维素钠的微晶纤维素(RC 591)、羧甲基纤维素钠(,CMC-Na,Frimulsion,Tylose )、聚丙烯酸(980 NF,981)、角豆荚果粉(LA-200,LID/150,LN-1)、果胶,优选来自柑桔类水果或者苹果(HM Medium Rapid Set)、糯质种玉米淀粉()、海藻酸钠(Frimulsion )、瓜尔豆粉(Frimulsion,Polygum)、极微小角叉菜胶(Frimulsion)、刺梧桐树胶、洁冷胶(Kelcogel,Kelcogel)、半乳甘露聚糖(Meyprogat)、塔拉石粉(Polygum)、丙撑二醇藻蛋白酸盐(Protanal-Ester)、透明质酸钠、西黄蓍胶、他拉胶(Vidogum SP)、发酵多醣文莱胶(K1A96)、黄单胞萤肢(xanthans)(比如黄原胶(Xantural))。特别优选黄单胞萤肢。括号内所述的名称为它们的商品名,通过该商品名所述物质在商业中已知。通常,相对于所述剂型的总量,为0.1-20wt.%的量的所述粘度增强剂足以满足上述状态,特别优选0.1~15wt.%。
当提供时,优选所述组分(b)粘度增强剂以每剂量单位(即,每给药单元)至少5mg的量存在于根据本发明的剂型中。
在本发明特别优选的实施方案中,用作组分(b)的粘度增强剂为,优选通过用必需的最低量含水液体提取剂型所得到,形成包括气泡的凝胶的那些物质。所得凝胶通过出现浑浊进行判断,这给可能的滥用者提供了附加的视觉警告,阻止他/她进行凝胶胃肠外给药。
组分(C)还可以任选起另外的粘度增强剂的作用,它在必需的最低量含水液体的辅助下形成凝胶。
还可以将根据本发明的剂型的粘度增强组分与其它组分空间彼此分离地布置。
此外,为了阻止和预防滥用,根据本发明的剂型可以进一步含有组分(c),即可能滥用的鸦片样物质和/或鸦片剂的一种或者多种拮抗剂,其中优选所述拮抗剂与根据本发明剂型的其它组分在空间上分离,当正确使用时,并不意图使其发挥任何作用。
预防鸦片样物质滥用的适宜拮抗剂自身是本领域熟练技术人员已知的,并且其可以就这样或者以其相应衍生物(特别是酯或者醚)的形式存在于根据本发明的剂型中,或者在各种情形中以其相应的生理学上可接受的化合物形式(特别是其盐或者溶剂化合物的形式)存在于根据本发明的剂型中。
优选所应用的拮抗剂选自纳洛酮、纳曲酮、纳美芬、nalide和戊烯二氢吗啡酮,在各种情形中其任选为相应的生理学上可接受的化合物,特别是碱、盐或者溶剂化物的形式。提供组分(c)的相应拮抗剂,在每个剂型(即,每个给药单元)中,优选以至少1mg的量使用,特别优选以3~100mg的量使用,非常特别优选以5~50mg的量使用。
优选根据本发明的剂型以本领域熟练技术人员熟知的常规治疗剂量含有拮抗剂组分,特别优选以每给药单元此剂量的二到三倍的量含有拮抗剂组分。
如果用于进一步阻止和防止滥用根据本发明的剂型的组合包含组分(d),那么它可以含有至少一种催吐剂,优选所述催吐剂以与根据本发明剂型的其它组分空间分离的布置存在,并且当正确使用时,并不意图使该组分在体内发挥其作用。
附加预防鸦片样物质滥用的适宜催吐药自身是本领域熟练技术人员已知的,并且其可以就这样或者以其相应衍生物(特别是酯或者醚)的形式存在于根据本发明的剂型中,或者在各种情形中以其相应的生理学上可接受的化合物形式(特别是其盐或者溶剂化合物的形式)存在于根据本发明的剂型中。
所述催吐剂以吐根(吐根树)根部的一种或者多种组分为基础,优选以吐根碱组分为基础的可以优选考虑用于根据本发明的剂型,如例如Prof.Dr.Hildebert Wagner的“Pharmazeutische Biologie-Drogenund ihre Inhaltsstoffe”,修订版第2版,Gustav Fischer Verlag,Stuttgart,New York 1982中所述。其对应的文献说明在此引入本文作为参考并且认为其属于公开内容的一部分。
优选根据本发明的剂型可以含有催吐剂吐根碱作为组分(d),优选在每个剂型(即,给药单元)中的量至少为3mg,特别优选为至少10mg,并且非常特别优选为至少20mg。
阿朴吗啡同样可以优选用作用于另外防止滥用的催吐剂,优选在每个给药单元中的量为至少3mg,特别优选为至少5mg,和非常特别优选为至少7mg。
如果根据本发明的剂型含有组分(e)作为另外的防滥用辅助性物质,那么所述染料的应用会给相应的水溶液带来强烈着色,特别是对于胃肠外给药(优选静脉内给药)试图提取出鸦片样物质时,所述着色可以充当可能滥用者的制止剂。通常通过水溶液提取鸦片样物质开始的口服滥用也可以通过上述着色得到预防。适宜的染料和必需制止所需要的量可以参照WO 03/015531,其中相应的公开内容应当视为部分本发明公开内容并且在此引入本文作为参考。
如果根据本发明的剂型含有组分(f)作为另外的防滥用辅助性物质,那么至少一种苦素的加入以及由此对剂型香味产生的破坏另外可以预防口服和/或经鼻滥用。
适宜的苦素和有效使用量可以参照US-2003/0064099,其中相应的公开内容应当视为本申请的公开内容并且在此引入本文作为参考。优选适宜的苦素为芳香油(优选薄荷油、桉油、苦杏仁油、薄荷醇)、水果芳香味物质(优选来自于柠檬、橙、酸橙、葡萄柚或者其混合物的芳香味物质)和/或地那铵苯甲酸盐特别优选使用地那铵苯甲酸盐。
为了确保每日给药一次,根据本发明的剂型至少部分以延迟释放形式含有可能滥用的鸦片样物质和/或鸦片剂,其中所述活性成分的延迟释放可以通过本领域熟练技术人员熟知的常规物质和方法的辅助得到实现,例如将鸦片样物质包埋在延迟释放的基质中或者应用一层或者多层延迟释放包衣。然而,必须对鸦片样物质的释放进行控制,从而使得上述条件在各种情形中都可以得到满足,例如,如果正确给药所述剂型,那么在任选存在的组分(c)和/或(d)能够产生削弱作用之前,鸦片样物质事实上已经得到了完全释放。特别是,鸦片样物质的释放必须确保止痛作用持续至少24小时。
如果利用至少一种延迟释放包衣对鸦片样物质从根据本发明的剂型中进行的释放进行控制,那么所述延迟释放包衣可以由本领域熟练技术人员熟知的常规物质组成。
在根据本发明剂型的优选实施方案中,优选所述延迟释放包衣基于水不溶性、任选改性的天然和/或合成聚合物,或者基于天然、半合成或合成蜡,或者基于脂肪或者脂肪醇,或者基于至少两种上述组分的混合物。
为了制备延迟释放包衣,优选水不溶性聚合物包含聚(甲基)丙烯酸酯,特别优选聚(C1-4)-烷基(甲基)丙烯酸酯、聚(C1-4)-二烷基氨基-(C1-4)-烷基(甲基)丙烯酸酯和/或其共聚物,非常特别优选单体摩尔比为2∶1的丙烯酸乙酯和甲基丙烯酸甲酯的共聚物(Eudragit),单体摩尔比为1∶2∶0.1的丙烯酸乙酯、甲基丙烯酸甲酯和三甲基铵甲基丙烯酸甲酯氯化物的共聚物(Eudragit),单体摩尔比为1∶2∶0.2的丙烯酸乙酯、甲基丙烯酸甲酯和三甲基铵甲基丙烯酸甲酯氯化物的共聚物(Eudragit)或者至少两种上述共聚物的混合物。这些包衣材料市售为30wt.%含水胶乳分散体,即,为Eudragit、Eudragit或者Eudragit,并且还优选就这样将其用作涂料。
同样优选聚醋酸乙烯酯任选与其它辅助性物质联合用作生产根据本发明剂型的延迟释放包衣的水不溶性聚合物。这些物质市售为含有27wt.%聚醋酸乙烯酯、2.5wt.%聚乙烯吡咯烷酮和0.3wt.%十二烷基硫酸钠的含水分散体(Kollicoat)。
在另外优选的实施方案中,根据本发明剂型的延迟释放包衣以水不溶性纤维素衍生物为基础,优选烷基纤维素,比如,例如为乙基纤维素,或者纤维素酯,比如,例如为纤维素乙酸酯。优选乙基纤维素或者纤维素乙酸酯的包衣由含水假胶乳分散体进行施加。含水乙基纤维素假胶乳分散体可以市场购买到,为30wt.%分散体()或者25wt.%分散体()。
如果所述延迟释放包衣基于水不溶性、任选改性的天然和/或合成聚合物,那么为了降低必需的最低膜温度,所述包衣分散体或者溶液除了相应的聚合物之外,还可以含有本领域熟练技术人员所熟知的常规的生理学上可接受的增塑剂。
适宜的增塑剂例如为由C6-C40脂族或者芳族二羧酸与C1-C8脂族醇得到的亲脂二酯(比如,例如为邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、癸二酸二丁酯或者癸二酸二乙酯)、柠檬酸的亲水或者亲脂酯(比如柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三丁酯或者乙酰柠檬酸三乙酯)、聚乙二醇、丙二醇、甘油酯(比如,例如为甘油三乙酸酯、(乙酰化单和二甘油酯、C23H44O5到C25H47O7)、中链甘油三酸酯油酸或者至少两种上述增塑剂的混合物。优选Eudragit的水分散体和任选Eudragit含有柠檬酸三乙酯。
优选根据本发明的剂型的延迟释放包衣相对于所应用的聚合物的量,以5~50wt.%的量含有增塑剂,特别优选10~40wt.%,并且非常特别优选10~30wt.%。在某些情形中,例如对于使用纤维素乙酸酯的情形,还可以以更大的量使用增塑剂。
此外,所述延迟释放包衣可以含有其它本领域熟练技术人员熟知的常规辅助性物质,比如,例如为滑爽剂(优选滑石或者单硬脂酸甘油酯)、着色颜料(优选氧化铁或者二氧化钛)或者表面活性剂(比如,例如为)。
通过本领域熟练技术人员所熟知的常规任选手段,可以对由鸦片样物质所得的释放分布进行进一步调节,例如包衣厚度或者利用其它辅助性物质作为包衣组分。适宜的辅助性物质例如为亲水或者pH值依赖型微孔模(比如,例如为羧甲基纤维素钠、醋酞纤维素、羟基丙基甲基纤维素乙酸酯琥珀酸盐、乳糖、聚乙二醇或者甘露醇)或者水溶性聚合物(比如,例如为聚乙烯吡咯烷酮或者水溶性的纤维素,优选为羟基丙基甲基纤维素或者羟基丙基纤维素)。
用于释放鸦片样物质的根据本发明的剂型可以另外还含有抗胃液包衣,其以pH值-依赖的方式溶解。该包衣可以确保根据本发明的剂型通过胃,不被溶解,所述鸦片样物质直至达到肠管才进行释放。
延迟释放包衣可以通过本领域熟练技术人员熟知的常规方法进行施加,比如,例如通过溶液、分散体或者悬浮液的喷雾、通过熔化方法或者粉末涂布方法。所述溶液、分散体或者悬浮液可以以水或者有机溶液或分散体的形式进行应用。在上下文中,优选使用水分散体。可以应用的有机溶剂为醇(例如乙醇或者异丙醇)、酮(比如,例如为丙酮)、酯(例如乙酸乙酯),其中优选使用醇和酮。所述包衣方法在现有技术中已知,例如H.Sucker,Georg Thieme Verlag,1991,347页及以下。它们在此引入本文作为参考并且据此应当将其视为本发明公开内容的一部分。
如果根据本发明的剂型为多颗粒形式,优选按照以下方式施加延迟释放包衣,从而使得在其得到生产之后,在流化床法的辅助下,含有鸦片样物质的多颗粒形式包衣有具体聚合物和任选其它来自于含水和/或有机介质的辅助性物质,优选来自于含水介质,优选在流化床中同时在常规温度下对所述包衣进行干燥。
优选聚(甲基)丙烯酸酯-基包衣在30~50℃的温度下进行干燥,特别优选35~45℃。对于纤维素-基包衣,比如,例如为乙基纤维素,优选在50~80℃的温度下进行干燥,特别优选在55~65℃的温度下进行干燥。如果需要,为了获得稳定的释放靠模,在干燥之后可以另外对其进行控温处理。
活性成分从根据本发明的剂型中进行的延迟释放还可以通过将鸦片样物质嵌入延迟释放基质中而得到实现。
优选可以用作延迟释放基质的物质为生理学上可接受的亲水聚合物,优选纤维素醚、纤维素酯和/或丙烯酸树脂。特别优选使用乙基纤维素、羟基丙基甲基纤维素、羟基丙基纤维素、羟基乙基纤维素、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。
当将疏水化合物用作延迟释放基质时,可以使用脂肪酸、脂肪醇或者其相应的酯或者醚或者其混合物。特别优选将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化合物。
此外,还可以应用上述亲水和疏水基质材料的混合物。
如果根据本发明的剂型的结构允许,作为粘度增强剂的组分(b)还优选可以充当延迟释放基质材料。
用于获得根据本发明所必需的至少500N,优选至少750N的断裂强度的组分(C)和任选存在的组分(D)任选还可以充当另外的延迟释放基质材料。
对应的延迟释放化合物和延迟释放根据本发明剂型和施加抗胃液包衣的方法是本领域熟练技术人员所熟知的,例如参见Kurt H.Bauer,K.Lehmann,Hermann P.Osterwald,Rothgang,Gerhart的“Coated Pharmaceutical Dosage Forms-Fundamentals,Manufacturing Techniques,Biopharmaceutical Aspects,Test Methodsand Raw Materials”,第1版,1998,Medpharm Scientific Publishers。
其对应的文献说明在此引入本文作为参考并且认为其属于本发明公开内容的一部分。
根据本发明的剂型适用于每日一次口服、阴道内或者直肠给药人类和动物,优选适用于口服给药至人类和动物。
根据本发明的剂型可以采用多颗粒形式,优选微片剂、微丸剂、粒剂、球剂、珠剂或者丸剂的形式,任选将其包装入胶囊中或者将其压模成片剂。优选多颗粒形式的尺寸或者尺寸分布为0.1~3mm,特别优选为0.5~2mm。取决于所期望的剂型,还任选使用常规辅助性物质
(B)配制所述剂型。
在特别优选的实施方案中,根据本发明的剂型采用片剂、胶囊的形式或者为口服渗透治疗学体系(OROS)的形式,优选如果还存在至少一种进一步防滥用组分(a)~(f)。
根据本发明的防滥用、固体剂型优选通过以下方式形成:混合组分(A)、(C)、任选(D)、任选至少一种另外的防滥用组分(a)~(f)和任选其它辅助性物质(B)(比如,优选延迟释放基质化合物),其中将如果需要的组分(a)~(f)分离地与组分(C)和任选(D)混合,并且在暴露加热之前或者同时,任选在进行粒化之后,通过施加作用力使所得混合物形成为剂型。
粒化可以通过熔化方法或者湿式粒化方式进行。
根据本发明剂型的组分的上述混合可以在本领域熟练技术人员熟知的混合器中进行。所述混合器可以是,例如翻滚混合器、摇动混合器、剪切混合器或者桨式混合器。
优选在暴露加热之前或者同时,通过施加作用力将所得混合物直接成形为根据本发明的剂型。例如,可以通过直接压片使所述混合物形成片剂。在暴露加热的同时进行的直接压片中,将压片工具(即下冲床、上冲床和冲模)短暂加热至少至聚合物组分(C)的软化温度并且将其冲压到一起。在暴露加热之前进行的直接压片中,在压片之前立即将要冲压的材料加热至少至组分(C)的软化温度,然后对其进行冲压。
还可以首先将所得的组分(A)、(C)、任选(D)、任选存在的组分(a)~(f)和任选的其它辅助性物质(B)特别是延迟释放基质化合物的混合物制成粒状,然后在暴露加热之前或者同时,通过施加作用力将其成形为根据本发明的剂型。
还可以通过施加作用力将含有活性成分和/或其一种或者多种药学上可接受的盐(A)和任选生理学上可接受的辅助性物质(B)(比如组分(a)~(f))和任选延迟释放的基质化合物以及至少一种合成或者天然聚合物(C)和任选的蜡(D)的所得混合物成形为所述剂型,任选使成型制品单一化和任选在各种情形中按大小对其进行分级,和在将其加热至至少组分(C)软化点之后或者期间,对它们施加作用力,直至成型制品表现出至少500N,优选至少750N的断裂硬度为止,任选对其提供任选具有延迟释放性能的覆盖物,和任选再次将所有成型制品混合在一起。该方法还在国际专利申请PCT/EP2004/014679中得到了提供,其相应的公开内容在此引入本文作为参考,并且由此将其视为本申请公开内容的一部分。本领域熟练技术人员熟知,通过在此应用抗氧化剂,生产工艺期间可以任选省却保持惰性气体气氛。
此外,在施加所需作用力之前或者期间,为了使得根据本发明的断裂强度或者硬度至少为500N,优选750N而需要对混合物和/或成型制品进行的加热可以在超声波辅助下实现。相应的方法公开于国际专利申请PCT/EP2005/004225中,其在此引入本文作为参考,并且由此将其视为本申请公开内容的一部分。
如果组分(c)和/或(d)和/或(f)存在于根据本发明的剂型中,那么必须谨慎处理以确保它们以一定方式得到配制或者以低剂量存在,从而当正确给药时,该剂型实际上不会产生任何削弱患者或者鸦片样物质效果的作用。
如果根据本发明的剂型含有组分(d)和/或(f),那么必须选择使得正确口服给药时,不会产生任何副作用的剂量。然而,如果无意中超过该剂型的预期剂量时,特别是对于儿童或者在滥用的情形中,则产生恶心或者呕吐感或者不良气味。在正确口服给药的情形中,患者依然可以忍受的组分(d)和/或(f)的具体量可以由本领域技术人员通过简单的先导试验进行确定。
然而,如果不考虑根据本发明的剂型事实上不可能被粉碎,含有组分(c)和/或(d)和/或(f)的剂型被提供有保护的事实,那么优选这些组分应当以充分高的剂量使用,从而当滥用给药时,它们可以对滥用者产生强烈的消极作用。优选上述作用通过至少将鸦片样物质与组分(c)和/或(d)和/或(f)进行空间隔离得到实现,其中鸦片样物质存在于至少一种亚单位(X)中,和组分(c)和/或(d)和/或(f)存在于至少一种亚单元(Y)中,和其中,当所述剂型得到正确给药时,组分(c)、(d)和(f)不会对摄取和/或体内产生它们的作用,并且所述制剂的剩余组分(特别是组分(C)和任选(D))是相同的。
如果根据本发明的剂型包含组分(c)和(d)或者(f)中的至少两种,那么它们各自可以存在于相同或者不同亚单元(Y)中。优选,当存在时,所有组分(c)和(d)和(f)存在于同一个亚单元(Y)中。
在空间隔离成亚单元(们)(X)和亚单元(们)(Y)并且不管这些亚单元在剂型中的布置的情形中,亚单元(X)含有延迟释放形式的活性成分,从而使得所述活性成分确保在每日一次给药时得到控制释放。
基于本发明的目的,所述亚单元为固体制剂,所述亚单元除了含有本领域熟练技术人员熟知的常规辅助性物质之外,在各种情形中,还含有鸦片样物质、至少一种聚合物(C)和任选至少一种任选存在的组分(a)和/或(b)和/或(e),或者在各种情形中还含有至少一种聚合物(C)和拮抗剂和/或催吐剂和/或组分(e)和/或组分(f)和任选至少一种任选存在的组分(a)和/或(b)以及任选的延迟释放基质化合物。为了确保各种亚单元根据上述方法得到配制,在此必须要提高注意。
将鸦片样物质与组分(c)或者(d)或者(f)分离配制在根据本发明剂型的亚单元(X)和(Y)中的一个显著有点在于,当正确给药时,组分(c)和/或(d)和/或(f)几乎不会在服用时被释放和/或在体内释放或者以使得它们不会产生损害患者或者治疗成功的效果的小剂量释放,或者在通过患者身体时,它们仅仅在它们不能被充分吸收从而产生效果的位置释放。当所述剂型被正确给药时,优选几乎没有任何组分(c)和/或(d)和/或(f)释放入患者身体内或者它们未被患者顾及。
本领域熟练技术人员应当理解,上述情况可以随所应用的具体组分(c)、(d)和/或(f)的函数以及亚单元或者剂型的制剂的函数而变化。具体剂型的最优制剂可以通过简单初步试验进行确定。至关重要的是各个亚单元都含有聚合物(C)和以所述方式对各个亚单元进行配制。
出乎意料地,滥用者可以成功粉碎根据本发明的剂型,其中所述剂型将组分(c)和/或(e)和/或(d)和/或(f)包含在亚单元(Y)中,为了滥用鸦片样物质和获得意欲用适宜提取剂提取的粉末,不仅鸦片样物质,而且具体组分(c)和/或(e)和/或(f)和/或(d)都将以不能轻易从鸦片样物质中分离的形式获得,从而当将已经受到影响(tamper)的剂型进行给药时,特别是通过口服和/或胃肠外给药时,它将立即在服用时发挥其影响和/或在体内发挥其作用,并与组分(c)和/或(d)和/或(f)相应的对滥用者的另外消极作用结合,或者当试图提取活性成分时,着色将起制止剂的作用和由此防止所述剂型的滥用。
根据本发明将鸦片样物质与组分(c)、(d)和/或(e)进行了空间隔离(优选通过配制成不同的亚单元进行空间隔离)的剂型,可以以多种不同的方式进行配制,其中相应的亚单元可以以任何期望的空间布置方式相对于其它亚单元存在于根据本发明的剂型中,条件是,一方面上述释放组分(c)和/或(d)的条件,和另一方面释放鸦片样物质(即,对于每日一次给药进行控制释放)的条件都得到了满足。
本领域熟练技术人员应当理解,可以优选将还任选存在的组分(a)和/或(b)配制在根据本发明的剂型中,二者均在具体亚单元(X)和(Y)中,并且为与亚单元(X)和(Y)相对应的独立亚单元(Y′)的形式,条件是在正确给药受制剂本性损害和聚合物(C)被包含入制剂中以及根据上述方法进行配制的情形中,防滥用和鸦片样物质释放都不能持续24小时。
在根据本发明剂型的优选实施方案中,亚单元(X)和(Y)以多颗粒形式存在,其中优选微片剂、微胶囊、微丸剂、粒剂、球剂、珠剂或者丸剂并且对于亚单元(X)和亚单元(Y)选择相同形式(即,形状),从而不能通过机械选择将亚单元(X)从(Y)中分离出来。优选多颗粒形式的尺寸为0.1~3mm,优选为0.5~2mm。
还可以优选将多颗粒形式的亚单元(X)和(Y)包装入胶囊中或者将其压模成片剂,其中在各种情形中,以使得亚单元(X)和(Y)还保持在所得剂型中的方式对最终剂型进行处理。
相同形状的多颗粒亚单元(X)和(Y)还应当不能通过视觉进行彼此区分,从而使得滥用者不能通过简单分选将其彼此分离。例如,这可以通过应用相同的包衣得到实现,所述包衣除了掩饰功能之外还可以包括其它功能,比如,例如控制一种或者多种鸦片样物质的释放或者对具体亚单元提供抗胃液的复层。
在本发明另一优选的实施方案中,在各种情形中,亚单元(X)和(Y)相对于彼此呈层状布置。
基于该目的,优选成层的亚单元(X)和(Y)在根据本发明的剂型中相对于彼此呈垂直或者水平布置,其中在各种情形中,在剂型中可以存在一层或者多层亚单元(X)和一层或者多层亚单元(Y),从而,除了优选层顺序(X)-(Y)或者(X)-(Y)-(X)之外,可以设想任何期望的其它层顺序,任选其中结合有含有组分(a)和/或(b)的层。
根据本发明的另一优选剂型为其中亚单元(Y)形成完全被延迟释放亚单元(X)包围的芯的剂型,其中隔离层(Z)可以存在于所述层之间。优选所述结构还适用于上述多颗粒形式,其中必需满足根据本发明所需的硬度的亚单元(X)和(Y)和任选存在的隔离层(Z)被配制在同一多颗粒形式中。
在根据本发明剂型的另一优选实施方案中,所述亚单元(X)形成被亚单元(Y)包围的核,其中后者包含至少一个从核通向剂型表面的通道。
根据本发明的剂型,在各种情形中,可以在一层亚单元(X)和一层亚单元(Y)之间含有一层或者多层优选一层任意可膨胀隔离层(Z),所述隔离层(Z)用于空间隔离亚单元(X)与(Y)。
如果根据本发明的剂型包含至少部分垂直或者水平布置的成层亚单元(X)和(Y)以及任选存在的隔离层(Z),那么优选所述剂型为片剂、共挤出物或者层压形式。
在一种特别优选的实施方案中,亚单元(Y)的全部自由表面和任选亚单元(X)的至少部分自由表面以及任选存在的隔离层(Z)的任选至少部分自由表面可以涂有至少一层防止组分(c)和/或(e)和/或(d)和/或(f)释放的阻挡层(Z’)。所述阻挡层(Z’)也必须满足根据本发明的硬度条件。
根据本发明剂型的另一特别优选实施方案包含垂直或者水平布置的亚单元(X)和(Y)层以及至少一层布置在它们之间的推动层(p),还任选包括隔离层(Z),在所述剂型中,由亚单元(X)和(Y)、推动层和任选存在的隔离层(Z)组成的层状结构的自由表面全部装备有半透性的包衣(E),所述包衣(E)能够透过释放介质,即通常为生理液体,但是基本上不能透过鸦片样物质和组分(c)和/或(d)和/或(f),并且其中该包衣(E)在亚单元(X)区域内包含至少一个释放鸦片样物质的开口。
相应的剂型是本领域熟练技术人员所熟知的,例如名称为口服渗透治疗学体系(OROS),生产其的适宜物质和方法同样是已知的,尤其是公开于US 4,612,008、US 4,765,989和US 4,783,337中。其对应的说明在此引入本文作为参考并且认为其属于公开内容的一部分。
对于本领域熟练技术人员而言,含有止痛鸦片样物质和作为厌恶剂的染料的渗透剂型在现有技术中同样是已知的(WO 03/015531)。所述片剂核优选由两层组成,含鸦片样物质层和推动层,其中所述推动层含有作为厌恶剂的染料。其对应的说明在此引入本文作为参考并且认为其属于公开内容的一部分。
在要求保护的本发明的另一优选实施方案中,根据本发明剂型的亚单元(X)为片剂形式,其端面和两个主表面中的任意一个表面覆盖有含有组分(c)和/或(d)和/或(f)的阻挡层(Z’)。
本领域熟练技术人员应当理解,用于配制根据本发明剂型的亚单元(X)或者(Y)和任选存在的隔离层(Z)和/或阻挡层(Z’)的辅助性物质将作为其在根据本发明剂型中的布置、给药模式以及具体鸦片样物质、任选存在的组分(a)和/或(b)和/或(e)与组分(c)和/或(d)和/或(f)的函数而变化,同时保持活性成分释放24小时。在各种情形中,具有必需性能的物质自身是本领域熟练技术人员所熟知的。
如果组分(c)和/或(d)和/或(f)从根据本发明的剂型的亚单元(Y)中的释放通过覆盖物(优选阻挡层)的辅助作用得到防止,那么亚单元可以由本领域熟练技术人员熟知的常规物质组成,条件是它含有至少一种聚合物(C)以满足根据本发明剂型的硬度条件。
如果没有提供相应的阻挡层(Z’)以防止组分(c)和/或(d)和/或(f)的释放,那么应当对亚单元材料进行选择,从而使得具体组分(c)和/或(d)从亚单元(Y)中进行的释放事实上得到排除。
以下所述适于形成阻挡层的材料优选可以用于该目的。优选所述材料为选自以下的物质: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[二(对-羧基苯氧基)-丙烷和癸二酸]的共聚物(优选摩尔比为20∶80(市售商品名为Polifeprosan))、羧基甲基纤维素、纤维素醚、纤维素酯、硝化纤维、基于(甲基)丙烯酸及其酯的聚合物、聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚氧化烯烃、聚对苯二甲酸亚烷基二醇酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、卤代聚乙烯、聚乙交酯、聚硅氧烷和聚氨酯以及其共聚物或混合物。
特别适宜的物质可以选自甲基纤维素、乙基纤维素、羟基丙基纤维素、羟基丙基甲基纤维素、羟基丁基甲基纤维素、纤维素乙酸酯、(低分子量、中等分子量或者高分子量)纤维素丙酸酯、醋酸丙酸纤维素、醋酸丁酸纤维素、苯二甲酸醋酸纤维素、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、聚甲基丙烯酸异丁酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸酯、聚甲基丙烯酸十二烷基酯、聚甲基丙烯酸苯酯、聚丙烯酸甲酯、聚丙烯酸异丙酯、聚丙烯酸异丁酯、聚丙烯酸十八烷酯、聚乙烯、低密度聚乙烯、高密度聚乙烯、聚丙烯、聚乙二醇、聚氧化乙烯、聚对苯二甲酸乙二酯、聚乙烯醇、聚乙烯基异丁基醚、聚醋酸乙烯酯和聚氯乙烯。
特别适宜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马来酸的共聚物、甲基乙烯醚和马来酸单乙酯的共聚物、甲基乙烯醚和马来酸酐的共聚物乙烯醇和醋酸乙烯酯的共聚物。
其它适合于配制阻挡层的物质为淀粉填充的聚己内酯(WO98/20073)、脂族聚酯酰胺(DE19 753 534 A1,DE19 800 698A1,EP 0820 698 A1)、脂族和芳香聚酯尿烷(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 309528)、聚交酯和共聚交酯(EP0 980 894 A1)。其对应的说明在此引入本文作为参考并且认为其属于公开内容的一部分。
上述物质任选可以与其它本领域熟练技术人员熟知的常规辅助性物质混合,优选所述辅助性物质选自单硬脂酸甘油酯、半合成甘油三酸酯衍生物、半合成甘油酯、氢化蓖麻油、棕榈酰硬脂酸甘油酯、山嵛酸甘油酯、聚乙烯基吡咯烷酮、明胶、硬脂酸镁、硬脂酸、硬脂酸钠、滑石、苯甲酸钠、硼酸和胶态氧化硅、脂肪酸、取代的甘油三酸酯、甘油酯、聚氧亚烷基二醇及其衍生物。
如果根据本发明的剂型包含隔离层(Z’),那么该层,同未覆盖的亚单元(Y)一样,可以优选由关于阻挡层所述的上述物质组成。本领域熟练技术人员应当理解,鸦片样物质和/或鸦片剂或者组分(c)和/或(d)从具体亚单元中的释放可以由隔离层的厚度进行控制。
根据本发明的剂型表现出至少24小时的活性成分控制释放,由此其适用于每日给药一次。
确定断裂强度的方法
为了分别验证聚合物或者蜡是否可以用作组分(C)或者(D),在至少对应于所述聚合物或者蜡软化点的温度下,使用150N的作用力将聚合物或者蜡压模成形为直径10mm和高度5mm的片剂,在聚合物或者蜡DSC图的辅助下进行测定。利用按照上述方式形成的片剂,利用如下所述的装置,根据公开于European Pharmacopoeia 1997,第143,144页,方法编号2.9.8中的确定片剂断裂强度的方法对其断裂强度进行确定。用于测定的装置为“Zwick Z 2.5”材料试验机,Fmax=2.5kN,绘制最大值1150mm,布局包含列和行(spindle),间隙宽度(clearance behind)100mm,测试速度0.1~800mm/min,和testControl软件。使用具有拧入式插头和汽缸(直径10mm)的压力活塞、力传感器(Fmax.1kN,直径=8mm,分为0.5~10N,第1类2N至ISO 7500-1,使用制造商的试验证明书M to DIN 55350-18,Zwick gross forceFmax=1.45kN)进行测定(所有装置都得自于Zwick GmbH&Co.KG,Ulm,Germany),试验器的顺序号为BTC-FR 2.5TH.D09,力传感器的顺序号为BTC-LC 0050N.P01,定心装置的顺序号为BO70000S06。
图1表示片剂断裂强度的测定,特别是用于此目的的测定之前和期间的片剂(4)调节装置(6)。为此目的,在两个2部分夹紧装置的辅助下,片剂(4)被保持在作用力施加装置(未显示)的上压板(1)和下压板(3)之间,在各种情形中,一旦容纳和对待测片剂定中心所需的空间(5)已经得到确定,将利用上下压板将其紧紧固定(未显示)。在各种情形中,通过在固定所述2部分夹紧装置的压板上水平向外或者向内移动该2部分夹紧装置,空间(5)可以得到确定。
在具体负载下,视为抗断裂的片剂不仅包括那些没有破碎的片剂,而且包括在作用力作用下可能已经受到塑性变形的那些片剂。
根据本发明剂型的断裂强度利用相同的测定方法进行确定,同时还对不是片剂的剂型进行试验。
以下参照实施例对本发明进行解释。这些解释仅仅是通过实例的方式进行给出的,并不是对本发明一般概念的限制。
具体实施方式
实施例1
a)含氧可酮的防滥用片剂的生产
在自由下落搅拌机中,对列于表1中的量的盐酸氧可酮、聚氧化乙烯粉末和作为延迟释放基质材料的羟基丙基甲基纤维素(Metholose90SH 100000)进行混合。在加热箱中,将由冲模、上冲床和直径为10mm的下冲床组成的压片工具加热至90℃。通过上述受热的工具对600mg部分的粉末混合物进行压模,其压力持续至少15秒钟。
表1
组分 | 每片剂 | 完成批次 |
盐酸氧可酮 | 80.0mg | 40.0g |
聚氧化乙烯,NF,MW 7000000(Polyox WSR 303,Dow Chemicals) | 470.0mg | 235.0g |
羟基丙基甲基纤维素100000mPa·s(Metholose 90SH 100000) | 50.0mg | 25.0g |
总重量 | 600.0mg | 300.0g |
利用上述方法,对所述片剂的断裂强度进行确定。当施加的作用力为500N,未产生任何断裂。所述片剂不能用锤砸碎,也不能使用杵棒和研钵捣碎。
从根据a)制成的片剂中进行的体外释放
在具有冲钻(sinker)的桨式搅拌装置中,根据EuropeanPharmacopoeia中所述的方法,对盐酸氧可酮从根据a)形成的片剂中进行的体外释放进行确定。释放介质的温度为37℃,和搅拌器的转速为75min-1。所应用的释放介质为肠液,pH值6.8。在各种情形中,通过分光光度法对任一时刻释放入溶解介质中的盐酸氧可酮的量进行确定。在各个时间点,相对于盐酸氧可酮总量的释放量百分比示于表2中。
表2
时间,分钟 | 释放量,wt.% |
30 | 11 |
240 | 40 |
480 | 61 |
720 | 76 |
1080 | 92 |
1440 | 97 |
Claims (35)
1.一种防滥用口服剂型,其是通过在暴露加热之前或者同时,通过施加作用力来生产的,其对于每日一次给药控制鸦片样物质释放,其特征在于,它包含
-0.5~80wt.%的至少一种可能滥用的鸦片样物质(A)和/或其生理学上可接受的盐、溶剂化物、酯、醚或者酰胺;
-20~99.9wt.%的至少一种合成或者天然聚合物(C),其选自聚氧化烯烃;
-至少一种延迟释放基质材料;
-任选至少一种延迟释放包衣;和/或
-任选至少一种生理学上可接受的辅助性物质(B);和
-任选至少一种蜡(D);
在各种情形中组分(C)或者(D)表现的断裂强度至少为500N,和组分(C)和任选(D)以使得该剂型表现出至少500N的断裂强度的量存在,根据公开于European Pharmacopoeia 1997,第143,144页,方法编号2.9.8中的确定片剂断裂强度的方法测定的,
其中所有组分的百分数之和为100wt.%。
2.根据权利要求1的剂型,其特征在于,所述鸦片样物质为至少一种选自以下的鸦片样物质:氧可酮、氢化吗啡酮、吗啡、氧吗啡酮、反胺苯环醇,其立体异构体、其外消旋物、其对映异构体、其非对映异构体、其生理学上可接受的盐和溶剂化物。
3.根据权利要求2的剂型,其特征在于,所述生理学上可接受的盐为盐酸盐、硫酸盐或糖精酸盐。
4.根据权利要求1的剂型,其特征在于,所存在的鸦片样物质为至少一种选自以下的鸦片样物质:(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-环己基)苯酚,其生理学上可接受的盐,生理学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物。
5.根据权利要求1~4任一项的剂型,其特征在于,它为片剂的形式。
6.根据权利要求1~4任一项的剂型,其特征在于,它为多颗粒形式,其任选被压模成片剂或者包装在胶囊中。
7.根据权利要求1的剂型,其特征在于,所述聚氧化烯烃为聚氧化甲烯、聚氧化乙烯和/或聚氧化丙烯。
8.根据权利要求1~4任一项的剂型,其特征在于,所述聚合物(C)是高分子量聚氧化乙烯。
9.根据权利要求1~4任一项的剂型,其特征在于,所述聚合物(C)为水溶性或者可水膨胀的聚合物。
10.根据权利要求1~4任一项的剂型,其特征在于,所述聚氧化乙烯(C)的分子量至少为0.5百万。
11.根据权利要求10的剂型,其特征在于,所述聚氧化乙烯(C)的分子量至少为1百万。
12.根据权利要求10的剂型,其特征在于,所述聚氧化乙烯(C)的分子量为1~15百万。
13.根据权利要求1~4任一项的剂型,其特征在于,至少一种软化点至少为60℃的天然、半合成或者合成蜡作为蜡(D)存在。
14.根据权利要求13的剂型,其特征在于,所述蜡(D)为巴西棕榈蜡或者蜂蜡。
15.根据权利要求1~4任一项的剂型,其特征在于所述聚合物组分(C)相对于所述剂型的总重量,以至少20wt.%的量使用。
16.根据权利要求1~15任一项的剂型,其特征在于,所述活性成分存在于延迟释放基质中。
17.根据权利要求16的剂型,其特征在于所述组分(C)和/或组分(D)还充当延迟释放基质组分。
18.根据权利要求1~4任一项的剂型,其特征在于,至少一种辅助性物质(B)充当延迟释放基质的材料。
19.根据权利要求1~4任一项的剂型,其特征在于,它包含包衣。
20.根据权利要求1~4任一项的剂型,其特征在于,它包含至少一种作为辅助性物质(B)的以下进一步防滥用组分(a)~(f):
(a)至少一种刺激鼻通道和/或咽的物质,
(b)至少一种粘度增强剂,其在必需的最低量含水液体的辅助下,形成凝胶,
(c)至少一种可能滥用的活性成分的拮抗剂,
(d)至少一种催吐剂,
(e)至少一种作为厌恶剂的染料,
(f)至少一种苦素。
21.根据权利要求20的剂型,其特征在于,所述组分(a)刺激剂引起灼烧、痒、喷嚏感、分泌物的形成增加或者至少两种上述刺激的结合。
22.根据权利要求20的剂型,其特征在于,所述组分(a)刺激剂基于至少一种辣物质药物的一种或者多种组分。
23.根据权利要求22的剂型,其特征在于,所述辣物质药物是至少一种选自以下物质的药物:大蒜、Asari根茎附带草、菖蒲根茎、辣椒果实、姜黄根茎、爪哇姜黄根茎、高良姜根茎、肉豆蔻籽、黑胡椒果实、白芥籽、黑芥籽、莪术根茎和姜根茎。
24.根据权利要求20的剂型,其特征在于,所述辣物质药物的组分是酰胺化合物、芥子油或者硫醚化合物。
25.根据权利要求20的剂型,其特征在于,所述辣物质药物的组分为至少一种选自以下的组分:肉豆蔻醚;榄香素;异丁子香酚;β-细辛醚;黄樟素;姜辣素;甜没药萜烯型倍半萜烯;辣椒碱;胡椒碱;葡糖异硫氰酸盐;甲基巯基芥子油或者甲磺酰基芥子油。
26.根据权利要求20的剂型,其特征在于,所述组分(b)是至少一种选自以下的粘度增强剂:含有11wt.%羧甲基纤维素钠的微晶纤维素、羧甲基纤维素钠、聚丙烯酸、角豆荚果粉、柑桔类水果或者苹果果胶、糯质种玉米淀粉、海藻酸钠、瓜尔豆粉、极微小角叉菜胶、刺梧桐树胶、洁冷胶、半乳甘露聚糖、塔拉石粉、丙撑二醇藻蛋白酸盐、苹果果胶、透明质酸钠、西黄蓍胶、他拉胶、发酵多醣文莱胶和黄原胶。
27.根据权利要求20的剂型,其特征在于,所述组分(c)为至少一种鸦片样物质拮抗剂。
28.根据权利要求20的剂型,其特征在于,所述组分(d)催吐剂基于吐根的一种或者多种组分,和/或为阿朴吗啡。
29.根据权利要求20的剂型,其特征在于,所述组分(e)为至少一种生理学上可接受的染料。
30.根据权利要求20的剂型,其特征在于,所述组分(f)为至少一种选自以下的苦素:芳香油及其混合物,水果芳香物质及其包含至少两种组分的混合物,地那铵苯甲酸盐及其包含至少两种组分的混合物。
31.一种生产根据权利要求1~30任一项的剂型的方法,其特征在于,
(1)将组分(A)、(C)、任选(B)和任选(D)以及任选的延迟释放基质化合物混合,
(2)所得的混合物,任选在粒化之后,通过施加作用力和暴露加热之前或者同时将其成形为剂型,和任选对其提供延迟释放包衣。
32.根据权利要求31的方法,其特征在于,所述粒化作用通过熔化方法进行。
33.根据权利要求31的方法,其特征在于,所述粒化作用通过湿式粒化进行。
34.一种生产根据权利要求1~30任一项的剂型的方法,其特征在于,
(1)通过施加作用力,将作为分离的混合物的含有组分(A)、(C)、任选(B)和任选(D)和任选延迟释放基质化合物的混合物成形为成型制品,
(2)任选对所得到的成型制品进行单一化和任选在各种情形中按大小对其进行分级,和
(3)在加热至至少组分(C)的软化点之后或者期间,将成型制品暴露于作用力下,直至成型制品表现出至少500N的断裂硬度为止,
(4)任选对其提供包衣,和任选将成型制品再次混合。
35.剂型,其通过根据权利要求31~34的一项或者多项的方法获得。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8114384B2 (en) | 2004-07-01 | 2012-02-14 | Gruenenthal Gmbh | Process for the production of an abuse-proofed solid dosage form |
US8114383B2 (en) | 2003-08-06 | 2012-02-14 | Gruenenthal Gmbh | Abuse-proofed dosage form |
US8192722B2 (en) | 2003-08-06 | 2012-06-05 | Grunenthal Gmbh | Abuse-proof dosage form |
US8383152B2 (en) | 2008-01-25 | 2013-02-26 | Gruenenthal Gmbh | Pharmaceutical dosage form |
US8420056B2 (en) | 2003-08-06 | 2013-04-16 | Grunenthal Gmbh | Abuse-proofed dosage form |
US8722086B2 (en) | 2007-03-07 | 2014-05-13 | Gruenenthal Gmbh | Dosage form with impeded abuse |
US9161917B2 (en) | 2008-05-09 | 2015-10-20 | Grünenthal GmbH | Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet |
Families Citing this family (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
US20040234602A1 (en) | 2001-09-21 | 2004-11-25 | Gina Fischer | Polymer release system |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
ATE495732T1 (de) | 2003-03-26 | 2011-02-15 | Egalet As | Morphin-system mit kontrollierter freisetzung |
DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
DE10361596A1 (de) * | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
DE102004020220A1 (de) * | 2004-04-22 | 2005-11-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform |
CA2534925A1 (en) * | 2003-08-06 | 2005-02-24 | Gruenenthal Gmbh | Dosage form that is safeguarded from abuse |
EP3326617A1 (en) | 2004-06-12 | 2018-05-30 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
DE102004032049A1 (de) * | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
DE102004032103A1 (de) * | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
DE102005005449A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
US20080292665A1 (en) * | 2007-05-25 | 2008-11-27 | Kulli John C | Simple mechanical procedure and product for deterring substance abuse |
BRPI0612802A2 (pt) * | 2005-07-07 | 2010-11-30 | Farnam Co Inc | composições farmacêuticas de liberação sustentada para medicamentos extremamente hidrossolúveis |
US20090082466A1 (en) * | 2006-01-27 | 2009-03-26 | Najib Babul | Abuse Resistant and Extended Release Formulations and Method of Use Thereof |
US9125833B2 (en) * | 2005-11-02 | 2015-09-08 | Relmada Therapeutics, Inc. | Multimodal abuse resistant and extended release opioid formulations |
US20100210732A1 (en) * | 2005-11-02 | 2010-08-19 | Najib Babul | Methods of Preventing the Serotonin Syndrome and Compositions for Use Therefor |
US8329744B2 (en) * | 2005-11-02 | 2012-12-11 | Relmada Therapeutics, Inc. | Methods of preventing the serotonin syndrome and compositions for use thereof |
US20100172989A1 (en) * | 2006-01-21 | 2010-07-08 | Abbott Laboratories | Abuse resistant melt extruded formulation having reduced alcohol interaction |
US20090317355A1 (en) * | 2006-01-21 | 2009-12-24 | Abbott Gmbh & Co. Kg, | Abuse resistant melt extruded formulation having reduced alcohol interaction |
US20090022798A1 (en) * | 2007-07-20 | 2009-01-22 | Abbott Gmbh & Co. Kg | Formulations of nonopioid and confined opioid analgesics |
WO2008011596A2 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophilic abuse deterrent delivery system |
SA07280459B1 (ar) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني |
DE102007025858A1 (de) | 2007-06-01 | 2008-12-04 | Grünenthal GmbH | Verfahren zur Herstellung einer Arzneimitteldarreichungsform |
EP2155167A2 (en) | 2007-06-04 | 2010-02-24 | Egalet A/S | Controlled release pharmaceutical compositions for prolonged effect |
DE102007039043A1 (de) | 2007-08-17 | 2009-02-19 | Grünenthal GmbH | Sternverteiler |
AU2008338207A1 (en) * | 2007-12-17 | 2009-06-25 | Labopharm (Barbados) Limited | Misuse preventative, controlled release formulation |
JP2011511782A (ja) | 2008-02-12 | 2011-04-14 | アボット・ラボラトリーズ | 長期放出性ヒドロコドンアセトアミノフェンならびにその関連方法および用途 |
EP2262484B1 (en) * | 2008-03-11 | 2013-01-23 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
US8372432B2 (en) | 2008-03-11 | 2013-02-12 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
EP2143336A1 (en) * | 2008-07-08 | 2010-01-13 | Alsiano A/S | Powdered chewing gum compositions, the use thereof and a method for preparing such compositions |
ES2414856T3 (es) * | 2008-12-12 | 2013-07-23 | Paladin Labs Inc. | Formulaciones de fármaco narcótico con potencial de adicción disminuido |
ES2509497T3 (es) * | 2008-12-16 | 2014-10-17 | Paladin Labs Inc. | Formulación de liberación controlada para evitar un uso indebido |
NZ594207A (en) | 2009-02-06 | 2013-03-28 | Egalet Ltd | Immediate release composition resistant to abuse by intake of alcohol |
NZ603579A (en) | 2009-06-24 | 2014-02-28 | Egalet Ltd | Controlled release formulations |
US9056054B2 (en) | 2009-06-25 | 2015-06-16 | Elite Laboratories, Inc. | Abuse resistant oral dosage forms |
KR101738369B1 (ko) | 2009-07-22 | 2017-05-22 | 그뤼넨탈 게엠베하 | 핫 멜트 압출된 제어 방출 투여형 |
RU2555531C2 (ru) * | 2009-07-22 | 2015-07-10 | Грюненталь Гмбх | Защищенная от применения не по назначению лекарственная форма для чувствительных к окислению опиоидов |
WO2011026125A2 (en) * | 2009-08-31 | 2011-03-03 | Depomed, Inc. | Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US9198861B2 (en) | 2009-12-22 | 2015-12-01 | Mallinckrodt Llc | Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans |
US8597681B2 (en) | 2009-12-22 | 2013-12-03 | Mallinckrodt Llc | Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans |
US9579285B2 (en) * | 2010-02-03 | 2017-02-28 | Gruenenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of an extruder |
AR082862A1 (es) | 2010-09-02 | 2013-01-16 | Gruenenthal Gmbh | Forma de dosificacion resistente a alteracion que comprende un polimero anionico |
EP2611426B1 (en) | 2010-09-02 | 2014-06-25 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
EP2632441A4 (en) * | 2010-10-29 | 2015-04-01 | Relmada Therapeutics Inc | (-) - 17- (CYCLOBUTYLMETHYL) MORPHINANE-3,14-DIOL COMPOSITIONS |
GB201020895D0 (en) * | 2010-12-09 | 2011-01-26 | Euro Celtique Sa | Dosage form |
EP2826468A1 (en) | 2010-12-22 | 2015-01-21 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
CN103327969A (zh) | 2010-12-23 | 2013-09-25 | 普渡制药公司 | 抗篡改固体口服剂型 |
US8858963B1 (en) | 2011-05-17 | 2014-10-14 | Mallinckrodt Llc | Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia |
US9050335B1 (en) | 2011-05-17 | 2015-06-09 | Mallinckrodt Llc | Pharmaceutical compositions for extended release of oxycodone and acetaminophen resulting in a quick onset and prolonged period of analgesia |
US8741885B1 (en) | 2011-05-17 | 2014-06-03 | Mallinckrodt Llc | Gastric retentive extended release pharmaceutical compositions |
EA201400172A1 (ru) | 2011-07-29 | 2014-06-30 | Грюненталь Гмбх | Устойчивая к разрушению таблетка, которая обеспечивает немедленное высвобождение лекарственного средства |
AR087359A1 (es) | 2011-07-29 | 2014-03-19 | Gruenenthal Gmbh | Tableta a prueba de alteracion que proporciona liberacion inmediata del farmaco |
EP2819656A1 (en) | 2012-02-28 | 2015-01-07 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
JP6067100B2 (ja) | 2012-04-18 | 2017-01-25 | マリンクロッド エルエルシー | 即放性乱用抑止医薬組成物 |
MX362357B (es) | 2012-04-18 | 2019-01-14 | Gruenenthal Gmbh | Forma de dosificacion farmaceutica resistente a la adulteracion y resistente a la liberacion inmediata de la dosis. |
JP2015516406A (ja) | 2012-05-11 | 2015-06-11 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 亜鉛を含む熱成形された不正使用防止医薬剤形 |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
CA2877183A1 (en) | 2012-07-06 | 2014-01-09 | Egalet Ltd. | Abuse deterrent pharmaceutical compositions for controlled release |
CA2877774C (en) | 2012-07-12 | 2017-07-18 | Mallinckrodt Llc | Extended release, abuse deterrent pharmaceutical compositions |
KR101840526B1 (ko) | 2013-02-05 | 2018-03-20 | 퍼듀 퍼머 엘피 | 내변조성 제약 제제 |
JP6255474B2 (ja) | 2013-03-15 | 2017-12-27 | マリンクロッド エルエルシー | 機能的割線を有する即時放出用の乱用抑止性固体剤形 |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
JP6445537B2 (ja) | 2013-05-29 | 2018-12-26 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 1個または複数の粒子を含有する改変防止(tamper−resistant)剤形 |
AR096439A1 (es) | 2013-05-29 | 2015-12-30 | Gruenenthal Gmbh | Forma de dosificación resistente al uso indebido que contiene una o más partículas |
EA032465B1 (ru) | 2013-07-12 | 2019-05-31 | Грюненталь Гмбх | Защищенная от применения не по назначению пероральная фармацевтическая лекарственная форма, содержащая этиленвинилацетатный полимер, и способ ее изготовления |
US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
AU2014356581C1 (en) | 2013-11-26 | 2020-05-28 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10632113B2 (en) | 2014-02-05 | 2020-04-28 | Kashiv Biosciences, Llc | Abuse-resistant drug formulations with built-in overdose protection |
AU2015261060A1 (en) | 2014-05-12 | 2016-11-03 | Grunenthal Gmbh | Tamper resistant immediate release capsule formulation comprising Tapentadol |
CA2949422A1 (en) | 2014-05-26 | 2015-12-03 | Grunenthal Gmbh | Multiparticles safeguarded against ethanolic dose-dumping |
ES2963078T3 (es) | 2014-07-03 | 2024-03-25 | SpecGx LLC | Formulaciones de liberación inmediata disuasorias del abuso que comprenden polisacáridos no celulósicos |
EP3169315B1 (en) | 2014-07-17 | 2020-06-24 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
US9132096B1 (en) | 2014-09-12 | 2015-09-15 | Alkermes Pharma Ireland Limited | Abuse resistant pharmaceutical compositions |
US20160106737A1 (en) | 2014-10-20 | 2016-04-21 | Pharmaceutical Manufacturing Research Services, Inc. | Extended Release Abuse Deterrent Liquid Fill Dosage Form |
EP3285745A1 (en) | 2015-04-24 | 2018-02-28 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
JP2018526414A (ja) | 2015-09-10 | 2018-09-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 乱用抑止性の即放性製剤を用いた経口過剰摂取に対する保護 |
US20170312226A1 (en) * | 2016-04-28 | 2017-11-02 | Ascent Pharmaceuticals, Inc. | Pharmaceutical dosage forms |
WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
EP3473246A1 (en) | 2017-10-19 | 2019-04-24 | Capsugel Belgium NV | Immediate release abuse deterrent formulations |
CA3112030A1 (en) | 2018-09-25 | 2020-04-02 | SpecGx LLC | Abuse deterrent immediate release capsule dosage forms |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997033566A2 (en) * | 1996-03-12 | 1997-09-18 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US20030068392A1 (en) * | 2001-08-06 | 2003-04-10 | Richard Sackler | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
DE10250083A1 (de) * | 2002-06-17 | 2003-12-24 | Gruenenthal Gmbh | Gegen Missbrauch gesicherte Darreichungsform |
WO2004037260A1 (de) * | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen missbrauch gesicherte darreichungsform |
WO2004037230A1 (de) * | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen missbrauch gesicherte darreichungsform |
Family Cites Families (576)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA722109A (en) | 1965-11-23 | W. Mock Henry | Extrusion of ethylene oxide polymers | |
US2524855A (en) | 1950-10-10 | Process for the manufacture of | ||
US2806033A (en) | 1955-08-03 | 1957-09-10 | Lewenstein | Morphine derivative |
US2987445A (en) | 1958-10-10 | 1961-06-06 | Rohm & Haas | Drug composition |
US3370035A (en) | 1961-06-23 | 1968-02-20 | Takeda Chemical Industries Ltd | Stabilization of polyalkylene oxide |
US3332950A (en) | 1963-03-23 | 1967-07-25 | Endo Lab | 14-hydroxydihydronormorphinone derivatives |
GB1147210A (en) | 1965-06-30 | 1969-04-02 | Eastman Kodak Co | Improvements in or relating to vitamins |
US3652589A (en) | 1967-07-27 | 1972-03-28 | Gruenenthal Chemie | 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols |
US3806603A (en) * | 1969-10-13 | 1974-04-23 | W Gaunt | Pharmaceutical carriers of plasticized dried milled particles of hydrated cooked rice endosperm |
CH503520A (de) | 1969-12-15 | 1971-02-28 | Inventa Ag | Verfahren zum Vermahlen von körnigen Materialien, insbesondere von Kunststoffgranulaten, bei tiefen Temperaturen |
DE2210071A1 (de) * | 1971-03-09 | 1972-09-14 | PPG Industries Inc., Pittsburgh, Pa. (V.StA.) | Verfahren zum Auftragen und Härten einer Vielzahl von Überzügen |
US3865108A (en) * | 1971-05-17 | 1975-02-11 | Ortho Pharma Corp | Expandable drug delivery device |
US3966747A (en) * | 1972-10-26 | 1976-06-29 | Bristol-Myers Company | 9-Hydroxy-6,7-benzomorphans |
US4014965A (en) * | 1972-11-24 | 1977-03-29 | The Dow Chemical Company | Process for scrapless forming of plastic articles |
US3980766A (en) | 1973-08-13 | 1976-09-14 | West Laboratories, Inc. | Orally administered drug composition for therapy in the treatment of narcotic drug addiction |
US3941865A (en) * | 1973-12-10 | 1976-03-02 | Union Carbide Corporation | Extrusion of ethylene oxide resins |
US4002173A (en) * | 1974-07-23 | 1977-01-11 | International Paper Company | Diester crosslinked polyglucan hydrogels and reticulated sponges thereof |
DE2530563C2 (de) * | 1975-07-09 | 1986-07-24 | Bayer Ag, 5090 Leverkusen | Analgetische Arzneimittel mit vermindertem Mißbrauchspotential |
JPS603286B2 (ja) | 1977-03-03 | 1985-01-26 | 日本化薬株式会社 | 定速溶出性製剤 |
US4207893A (en) * | 1977-08-29 | 1980-06-17 | Alza Corporation | Device using hydrophilic polymer for delivering drug to biological environment |
US4175119A (en) | 1978-01-11 | 1979-11-20 | Porter Garry L | Composition and method to prevent accidental and intentional overdosage with psychoactive drugs |
DE2822324C3 (de) * | 1978-05-22 | 1981-02-26 | Basf Ag, 6700 Ludwigshafen | Herstellung von Vitamin-E-Trockenpulver |
US4211681A (en) | 1978-08-16 | 1980-07-08 | Union Carbide Corporation | Poly(ethylene oxide) compositions |
US4200704A (en) * | 1978-09-28 | 1980-04-29 | Union Carbide Corporation | Controlled degradation of poly(ethylene oxide) |
NO793297L (no) | 1978-10-19 | 1980-04-22 | Mallinckrodt Inc | Fremgangsmaate til fremstilling av oksymorfon |
US4258027A (en) | 1979-03-26 | 1981-03-24 | Mead Johnson & Company | Multi-fractionable tablet structure |
US4215104A (en) | 1979-03-26 | 1980-07-29 | Mead Johnson & Company | Multi-fractionable tablet structure |
CA1146866A (en) | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
US4353887A (en) | 1979-08-16 | 1982-10-12 | Ciba-Geigy Corporation | Divisible tablet having controlled and delayed release of the active substance |
CH648754A5 (en) | 1979-08-16 | 1985-04-15 | Ciba Geigy Ag | Pharmaceutical slow release tablet |
US4457933A (en) * | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
JPS56169622A (en) | 1980-06-03 | 1981-12-26 | Kissei Pharmaceut Co Ltd | Method of making solid preparation from oily substance |
DE3024416C2 (de) | 1980-06-28 | 1982-04-15 | Gödecke AG, 1000 Berlin | Verfahren zur Herstellung von Arzneimitteln mit retardierter Wirkstoff-Freisetzung |
US4473640A (en) | 1982-06-03 | 1984-09-25 | Combie Joan D | Detection of morphine and its analogues using enzymatic hydrolysis |
US4462941A (en) | 1982-06-10 | 1984-07-31 | The Regents Of The University Of California | Dynorphin amide analogs |
US4427778A (en) | 1982-06-29 | 1984-01-24 | Biochem Technology, Inc. | Enzymatic preparation of particulate cellulose for tablet making |
US4485211A (en) | 1982-09-15 | 1984-11-27 | The B. F. Goodrich Company | Poly(glycidyl ether)block copolymers and process for their preparation |
US4427681A (en) * | 1982-09-16 | 1984-01-24 | Richardson-Vicks, Inc. | Thixotropic compositions easily convertible to pourable liquids |
US4529583A (en) | 1983-03-07 | 1985-07-16 | Clear Lake Development Group | Composition and method of immobilizing emetics and method of treating human beings with emetics |
US4603143A (en) | 1983-05-02 | 1986-07-29 | Basf Corporation | Free-flowing, high density, fat soluble vitamin powders with improved stability |
US4765989A (en) | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
US4783337A (en) | 1983-05-11 | 1988-11-08 | Alza Corporation | Osmotic system comprising plurality of members for dispensing drug |
US4612008A (en) | 1983-05-11 | 1986-09-16 | Alza Corporation | Osmotic device with dual thermodynamic activity |
US5082668A (en) * | 1983-05-11 | 1992-01-21 | Alza Corporation | Controlled-release system with constant pushing source |
US4599342A (en) * | 1984-01-16 | 1986-07-08 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
US4629621A (en) | 1984-07-23 | 1986-12-16 | Zetachron, Inc. | Erodible matrix for sustained release bioactive composition |
AU592065B2 (en) | 1984-10-09 | 1990-01-04 | Dow Chemical Company, The | Sustained release dosage form based on highly plasticized cellulose ether gels |
GB8507779D0 (en) | 1985-03-26 | 1985-05-01 | Fujisawa Pharmaceutical Co | Drug carrier |
AU583639B2 (en) | 1985-06-24 | 1989-05-04 | Pitman-Moore Australia Limited | Ingestible capsules |
EP0328775B1 (en) | 1985-06-28 | 1993-10-20 | Carrington Laboratories, Inc. | Processes for preparation of aloe products, products produced thereby and compositions thereof |
US4992279A (en) * | 1985-07-03 | 1991-02-12 | Kraft General Foods, Inc. | Sweetness inhibitor |
US4851521A (en) | 1985-07-08 | 1989-07-25 | Fidia, S.P.A. | Esters of hyaluronic acid |
DE3689650T2 (de) | 1985-12-17 | 1994-05-26 | United States Surgical Corp | Bioresorbierbare Polymere von hohem Molekulargewicht und Implantate davon. |
US5229164A (en) | 1985-12-19 | 1993-07-20 | Capsoid Pharma Gmbh | Process for producing individually dosed administration forms |
US4711894A (en) | 1986-01-16 | 1987-12-08 | Henkel Corporation | Stabilized tocopherol in dry, particulate, free-flowing form |
US4940556A (en) | 1986-01-30 | 1990-07-10 | Syntex (U.S.A.) Inc. | Method of preparing long acting formulation |
US5198226A (en) * | 1986-01-30 | 1993-03-30 | Syntex (U.S.A.) Inc. | Long acting nicardipine hydrochloride formulation |
US4764378A (en) | 1986-02-10 | 1988-08-16 | Zetachron, Inc. | Buccal drug dosage form |
JPS62232433A (ja) | 1986-03-31 | 1987-10-12 | ユニオン、カ−バイド、コ−ポレ−シヨン | アルキレンオキシド重合用触媒の製造方法 |
DE3612211A1 (de) | 1986-04-11 | 1987-10-15 | Basf Ag | Kontinuierliches verfahren zum tablettieren |
US4667013A (en) * | 1986-05-02 | 1987-05-19 | Union Carbide Corporation | Process for alkylene oxide polymerization |
USRE33093E (en) | 1986-06-16 | 1989-10-17 | Johnson & Johnson Consumer Products, Inc. | Bioadhesive extruded film for intra-oral drug delivery and process |
US4713243A (en) | 1986-06-16 | 1987-12-15 | Johnson & Johnson Products, Inc. | Bioadhesive extruded film for intra-oral drug delivery and process |
USRE34990E (en) | 1986-08-07 | 1995-07-04 | Ciba-Geigy Corporation | Oral therapeutic system having systemic action |
CA1335748C (en) | 1986-09-25 | 1995-05-30 | Jeffrey Lawrence Finnan | Crosslinked gelatins |
US5227157A (en) * | 1986-10-14 | 1993-07-13 | Board Of Regents, The University Of Texas System | Delivery of therapeutic agents |
EP0277289B8 (en) | 1986-11-10 | 2003-05-21 | Biopure Corporation | Extra pure semi-synthetic blood substitute |
US4892889A (en) * | 1986-11-18 | 1990-01-09 | Basf Corporation | Process for making a spray-dried, directly-compressible vitamin powder comprising unhydrolyzed gelatin |
JPH0831303B2 (ja) | 1986-12-01 | 1996-03-27 | オムロン株式会社 | チツプ型ヒユ−ズ |
ATE72111T1 (de) * | 1987-01-14 | 1992-02-15 | Ciba Geigy Ag | Therapeutisches system fuer schwerloesliche wirkstoffe. |
US4892778A (en) * | 1987-05-27 | 1990-01-09 | Alza Corporation | Juxtaposed laminated arrangement |
US5051261A (en) | 1987-11-24 | 1991-09-24 | Fmc Corporation | Method for preparing a solid sustained release form of a functionally active composition |
EP0391959B1 (en) | 1987-12-17 | 1993-01-27 | The Upjohn Company | Tri-scored drug tablet |
DE3812567A1 (de) | 1988-04-15 | 1989-10-26 | Basf Ag | Verfahren zur herstellung pharmazeutischer mischungen |
US4954346A (en) | 1988-06-08 | 1990-09-04 | Ciba-Geigy Corporation | Orally administrable nifedipine solution in a solid light resistant dosage form |
US4960814A (en) | 1988-06-13 | 1990-10-02 | Eastman Kodak Company | Water-dispersible polymeric compositions |
US5350741A (en) | 1988-07-30 | 1994-09-27 | Kanji Takada | Enteric formulations of physiologically active peptides and proteins |
JPH0249719A (ja) | 1988-08-11 | 1990-02-20 | Dai Ichi Kogyo Seiyaku Co Ltd | 易水分散・可溶性能を有する油溶性ビタミン粉末 |
GB8820327D0 (en) | 1988-08-26 | 1988-09-28 | May & Baker Ltd | New compositions of matter |
DE3830353A1 (de) | 1988-09-07 | 1990-03-15 | Basf Ag | Verfahren zur kontinuierlichen herstellung von festen pharmazeutischen formen |
US5004601A (en) * | 1988-10-14 | 1991-04-02 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
US5139790A (en) | 1988-10-14 | 1992-08-18 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
US4957668A (en) | 1988-12-07 | 1990-09-18 | General Motors Corporation | Ultrasonic compacting and bonding particles |
US5190760A (en) | 1989-07-08 | 1993-03-02 | Coopers Animal Health Limited | Solid pharmaceutical composition |
US5169645A (en) | 1989-10-31 | 1992-12-08 | Duquesne University Of The Holy Ghost | Directly compressible granules having improved flow properties |
US5200197A (en) * | 1989-11-16 | 1993-04-06 | Alza Corporation | Contraceptive pill |
GB8926612D0 (en) | 1989-11-24 | 1990-01-17 | Erba Farmitalia | Pharmaceutical compositions |
EP0449775A3 (en) | 1990-03-29 | 1992-09-02 | Ciba-Geigy Ag | Polyether-polyester block copolymers and their use as dispersing agents |
FR2664851B1 (fr) * | 1990-07-20 | 1992-10-16 | Oreal | Procede de compactage d'un melange pulverulent permettant d'obtenir un produit compact absorbant ou partiellement delitable et produit obtenu par ce procede. |
EP0477135A1 (en) | 1990-09-07 | 1992-03-25 | Warner-Lambert Company | Chewable spheroidal coated microcapsules and methods for preparing same |
US5126151A (en) * | 1991-01-24 | 1992-06-30 | Warner-Lambert Company | Encapsulation matrix |
EP0500091B1 (en) * | 1991-02-20 | 1998-07-15 | Hitachi, Ltd. | Television telephone |
US5273758A (en) | 1991-03-18 | 1993-12-28 | Sandoz Ltd. | Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms |
US5149538A (en) | 1991-06-14 | 1992-09-22 | Warner-Lambert Company | Misuse-resistive transdermal opioid dosage form |
JP3073054B2 (ja) | 1991-07-11 | 2000-08-07 | 住友精化株式会社 | アルキレンオキシド重合体の製造方法 |
WO1993004670A1 (en) | 1991-08-30 | 1993-03-18 | Showa Yakuhin Kako Co., Ltd. | Dry gel composition |
WO1993006723A1 (en) * | 1991-10-04 | 1993-04-15 | Olin Corporation | Fungicide tablet |
DE69229881T2 (de) | 1991-10-04 | 1999-12-09 | Yoshitomi Pharmaceutical | Tablette mit verzögerter freisetzung |
DE4138513A1 (de) | 1991-11-23 | 1993-05-27 | Basf Ag | Feste pharmazeutische retardform |
US5266331A (en) | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
ATE140620T1 (de) | 1991-12-05 | 1996-08-15 | Mallinckrodt Veterinary Inc | Glasartige kohlenhydratenmatrize zur verabreichung von heilmitteln mit verzögerter wirkstoffabgabe |
US5200194A (en) | 1991-12-18 | 1993-04-06 | Alza Corporation | Oral osmotic device |
EP0617612B1 (en) | 1991-12-18 | 1997-09-10 | Warner-Lambert Company | A process for the preparation of a solid dispersion |
US5225417A (en) | 1992-01-21 | 1993-07-06 | G. D. Searle & Co. | Opioid agonist compounds |
IL105553A (en) | 1992-05-06 | 1998-01-04 | Janssen Pharmaceutica Inc | Solid dosage forms consisting of a porous network of matrix that releases a substance that dissipates rapidly in water |
AU4316393A (en) | 1992-05-22 | 1993-12-30 | Godecke Aktiengesellschaft | Process for preparing delayed-action medicinal compositions |
GB9217295D0 (en) | 1992-08-14 | 1992-09-30 | Wellcome Found | Controlled released tablets |
DE4227385A1 (de) | 1992-08-19 | 1994-02-24 | Kali Chemie Pharma Gmbh | Pankreatinmikropellets |
DE4229085C2 (de) | 1992-09-01 | 1996-07-11 | Boehringer Mannheim Gmbh | Längliche, teilbare Tablette |
AU682827B2 (en) | 1992-09-18 | 1997-10-23 | Astellas Pharma Inc. | Sustained-release hydrogel preparation |
US5472943A (en) | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
FI101039B (fi) | 1992-10-09 | 1998-04-15 | Eeva Kristoffersson | Menetelmä lääkepellettien valmistamiseksi |
AU679937B2 (en) | 1992-11-18 | 1997-07-17 | Johnson & Johnson Consumer Products, Inc. | Extrudable compositions for topical or transdermal drug delivery |
JP3459421B2 (ja) | 1992-12-23 | 2003-10-20 | サイテック ソチエタ レスポンサビリタ リミテ | 調節された開放医薬形の調製法及びそのようにして得られた医薬形 |
GB2273874A (en) | 1992-12-31 | 1994-07-06 | Pertti Olavi Toermaelae | Preparation of pharmaceuticals in a polymer matrix |
US6071970A (en) | 1993-02-08 | 2000-06-06 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
US5914132A (en) | 1993-02-26 | 1999-06-22 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
DE4309528C2 (de) | 1993-03-24 | 1998-05-20 | Doxa Gmbh | Folie oder Folienschlauch aus Casein, Verfahren zu deren Herstellung und deren Verwendung |
IL119660A (en) | 1993-05-10 | 2002-09-12 | Euro Celtique Sa | Controlled release formulation comprising tramadol |
IL109944A (en) | 1993-07-01 | 1998-12-06 | Euro Celtique Sa | Continuous release dosage form containing morphine and a method of preparing such sustained release unit dosage forms |
DE4329794C2 (de) * | 1993-09-03 | 1997-09-18 | Gruenenthal Gmbh | Tramadolsalz enthaltende Arzneimittel mit verzögerter Wirkstofffreisetzung |
EP0647448A1 (en) | 1993-10-07 | 1995-04-12 | Euroceltique S.A. | Orally administrable opioid formulations having extended duration of effect |
KR100354702B1 (ko) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | 약학조성물의제조방법및서방형조성물 |
ES2168290T3 (es) * | 1993-11-23 | 2002-06-16 | Euro Celtique Sa | Metodo para preparar una composicion de liberacion sostenida. |
WO1995017174A1 (en) | 1993-12-20 | 1995-06-29 | The Procter & Gamble Company | Process for making laxatives containing dioctyl sulfosuccinate |
IL112106A0 (en) | 1993-12-22 | 1995-03-15 | Ergo Science Inc | Accelerated release composition containing bromocriptine |
GB9401894D0 (en) | 1994-02-01 | 1994-03-30 | Rhone Poulenc Rorer Ltd | New compositions of matter |
CA2182282C (en) | 1994-02-16 | 2006-04-18 | Jacqueline E. Briskin | Process for preparing fine particle pharmaceutical formulations |
SE9503924D0 (sv) | 1995-08-18 | 1995-11-07 | Astra Ab | Novel opioid peptides |
US5458887A (en) | 1994-03-02 | 1995-10-17 | Andrx Pharmaceuticals, Inc. | Controlled release tablet formulation |
DE4413350A1 (de) | 1994-04-18 | 1995-10-19 | Basf Ag | Retard-Matrixpellets und Verfahren zu ihrer Herstellung |
JP2977907B2 (ja) | 1994-05-06 | 1999-11-15 | ファイザー・インコーポレーテッド | アジスロマイシンの放出調節された剤形 |
DE19509807A1 (de) * | 1995-03-21 | 1996-09-26 | Basf Ag | Verfahren zur Herstellung von Wirkstoffzubereitungen in Form einer festen Lösung des Wirkstoffs in einer Polymermatrix sowie mit diesem Verfahren hergestellte Wirkstoffzubereitungen |
AT403988B (de) * | 1994-05-18 | 1998-07-27 | Lannacher Heilmittel | Festes orales retardpräparat |
US5460826A (en) | 1994-06-27 | 1995-10-24 | Alza Corporation | Morphine therapy |
DE4426245A1 (de) * | 1994-07-23 | 1996-02-22 | Gruenenthal Gmbh | 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung |
IT1274879B (it) | 1994-08-03 | 1997-07-25 | Saitec Srl | Apparecchio e metodo per preparare forme farmaceutiche solide a rilascio controllato del principio attivo. |
US5837790A (en) | 1994-10-24 | 1998-11-17 | Amcol International Corporation | Precipitation polymerization process for producing an oil adsorbent polymer capable of entrapping solid particles and liquids and the product thereof |
AUPM897594A0 (en) | 1994-10-25 | 1994-11-17 | Daratech Pty Ltd | Controlled release container |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
DE4446470A1 (de) | 1994-12-23 | 1996-06-27 | Basf Ag | Verfahren zur Herstellung von teilbaren Tabletten |
DE19504832A1 (de) | 1995-02-14 | 1996-08-22 | Basf Ag | Feste Wirkstoff-Zubereitungen |
US5945125A (en) | 1995-02-28 | 1999-08-31 | Temple University | Controlled release tablet |
US6348469B1 (en) * | 1995-04-14 | 2002-02-19 | Pharma Pass Llc | Solid compositions containing glipizide and polyethylene oxide |
US6117453A (en) | 1995-04-14 | 2000-09-12 | Pharma Pass | Solid compositions containing polyethylene oxide and an active ingredient |
US5900425A (en) | 1995-05-02 | 1999-05-04 | Bayer Aktiengesellschaft | Pharmaceutical preparations having controlled release of active compound and processes for their preparation |
DE19522899C1 (de) | 1995-06-23 | 1996-12-19 | Hexal Pharmaforschung Gmbh | Verfahren zum kontinuierlichen Ersintern eines Granulats |
US5759583A (en) | 1995-08-30 | 1998-06-02 | Syntex (U.S.A.) Inc. | Sustained release poly (lactic/glycolic) matrices |
US6063405A (en) | 1995-09-29 | 2000-05-16 | L.A.M. Pharmaceuticals, Llc | Sustained release delivery system |
US5811126A (en) | 1995-10-02 | 1998-09-22 | Euro-Celtique, S.A. | Controlled release matrix for pharmaceuticals |
DE19539361A1 (de) | 1995-10-23 | 1997-04-24 | Basf Ag | Verfahren zur Herstellung von mehrschichtigen, festen Arzneiformen zur oralen oder rektalen Verabreichung |
US6355656B1 (en) * | 1995-12-04 | 2002-03-12 | Celgene Corporation | Phenidate drug formulations having diminished abuse potential |
US5908850A (en) * | 1995-12-04 | 1999-06-01 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
DE19547766A1 (de) | 1995-12-20 | 1997-06-26 | Gruenenthal Gmbh | 1-Phenyl-2-dimethylaminomethyl-cyclohexan-1-ol-verbindungen als pharmazeutische Wirkstoffe |
US6461644B1 (en) | 1996-03-25 | 2002-10-08 | Richard R. Jackson | Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods |
US20020114838A1 (en) | 1996-04-05 | 2002-08-22 | Ayer Atul D. | Uniform drug delivery therapy |
US6096339A (en) | 1997-04-04 | 2000-08-01 | Alza Corporation | Dosage form, process of making and using same |
EP0914158B2 (en) | 1996-04-05 | 2006-01-25 | Takeda Chemical Industries, Ltd. | Pharmaceutical combination containing a compound having angiotensin ii antagonistic activity and a compound which increases the insulin-sensitivity |
US5817343A (en) | 1996-05-14 | 1998-10-06 | Alkermes, Inc. | Method for fabricating polymer-based controlled-release devices |
US6455052B1 (en) | 1996-06-06 | 2002-09-24 | Bifodan A/S | Enteric coating, comprising alginic acid, for an oral preparation |
DE09003265T1 (de) | 1996-06-26 | 2010-04-29 | Board of Regents, The University of Texas System, Austin | Extrudierbare pharmazeutische Schmelzklebstoffformulierung |
WO1998001117A1 (en) | 1996-07-08 | 1998-01-15 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
DE19629753A1 (de) | 1996-07-23 | 1998-01-29 | Basf Ag | Verfahren zur Herstellung von festen Arzneiformen |
NL1003684C2 (nl) | 1996-07-25 | 1998-01-28 | Weterings B V H | Inrichting voor het afgeven van een vloeistof. |
DE19630236A1 (de) | 1996-07-26 | 1998-01-29 | Wolff Walsrode Ag | Biaxial gereckte, biologisch abbaubare und kompostierbare Wursthülle |
BE1010353A5 (fr) | 1996-08-14 | 1998-06-02 | Boss Pharmaceuticals Ag | Procede pour la fabrication de produits pharmaceutiques, dispositif pour un tel procede et produits pharmaceutiques ainsi obtenus. |
JP4034357B2 (ja) * | 1996-11-05 | 2008-01-16 | ノバモント・ソシエタ・ペル・アチオニ | デンプンと熱可塑性ポリマーからなる生分解性ポリマー組成物 |
US5991799A (en) | 1996-12-20 | 1999-11-23 | Liberate Technologies | Information retrieval system using an internet multiplexer to focus user selection |
DE19705538C1 (de) | 1997-02-14 | 1998-08-27 | Goedecke Ag | Verfahren zur Trennung von Wirkstoffen in festen pharmazeutischen Zubereitungen |
US5948787A (en) * | 1997-02-28 | 1999-09-07 | Alza Corporation | Compositions containing opiate analgesics |
DE19710213A1 (de) | 1997-03-12 | 1998-09-17 | Basf Ag | Verfahren zur Herstellung von festen Kombinationsarzneiformen |
DE19710008A1 (de) | 1997-03-12 | 1998-09-17 | Basf Ag | Feste, mindestens zweiphasige Zubereitungsformen eines Opioid-Analgeticums mit verzögerter Freisetzung |
DE19710009A1 (de) | 1997-03-12 | 1998-09-24 | Knoll Ag | Mehrphasige wirkstoffhaltige Zubereitungsformen |
US6139770A (en) | 1997-05-16 | 2000-10-31 | Chevron Chemical Company Llc | Photoinitiators and oxygen scavenging compositions |
DE19721467A1 (de) | 1997-05-22 | 1998-11-26 | Basf Ag | Verfahren zur Herstellung kleinteiliger Zubereitungen biologisch aktiver Stoffe |
US6635280B2 (en) | 1997-06-06 | 2003-10-21 | Depomed, Inc. | Extending the duration of drug release within the stomach during the fed mode |
EP0998271B3 (en) * | 1997-06-06 | 2014-10-29 | Depomed, Inc. | Gastric-retentive oral drug dosage forms for controlled release of highly soluble drugs |
DK1009387T3 (da) | 1997-07-02 | 2006-08-14 | Euro Celtique Sa | Stabiliserede tramadolformuleringer med langvarig frigivelse |
IE970588A1 (en) * | 1997-08-01 | 2000-08-23 | Elan Corp Plc | Controlled release pharmaceutical compositions containing tiagabine |
AU741599B2 (en) | 1997-09-10 | 2001-12-06 | Fram Group Ip Llc | Injection molding of structural zirconia-based materials by an aqueous process |
US6009390A (en) | 1997-09-11 | 1999-12-28 | Lucent Technologies Inc. | Technique for selective use of Gaussian kernels and mixture component weights of tied-mixture hidden Markov models for speech recognition |
PT1033975E (pt) * | 1997-11-28 | 2002-07-31 | Knoll Ag | Processo para a preparacao de substancias biologicamente activas nao-cristalinas isentas de dissolventes |
DE19753534A1 (de) | 1997-12-03 | 1999-06-10 | Bayer Ag | Schnell kristallisierende, biologisch abbaubare Polyesteramide |
CN1278839A (zh) * | 1997-12-03 | 2001-01-03 | 拜尔公司 | 聚醚酯酰胺 |
CA2314896C (en) * | 1997-12-22 | 2005-09-13 | Euro-Celtique, S.A. | A method of preventing abuse of opioid dosage forms |
US6375957B1 (en) * | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
DE19800689C1 (de) | 1998-01-10 | 1999-07-15 | Deloro Stellite Gmbh | Formkörper aus einem verschleißfesten Werkstoff |
DE19800698A1 (de) | 1998-01-10 | 1999-07-15 | Bayer Ag | Biologisch abbaubare Polyesteramide mit blockartig aufgebauten Polyester- und Polyamid-Segmenten |
US6251430B1 (en) | 1998-02-04 | 2001-06-26 | Guohua Zhang | Water insoluble polymer based sustained release formulation |
EP1045885A1 (en) | 1998-02-06 | 2000-10-25 | Union Carbide Chemicals & Plastics Technology Corporation | Alkylene oxide polymer compositions |
EP0980894B1 (en) | 1998-03-05 | 2004-06-23 | Mitsui Chemicals, Inc. | Polylactic acid composition and film thereof |
US6245357B1 (en) * | 1998-03-06 | 2001-06-12 | Alza Corporation | Extended release dosage form |
US6090411A (en) | 1998-03-09 | 2000-07-18 | Temple University | Monolithic tablet for controlled drug release |
US6110500A (en) | 1998-03-25 | 2000-08-29 | Temple University | Coated tablet with long term parabolic and zero-order release kinetics |
JP2002510878A (ja) | 1998-04-02 | 2002-04-09 | アプライド マテリアルズ インコーポレイテッド | 低k誘電体をエッチングする方法 |
CA2327685C (en) | 1998-04-03 | 2008-11-18 | Bm Research A/S | Controlled release composition |
US5962488A (en) | 1998-04-08 | 1999-10-05 | Roberts Laboratories, Inc. | Stable pharmaceutical formulations for treating internal bowel syndrome containing isoxazole derivatives |
DE19822979A1 (de) | 1998-05-25 | 1999-12-02 | Kalle Nalo Gmbh & Co Kg | Folie mit Stärke oder Stärkederivaten und Polyesterurethanen sowie Verfahren zu ihrer Herstellung |
US6333087B1 (en) * | 1998-08-27 | 2001-12-25 | Chevron Chemical Company Llc | Oxygen scavenging packaging |
DE19841244A1 (de) | 1998-09-09 | 2000-03-16 | Knoll Ag | Verfahren und Vorrichtung zum Herstellen von Tabletten |
GT199900148A (es) | 1998-09-10 | 2001-02-28 | Desnaturalizantes para las sales aminas simpaticomimeticas. | |
US6268177B1 (en) | 1998-09-22 | 2001-07-31 | Smithkline Beecham Corporation | Isolated nucleic acid encoding nucleotide pyrophosphorylase |
WO2000023073A1 (en) | 1998-10-20 | 2000-04-27 | Korea Institute Of Science And Technology | Bioflavonoids as plasma high density lipoprotein level increasing agent |
US6322819B1 (en) | 1998-10-21 | 2001-11-27 | Shire Laboratories, Inc. | Oral pulsed dose drug delivery system |
US20060240105A1 (en) | 1998-11-02 | 2006-10-26 | Elan Corporation, Plc | Multiparticulate modified release composition |
ES2141688B1 (es) | 1998-11-06 | 2001-02-01 | Vita Invest Sa | Nuevos esteres derivados de compuestos fenil-ciclohexil sustituidos. |
DE19855440A1 (de) | 1998-12-01 | 2000-06-08 | Basf Ag | Verfahren zum Herstellen fester Darreichungsformen mittels Schmelzextrusion |
EP1005863A1 (en) | 1998-12-04 | 2000-06-07 | Synthelabo | Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof |
DE19856147A1 (de) | 1998-12-04 | 2000-06-08 | Knoll Ag | Teilbare feste Dosierungsformen und Verfahren zu ihrer Herstellung |
US6419960B1 (en) * | 1998-12-17 | 2002-07-16 | Euro-Celtique S.A. | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US6238697B1 (en) * | 1998-12-21 | 2001-05-29 | Pharmalogix, Inc. | Methods and formulations for making bupropion hydrochloride tablets using direct compression |
WO2000040205A2 (en) * | 1999-01-05 | 2000-07-13 | Copley Pharmaceutical Inc. | Sustained release formulation with reduced moisture sensitivity |
WO2000045830A1 (fr) | 1999-02-04 | 2000-08-10 | Nichimo Co., Ltd. | Substances permettant d'eviter la survenue de l'arteriosclerose, substances immunostimulantes, vertebres nourris a l'aide ces substances et oeufs de ces vertebres |
US7374779B2 (en) | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
US6375963B1 (en) * | 1999-06-16 | 2002-04-23 | Michael A. Repka | Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof |
US6384020B1 (en) | 1999-07-14 | 2002-05-07 | Shire Laboratories, Inc. | Rapid immediate release oral dosage form |
MXPA02000725A (es) * | 1999-07-29 | 2003-07-14 | Roxane Lab Inc | Formulacion opioide de liberacion sostenida. |
US20030118641A1 (en) * | 2000-07-27 | 2003-06-26 | Roxane Laboratories, Inc. | Abuse-resistant sustained-release opioid formulation |
US6562375B1 (en) * | 1999-08-04 | 2003-05-13 | Yamanouchi Pharmaceuticals, Co., Ltd. | Stable pharmaceutical composition for oral use |
PT1205190E (pt) | 1999-08-04 | 2006-09-29 | Astellas Pharma Inc | Composicoes medicinais estaveis para uso oral utilizando oxidos de ferro |
KR100345214B1 (ko) | 1999-08-17 | 2002-07-25 | 이강춘 | 생체적합성 고분자가 수식된 펩타이드의 비점막 전달 |
DE19940740A1 (de) * | 1999-08-31 | 2001-03-01 | Gruenenthal Gmbh | Pharmazeutische Salze |
DE19940944B4 (de) * | 1999-08-31 | 2006-10-12 | Grünenthal GmbH | Retardierte, orale, pharmazeutische Darreichungsformen |
ATE279186T1 (de) | 1999-08-31 | 2004-10-15 | Gruenenthal Gmbh | Retardierte darreichungsform enthaltend tramadolsaccharinat |
DE19960494A1 (de) | 1999-12-15 | 2001-06-21 | Knoll Ag | Vorrichtung und Verfahren zum Herstellen von festen wirkstoffhaltigen Formen |
ES2160534B1 (es) | 1999-12-30 | 2002-04-16 | Vita Invest Sa | Nuevos esteres derivados de (rr,ss)-2-hidroxibenzoato de 3-(2-dimetilaminometil-1-hidroxiciclohexil) fenilo. |
US6680070B1 (en) | 2000-01-18 | 2004-01-20 | Albemarle Corporation | Particulate blends and compacted products formed therefrom, and the preparation thereof |
HUP0204163A2 (hu) | 2000-02-08 | 2003-04-28 | Euro-Celtique S.A. | Opioid agonistát és antagonistát tartalmazó szabályozott leadású készítmény és eljárás az előállítására |
US20020015730A1 (en) * | 2000-03-09 | 2002-02-07 | Torsten Hoffmann | Pharmaceutical formulations and method for making |
DE10015479A1 (de) | 2000-03-29 | 2001-10-11 | Basf Ag | Feste orale Darreichungsformen mit retardierter Wirkstofffreisetzung und hoher mechanischer Stabilität |
US8012504B2 (en) | 2000-04-28 | 2011-09-06 | Reckitt Benckiser Inc. | Sustained release of guaifenesin combination drugs |
US6572887B2 (en) | 2000-05-01 | 2003-06-03 | National Starch And Chemical Investment Holding Corporation | Polysaccharide material for direct compression |
US6419954B1 (en) | 2000-05-19 | 2002-07-16 | Yamanouchi Pharmaceutical Co., Ltd. | Tablets and methods for modified release of hydrophilic and other active agents |
CA2409996C (en) * | 2000-05-23 | 2016-03-01 | Cenes Pharmaceuticals, Inc. | Nrg-2 nucleic acid molecules, polypeptides, and diagnostic and therapeutic methods |
DE10029201A1 (de) * | 2000-06-19 | 2001-12-20 | Basf Ag | Verfahren zur Herstellung fester oraler Darreichungsformen mit retardierender Wirkstoffreisetzung |
US6488962B1 (en) | 2000-06-20 | 2002-12-03 | Depomed, Inc. | Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms |
US6607748B1 (en) | 2000-06-29 | 2003-08-19 | Vincent Lenaerts | Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture |
DE10036400A1 (de) | 2000-07-26 | 2002-06-06 | Mitsubishi Polyester Film Gmbh | Weiße, biaxial orientierte Polyesterfolie |
US6642205B2 (en) | 2000-09-25 | 2003-11-04 | Pro-Pharmaceuticals, Inc. | Methods and compositions for reducing side effects in chemotherapeutic treatments |
WO2002026061A1 (en) | 2000-09-27 | 2002-04-04 | Danisco A/S | Antimicrobial agent |
WO2002026928A1 (en) | 2000-09-28 | 2002-04-04 | The Dow Chemical Company | Polymer composite structures useful for controlled release systems |
GB0026137D0 (en) | 2000-10-25 | 2000-12-13 | Euro Celtique Sa | Transdermal dosage form |
US6344215B1 (en) | 2000-10-27 | 2002-02-05 | Eurand America, Inc. | Methylphenidate modified release formulations |
AU2738302A (en) * | 2000-10-30 | 2002-05-15 | Euro Celtique Sa | Controlled release hydrocodone formulations |
AU2002226098A1 (en) | 2000-10-30 | 2002-05-15 | The Board Of Regents, The University Of Texas System | Spherical particles produced by a hot-melt extrusion/spheronization process |
DE10109763A1 (de) | 2001-02-28 | 2002-09-05 | Gruenenthal Gmbh | Pharmazeutische Salze |
JP2002265592A (ja) | 2001-03-07 | 2002-09-18 | Sumitomo Seika Chem Co Ltd | アルキレンオキシド重合体の製造方法 |
WO2002071860A1 (en) | 2001-03-13 | 2002-09-19 | L.A. Dreyfus Co. | Gum base and gum manufacturing using particulated gum base ingredients |
JP3967554B2 (ja) | 2001-03-15 | 2007-08-29 | 株式会社ポッカコーポレーション | フラボノイド化合物及びその製造方法 |
EP1241110A1 (en) | 2001-03-16 | 2002-09-18 | Pfizer Products Inc. | Dispensing unit for oxygen-sensitive drugs |
US20020132395A1 (en) | 2001-03-16 | 2002-09-19 | International Business Machines Corporation | Body contact in SOI devices by electrically weakening the oxide under the body |
EP1385486A4 (en) * | 2001-04-18 | 2006-05-17 | Nostrum Pharmaceuticals Inc | NEW COATING OF SLOW RELEASE PHARMACEUTICAL COMPOSITION |
US20020187192A1 (en) | 2001-04-30 | 2002-12-12 | Yatindra Joshi | Pharmaceutical composition which reduces or eliminates drug abuse potential |
EP1385898B1 (en) | 2001-05-01 | 2006-05-31 | Union Carbide Chemicals & Plastics Technology Corporation | Pharmaceutical composition comprising poly(alkylene oxides) having reduced amounts of formic compounds |
UA81224C2 (uk) | 2001-05-02 | 2007-12-25 | Euro Celtic S A | Дозована форма оксикодону та її застосування |
WO2002090316A1 (en) | 2001-05-08 | 2002-11-14 | The Johns Hopkins University | Method of inhibiting methamphetamine synthesis |
US20030065002A1 (en) | 2001-05-11 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
DE60216078T2 (de) * | 2001-05-11 | 2007-07-05 | Endo Pharmaceuticals Inc. | Opioid enthaltende arzneiform gegen missbrauch |
US6623754B2 (en) | 2001-05-21 | 2003-09-23 | Noveon Ip Holdings Corp. | Dosage form of N-acetyl cysteine |
US7125561B2 (en) | 2001-05-22 | 2006-10-24 | Euro-Celtique S.A. | Compartmentalized dosage form |
US20030064122A1 (en) | 2001-05-23 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse resistant pharmaceutical composition containing capsaicin |
US7968119B2 (en) * | 2001-06-26 | 2011-06-28 | Farrell John J | Tamper-proof narcotic delivery system |
US20030008409A1 (en) * | 2001-07-03 | 2003-01-09 | Spearman Steven R. | Method and apparatus for determining sunlight exposure |
PL207748B1 (pl) | 2001-07-06 | 2011-01-31 | Penwest Pharmaceuticals Company | Preparat o przedłużonym uwalnianiu zawierający oksymorfon oraz jego zastosowanie |
US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
CA2452874A1 (en) | 2001-07-06 | 2003-01-16 | Endo Pharmaceuticals, Inc. | Oral administration of 6-hydroxy-oxymorphone for use as an analgesic |
JP2003020517A (ja) | 2001-07-10 | 2003-01-24 | Calp Corp | 複合繊維用樹脂組成物 |
JP2003032524A (ja) * | 2001-07-16 | 2003-01-31 | Olympus Optical Co Ltd | 顕微鏡用デジタルカメラ |
PT1416842E (pt) | 2001-07-18 | 2009-03-31 | Euro Celtique Sa | Composições farmacêuticas de oxicodona e naloxona |
US6883976B2 (en) * | 2001-07-30 | 2005-04-26 | Seikoh Giken Co., Ltd. | Optical fiber ferrule assembly and optical module and optical connector using the same |
US20030044458A1 (en) * | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US7141250B2 (en) * | 2001-08-06 | 2006-11-28 | Euro-Celtique S.A. | Pharmaceutical formulation containing bittering agent |
US7144587B2 (en) * | 2001-08-06 | 2006-12-05 | Euro-Celtique S.A. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
US7842307B2 (en) * | 2001-08-06 | 2010-11-30 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent |
US20030157168A1 (en) | 2001-08-06 | 2003-08-21 | Christopher Breder | Sequestered antagonist formulations |
CA2455420A1 (en) | 2001-08-06 | 2003-02-20 | Euro-Celtique, S.A. | Compositions and methods to prevent abuse of opioids |
US7157103B2 (en) | 2001-08-06 | 2007-01-02 | Euro-Celtique S.A. | Pharmaceutical formulation containing irritant |
US20030068375A1 (en) * | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
WO2003015531A2 (en) | 2001-08-06 | 2003-02-27 | Thomas Gruber | Pharmaceutical formulation containing dye |
CA2456322A1 (en) | 2001-08-06 | 2003-02-20 | Euro-Celtique, S.A. | Compositions and methods to prevent abuse of opioids |
US20030049272A1 (en) | 2001-08-30 | 2003-03-13 | Yatindra Joshi | Pharmaceutical composition which produces irritation |
US20030059467A1 (en) | 2001-09-14 | 2003-03-27 | Pawan Seth | Pharmaceutical composition comprising doxasozin |
US6691698B2 (en) | 2001-09-14 | 2004-02-17 | Fmc Technologies Inc. | Cooking oven having curved heat exchanger |
US20030068276A1 (en) * | 2001-09-17 | 2003-04-10 | Lyn Hughes | Dosage forms |
US20030059397A1 (en) * | 2001-09-17 | 2003-03-27 | Lyn Hughes | Dosage forms |
US20030092724A1 (en) | 2001-09-18 | 2003-05-15 | Huaihung Kao | Combination sustained release-immediate release oral dosage forms with an opioid analgesic and a non-opioid analgesic |
US20050019399A1 (en) | 2001-09-21 | 2005-01-27 | Gina Fischer | Controlled release solid dispersions |
US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
EP1429735A2 (de) | 2001-09-26 | 2004-06-23 | Klaus-Jürgen Steffens | Verfahren und vorrichtung zur herstellung von granulaten umfassend mindestens einen pharmazeutischen wirkstoff |
US20030091635A1 (en) | 2001-09-26 | 2003-05-15 | Baichwal Anand R. | Opioid formulations having reduced potential for abuse |
US6837696B2 (en) | 2001-09-28 | 2005-01-04 | Mcneil-Ppc, Inc. | Apparatus for manufacturing dosage forms |
JP2005508325A (ja) | 2001-09-28 | 2005-03-31 | マクニール−ピーピーシー・インコーポレイテッド | 内側コア及び外側シェルを有する投薬形態 |
MXPA04003306A (es) | 2001-10-09 | 2004-07-23 | Procter & Gamble | Composiciones acuosas para tratar superficies. |
US6592901B2 (en) | 2001-10-15 | 2003-07-15 | Hercules Incorporated | Highly compressible ethylcellulose for tableting |
JP2003125706A (ja) | 2001-10-23 | 2003-05-07 | Lion Corp | 口中清涼製剤 |
PE20030527A1 (es) * | 2001-10-24 | 2003-07-26 | Gruenenthal Chemie | Formulacion farmaceutica con liberacion retardada que contiene 3-(3-dimetilamino-1-etil-2-metil-propil) fenol o una sal farmaceuticamente aceptable del mismo y tabletas para administracion oral que la contienen |
US20030104052A1 (en) * | 2001-10-25 | 2003-06-05 | Bret Berner | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
US20030152622A1 (en) | 2001-10-25 | 2003-08-14 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral diuretic |
CA2409552A1 (en) | 2001-10-25 | 2003-04-25 | Depomed, Inc. | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
US6723340B2 (en) * | 2001-10-25 | 2004-04-20 | Depomed, Inc. | Optimal polymer mixtures for gastric retentive tablets |
US20030091630A1 (en) | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
TWI312285B (en) * | 2001-10-25 | 2009-07-21 | Depomed Inc | Methods of treatment using a gastric retained gabapentin dosage |
US7300668B2 (en) | 2001-10-29 | 2007-11-27 | Massachusetts Institute Of Technology | System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing |
US20040126428A1 (en) * | 2001-11-02 | 2004-07-01 | Lyn Hughes | Pharmaceutical formulation including a resinate and an aversive agent |
EP1450824A4 (en) | 2001-11-02 | 2005-09-28 | Elan Corp Plc | PHARMACEUTICAL COMPOSITION |
CA2484528A1 (en) | 2001-12-06 | 2003-06-19 | Michael P. Hite | Isoflavone composition for oral delivery |
FR2833838B1 (fr) * | 2001-12-21 | 2005-09-16 | Ellipse Pharmaceuticals | Procede de fabrication d'un comprime incluant un analgesique de type morphinique et comprime obtenu |
AUPS044502A0 (en) | 2002-02-11 | 2002-03-07 | Commonwealth Scientific And Industrial Research Organisation | Novel catalysts and processes for their preparation |
US20040033253A1 (en) | 2002-02-19 | 2004-02-19 | Ihor Shevchuk | Acyl opioid antagonists |
US20030158265A1 (en) | 2002-02-20 | 2003-08-21 | Ramachandran Radhakrishnan | Orally administrable pharmaceutical formulation comprising pseudoephedrine hydrochloride and process for preparing the same |
US20030190343A1 (en) | 2002-03-05 | 2003-10-09 | Pfizer Inc. | Palatable pharmaceutical compositions for companion animals |
US6572889B1 (en) | 2002-03-07 | 2003-06-03 | Noveon Ip Holdings Corp. | Controlled release solid dosage carbamazepine formulations |
US6753009B2 (en) * | 2002-03-13 | 2004-06-22 | Mcneil-Ppc, Inc. | Soft tablet containing high molecular weight polyethylene oxide |
US6476203B1 (en) | 2002-03-14 | 2002-11-05 | Xinxian Zhao | Safe pharmaceutical composition for treating and preventing infertility and increasing immune function |
SI2425824T1 (sl) | 2002-04-05 | 2017-06-30 | Mundipharma Medical Cee Gmbh | Farmacevtski pripravek, ki vsebuje oksikodon in nalokson |
DE10217232B4 (de) | 2002-04-18 | 2004-08-19 | Ticona Gmbh | Verfahren zur Herstellung gefüllter Granulate aus Polyethylenen hohen bzw. ultrahohen Molekulargewichts |
US6960617B2 (en) | 2002-04-22 | 2005-11-01 | Purdue Research Foundation | Hydrogels having enhanced elasticity and mechanical strength properties |
CN1665482A (zh) | 2002-04-29 | 2005-09-07 | 阿尔扎公司 | 羟可待酮控制输送给药的方法和剂型 |
US20050106249A1 (en) * | 2002-04-29 | 2005-05-19 | Stephen Hwang | Once-a-day, oral, controlled-release, oxycodone dosage forms |
AU2003234395B2 (en) * | 2002-05-13 | 2008-01-24 | Endo Pharmaceuticals Inc. | Abuse-resistant opioid solid dosage form |
WO2003101384A2 (en) | 2002-05-31 | 2003-12-11 | Alza Corporation | Dosage forms and compositions for osmotic delivery of variable dosages of oxycodone |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
CA2491572C (en) | 2002-07-05 | 2010-03-23 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
US20040011806A1 (en) | 2002-07-17 | 2004-01-22 | Luciano Packaging Technologies, Inc. | Tablet filler device with star wheel |
US20070196481A1 (en) | 2002-07-25 | 2007-08-23 | Amidon Gregory E | Sustained-release tablet composition |
JP2006501234A (ja) | 2002-08-21 | 2006-01-12 | フォークス ファーマシューティカルズ リミテッド | 錠剤製造における、クエン酸およびラクチトール等の水溶性糖水溶液の、造粒液としての使用 |
US7388068B2 (en) | 2002-08-21 | 2008-06-17 | Clariant Produkte (Deutschland) Gmbh | Copolymers made of alkylene oxides and glycidyl ethers and use thereof as polymerizable emulsifiers |
US20040052844A1 (en) * | 2002-09-16 | 2004-03-18 | Fang-Hsiung Hsiao | Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins |
ES2315530T3 (es) | 2002-09-17 | 2009-04-01 | Wyeth | Formulacion granulada de un ester de rapamicina cci-779. |
EP1539098B1 (en) | 2002-09-20 | 2011-08-10 | Fmc Corporation | Cosmetic composition containing microcrystalline cellulose |
WO2004026308A1 (fr) | 2002-09-21 | 2004-04-01 | Shuyi Zhang | Compose d'acetamidophenol et de tramadol a liberation prolongee |
CA2499994C (en) | 2002-09-23 | 2012-07-10 | Verion, Inc. | Abuse-resistant pharmaceutical compositions |
JP2004143071A (ja) | 2002-10-23 | 2004-05-20 | Hosokawa Funtai Gijutsu Kenkyusho:Kk | 薬物含有複合粒子の製造方法および薬物含有複合粒子 |
PT1594460E (pt) | 2002-10-25 | 2008-06-27 | Labopharm Inc | Formulações de tramadol de libertação sustentada com eficácia durante 24 horas |
US20050191244A1 (en) | 2002-10-25 | 2005-09-01 | Gruenenthal Gmbh | Abuse-resistant pharmaceutical dosage form |
US20050186139A1 (en) * | 2002-10-25 | 2005-08-25 | Gruenenthal Gmbh | Abuse-proofed dosage form |
DE10250084A1 (de) | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
DE10252667A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
US20040091528A1 (en) * | 2002-11-12 | 2004-05-13 | Yamanouchi Pharma Technologies, Inc. | Soluble drug extended release system |
US7018658B2 (en) | 2002-11-14 | 2006-03-28 | Synthon Bv | Pharmaceutical pellets comprising tamsulosin |
US20040121003A1 (en) | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
US20040185097A1 (en) | 2003-01-31 | 2004-09-23 | Glenmark Pharmaceuticals Ltd. | Controlled release modifying complex and pharmaceutical compositions thereof |
US7442387B2 (en) | 2003-03-06 | 2008-10-28 | Astellas Pharma Inc. | Pharmaceutical composition for controlled release of active substances and manufacturing method thereof |
DE602004024963D1 (de) | 2003-03-13 | 2010-02-25 | Controlled Chemicals Inc | Oxycodon- konjugate mit niedrigerem missbrauch- potential und ausgedehnter tätigkeitsdauer |
CA2520312C (en) | 2003-03-26 | 2013-06-18 | Egalet A/S | Matrix compositions for controlled delivery of drug substances |
ATE495732T1 (de) | 2003-03-26 | 2011-02-15 | Egalet As | Morphin-system mit kontrollierter freisetzung |
CA2519556C (en) * | 2003-04-21 | 2011-01-18 | Benjamin Oshlack | Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same |
TWI347201B (en) | 2003-04-21 | 2011-08-21 | Euro Celtique Sa | Pharmaceutical products,uses thereof and methods for preparing the same |
CL2004000927A1 (es) | 2003-04-30 | 2005-01-28 | Purdue Pharma Lp | Forma de dosificacion transdermica que comprende un agente activo, una superficie proxima y una superficie distal. |
US8906413B2 (en) | 2003-05-12 | 2014-12-09 | Supernus Pharmaceuticals, Inc. | Drug formulations having reduced abuse potential |
HU227142B1 (en) * | 2003-07-02 | 2010-08-30 | Egis Gyogyszergyar Nyilvanosan | Capsule of improved release containing fluconazole |
US20050015730A1 (en) | 2003-07-14 | 2005-01-20 | Srimanth Gunturi | Systems, methods and computer program products for identifying tab order sequence of graphically represented elements |
US6886808B2 (en) * | 2003-07-14 | 2005-05-03 | Magic Plastics, Inc. | Axially actuated drain valve for pools and spas |
RU2339365C2 (ru) | 2003-08-06 | 2008-11-27 | Грюненталь Гмбх | Защищенная от применения не по назначению лекарственная форма |
CA2534925A1 (en) | 2003-08-06 | 2005-02-24 | Gruenenthal Gmbh | Dosage form that is safeguarded from abuse |
DE102004032051A1 (de) * | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform |
DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
DE102004020220A1 (de) | 2004-04-22 | 2005-11-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform |
US8075872B2 (en) * | 2003-08-06 | 2011-12-13 | Gruenenthal Gmbh | Abuse-proofed dosage form |
DE10361596A1 (de) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
US20070048228A1 (en) * | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
US20050063214A1 (en) | 2003-09-22 | 2005-03-24 | Daisaburo Takashima | Semiconductor integrated circuit device |
DE602004026604D1 (de) | 2003-09-25 | 2010-05-27 | Euro Celtique Sa | Pharmazeutische kombinationen von hydrocodon und naltrexon |
BRPI0414941A (pt) | 2003-09-30 | 2006-11-07 | Alza Corp | dispositivo de distribuição de agente ativo acionado osmoticamente proporcionando um perfil de liberação ascendente |
US20060172006A1 (en) | 2003-10-10 | 2006-08-03 | Vincent Lenaerts | Sustained-release tramadol formulations with 24-hour clinical efficacy |
US20060009478A1 (en) | 2003-10-15 | 2006-01-12 | Nadav Friedmann | Methods for the treatment of back pain |
EP1677798A2 (en) | 2003-10-29 | 2006-07-12 | Alza Corporation | Once-a-day, oral, controlled-release, oxycodone dosage forms |
US7201920B2 (en) | 2003-11-26 | 2007-04-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of opioid containing dosage forms |
JP2007513147A (ja) | 2003-12-04 | 2007-05-24 | ファイザー・プロダクツ・インク | 押し出し機を使用して、好ましくはポロキサマーとグリセリドを含有する多粒子結晶性医薬組成物を製造するための噴霧凝結方法 |
US20070269505A1 (en) | 2003-12-09 | 2007-11-22 | Flath Robert P | Tamper Resistant Co-Extruded Dosage Form Containing An Active Agent And An Adverse Agent And Process Of Making Same |
WO2005060942A1 (en) | 2003-12-19 | 2005-07-07 | Aurobindo Pharma Ltd | Extended release pharmaceutical composition of metformin |
DE10360792A1 (de) | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
CA2551815A1 (en) | 2003-12-29 | 2005-07-21 | Alza Corporation | Novel drug compositions and dosage forms |
WO2005079752A2 (en) | 2004-02-11 | 2005-09-01 | Rubicon Research Private Limited | Controlled release pharmaceutical compositions with improved bioavailability |
GB0403098D0 (en) | 2004-02-12 | 2004-03-17 | Euro Celtique Sa | Extrusion |
TWI350762B (en) | 2004-02-12 | 2011-10-21 | Euro Celtique Sa | Particulates |
GB0403100D0 (en) | 2004-02-12 | 2004-03-17 | Euro Celtique Sa | Particulates |
LT2351555T (lt) | 2004-02-23 | 2016-12-27 | Euro-Celtique S.A. | Piktnaudžiavimui atspari priemonė, skirta transderminiam opoido įvedimui |
TW201509943A (zh) * | 2004-03-30 | 2015-03-16 | Euro Celtique Sa | 含有小於25ppm14-羥可待因酮之羥可酮鹽酸鹽之組成物、醫藥劑型、延遲釋出口服劑型及醫藥上可以接受的包裝 |
US20050220877A1 (en) | 2004-03-31 | 2005-10-06 | Patel Ashish A | Bilayer tablet comprising an antihistamine and a decongestant |
DE102004019916A1 (de) | 2004-04-21 | 2005-11-17 | Grünenthal GmbH | Gegen Missbrauch gesichertes wirkstoffhaltiges Pflaster |
WO2005102286A1 (de) | 2004-04-22 | 2005-11-03 | Grünenthal GmbH | Verfahren zur herstellung einer gegen missbrauch gesicherten, festen darreinchungsform |
WO2005105036A1 (en) | 2004-04-28 | 2005-11-10 | Natco Pharma Limited | Controlled release mucoadhesive matrix formulation containing tolterodine and a process for its preparation |
US20050271594A1 (en) | 2004-06-04 | 2005-12-08 | Groenewoud Pieter J | Abuse resistent pharmaceutical composition |
TWI547431B (zh) | 2004-06-09 | 2016-09-01 | 史密斯克萊美占公司 | 生產藥物之裝置及方法 |
PL1612203T3 (pl) | 2004-06-28 | 2007-12-31 | Gruenenthal Gmbh | Krystaliczne postacie chlorowodorku (-)-(1R,2R)-3-(3-dimetyloamino-1-etylo-2-metylo-propylo)fenolu |
ITMI20041317A1 (it) | 2004-06-30 | 2004-09-30 | Ibsa Inst Biochimique Sa | Formulazioni farmaceutiche per la somministrazione sicura di farmaci utilizzati nel trattamento della tossicodipendenza e procedimento per il loro ottenimento |
AR053304A1 (es) | 2004-07-01 | 2007-05-02 | Gruenenthal Gmbh | Formas farmaceuticas orales protegidas frente al abuso con liberacion controlada de (1r,2r)-3-(3 dimetilamino-1-etil-2metil-propil)fenol y procedimiento para su produccion. |
DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
DE102004032103A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
PL1765303T5 (pl) | 2004-07-01 | 2023-05-22 | Grünenthal GmbH | Tabletka doustna zabezpieczona przed nadużywaniem |
AR049839A1 (es) | 2004-07-01 | 2006-09-06 | Gruenenthal Gmbh | Procedimiento para la produccion deuna forma farmaceutica solida, protegida frente al abuso |
US7947259B2 (en) | 2004-07-27 | 2011-05-24 | Conopco, Inc. | Hair care compositions |
GB2418854B (en) * | 2004-08-31 | 2009-12-23 | Euro Celtique Sa | Multiparticulates |
US20060064009A1 (en) * | 2004-09-21 | 2006-03-23 | Webler William E | Vessel imaging devices and methods |
US20070077297A1 (en) | 2004-09-30 | 2007-04-05 | Scolr Pharma, Inc. | Modified release ibuprofen dosage form |
US20060068009A1 (en) | 2004-09-30 | 2006-03-30 | Scolr Pharma, Inc. | Modified release ibuprofen dosage form |
US7426948B2 (en) | 2004-10-08 | 2008-09-23 | Phibrowood, Llc | Milled submicron organic biocides with narrow particle size distribution, and uses thereof |
US20060177380A1 (en) | 2004-11-24 | 2006-08-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of orally administered pharmaceutical products |
US20080152595A1 (en) | 2004-11-24 | 2008-06-26 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of orally administered pharmaceutical products |
US20070231268A1 (en) | 2004-11-24 | 2007-10-04 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of orally administered pharmaceutical products |
PT1849470T (pt) | 2005-01-26 | 2017-09-22 | Taiho Pharmaceutical Co Ltd | Fármaco anticancro contendo alfa, alfa, alfa-trifluorotimidina e inibidor da timidina-fosforilase |
MX2007009162A (es) | 2005-01-28 | 2007-10-23 | Euro Celtique Sa | Formas de dosis rsistente al alcohol. |
DE102005005449A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
FR2889810A1 (fr) | 2005-05-24 | 2007-02-23 | Flamel Technologies Sa | Forme medicamenteuse orale, microparticulaire, anti-mesurage |
EP1853249A2 (en) | 2005-02-10 | 2007-11-14 | LifeCycle Pharma A/S | A stable pharmaceutical composition comprising a fixed dose combination of fenofibrate and an hmg-coa reductase inhibitor |
US20060194759A1 (en) | 2005-02-25 | 2006-08-31 | Eidelson Stewart G | Topical compositions and methods for treating pain and inflammation |
EP1695700A1 (en) | 2005-02-28 | 2006-08-30 | Euro-Celtique S.A. | Dosage form containing oxycodone and naloxone |
KR100941761B1 (ko) * | 2005-03-04 | 2010-02-11 | 유로-셀띠끄 소시에떼 아노님 | 오피오이드 조성물에서 α,β-불포화 케톤의 감소 방법 |
US20060204575A1 (en) | 2005-03-11 | 2006-09-14 | Hengsheng Feng | Amphetamine formulations |
US7732427B2 (en) | 2005-03-31 | 2010-06-08 | University Of Delaware | Multifunctional and biologically active matrices from multicomponent polymeric solutions |
CN101227892B (zh) | 2005-04-08 | 2013-06-05 | 舌交付有限公司 | 口腔给药系统 |
RU2405539C2 (ru) | 2005-05-10 | 2010-12-10 | Новартис Аг | Экструзионный способ приготовления композиций, содержащих плохо прессующиеся лекарственные соединения |
AU2006254554B2 (en) | 2005-06-03 | 2011-11-24 | Egalet Ltd | A solid pharmaceutical composition with a first fraction of a dispersion medium and a second fraction of a matrix, the latter being at least partially first exposed to gastrointestinal fluids |
WO2006133733A1 (en) | 2005-06-13 | 2006-12-21 | Flamel Technologies | Oral dosage form comprising an antimisuse system |
WO2007005716A2 (en) | 2005-06-30 | 2007-01-11 | Cinergen, Llc | Methods of treatment and compositions for use thereof |
BRPI0612802A2 (pt) * | 2005-07-07 | 2010-11-30 | Farnam Co Inc | composições farmacêuticas de liberação sustentada para medicamentos extremamente hidrossolúveis |
DE102005032806A1 (de) | 2005-07-12 | 2007-01-18 | Röhm Gmbh | Verwendung eines teilneutralisierten, anionischen (Meth)acrylat-Copolymers als Überzug für die Herstellung einer Arzneiform mit einer Wirkstofffreisetzung bei erniedrigten pH-Werten |
US8858993B2 (en) | 2005-07-25 | 2014-10-14 | Metrics, Inc. | Coated tablet with zero-order or near zero-order release kinetics |
US20090155357A1 (en) * | 2005-08-01 | 2009-06-18 | Alpharma Inc. | Alcohol Resistant Pharmaceutical Formulations |
US20070184117A1 (en) | 2005-08-03 | 2007-08-09 | Stephen Gregory | Tocopheryl polyethylene glycol succinate powder and process for preparing same |
US20070048373A1 (en) | 2005-08-30 | 2007-03-01 | Cima Labs Inc. | Dried milled granulate and methods |
EP1950219B1 (en) | 2005-10-14 | 2011-06-22 | The Kitasato Institute | Novel dihydropseudoerythromycin derivatives |
US20070092573A1 (en) | 2005-10-24 | 2007-04-26 | Laxminarayan Joshi | Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist |
PL116330U1 (en) | 2005-10-31 | 2007-04-02 | Alza Corp | Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation |
US8329744B2 (en) | 2005-11-02 | 2012-12-11 | Relmada Therapeutics, Inc. | Methods of preventing the serotonin syndrome and compositions for use thereof |
US9125833B2 (en) | 2005-11-02 | 2015-09-08 | Relmada Therapeutics, Inc. | Multimodal abuse resistant and extended release opioid formulations |
US8652529B2 (en) * | 2005-11-10 | 2014-02-18 | Flamel Technologies | Anti-misuse microparticulate oral pharmaceutical form |
FR2892937B1 (fr) | 2005-11-10 | 2013-04-05 | Flamel Tech Sa | Forme pharmaceutique orale microparticulaire anti-mesusage |
DE102005058569B4 (de) | 2005-12-08 | 2010-07-15 | Lts Lohmann Therapie-Systeme Ag | Schaumwafer mit Polyvinylalkohol-Polyethylenglycol-Pfropfcopolymer |
JP2009523833A (ja) | 2006-01-21 | 2009-06-25 | アボット ゲーエムベーハー ウント カンパニー カーゲー | 乱用薬剤送達のための製剤および方法 |
US20100172989A1 (en) | 2006-01-21 | 2010-07-08 | Abbott Laboratories | Abuse resistant melt extruded formulation having reduced alcohol interaction |
US20090317355A1 (en) | 2006-01-21 | 2009-12-24 | Abbott Gmbh & Co. Kg, | Abuse resistant melt extruded formulation having reduced alcohol interaction |
US20090022798A1 (en) | 2007-07-20 | 2009-01-22 | Abbott Gmbh & Co. Kg | Formulations of nonopioid and confined opioid analgesics |
EP1813276A1 (en) | 2006-01-27 | 2007-08-01 | Euro-Celtique S.A. | Tamper resistant dosage forms |
FR2897267A1 (fr) | 2006-02-16 | 2007-08-17 | Flamel Technologies Sa | Formes pharmaceutiques multimicroparticulaires pour administration per os |
ZA200807571B (en) | 2006-03-01 | 2009-08-26 | Ethypharm Sa | Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion |
EP2086515A2 (en) | 2006-03-02 | 2009-08-12 | Vaunnex, Inc. | Rate-controlled bioadhesive oral dosage formulations |
AU2007224221B2 (en) | 2006-03-02 | 2013-02-14 | SpecGx LLC | Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds |
US20070224637A1 (en) | 2006-03-24 | 2007-09-27 | Mcauliffe Joseph C | Oxidative protection of lipid layer biosensors |
JP5336351B2 (ja) | 2006-03-24 | 2013-11-06 | オクシリウム インターナショナル ホールディングス,インコーポレイティド | ホットメルト押出しラミネートの調製方法 |
AU2007230730B2 (en) | 2006-03-24 | 2013-03-28 | Auxilium International Holdings, Inc. | Stabilized compositions containing alkaline labile drugs |
US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
US9023400B2 (en) | 2006-05-24 | 2015-05-05 | Flamel Technologies | Prolonged-release multimicroparticulate oral pharmaceutical form |
WO2007138466A2 (en) * | 2006-06-01 | 2007-12-06 | Wockhardt Ltd | Pharmaceutical compositions comprising meloxicam and tramadol combination |
US20070292508A1 (en) | 2006-06-05 | 2007-12-20 | Balchem Corporation | Orally disintegrating dosage forms |
US20080069891A1 (en) | 2006-09-15 | 2008-03-20 | Cima Labs, Inc. | Abuse resistant drug formulation |
EP2484346B1 (en) * | 2006-06-19 | 2017-02-22 | Alpharma Pharmaceuticals LLC | Pharmaceutical compositions |
CN101091721A (zh) | 2006-06-22 | 2007-12-26 | 孙明 | 阿胶新剂型的制备方法 |
EP2043613A1 (en) | 2006-07-14 | 2009-04-08 | Fmc Corporation | Solid form |
JP4029109B1 (ja) | 2006-07-18 | 2008-01-09 | タマ生化学株式会社 | ビタミンeとプロリンの複合体粉末及びその製造方法 |
WO2008011596A2 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophilic abuse deterrent delivery system |
SA07280459B1 (ar) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني |
US8445018B2 (en) | 2006-09-15 | 2013-05-21 | Cima Labs Inc. | Abuse resistant drug formulation |
KR101400824B1 (ko) | 2006-09-25 | 2014-05-29 | 후지필름 가부시키가이샤 | 레지스트 조성물, 이 레지스트 조성물에 사용되는 수지, 이수지의 합성에 사용되는 화합물, 및 상기 레지스트조성물을 사용한 패턴형성방법 |
US8187636B2 (en) | 2006-09-25 | 2012-05-29 | Atlantic Pharmaceuticals, Inc. | Dosage forms for tamper prone therapeutic agents |
US20080085304A1 (en) | 2006-10-10 | 2008-04-10 | Penwest Pharmaceuticals Co. | Robust sustained release formulations |
MX2009003771A (es) * | 2006-10-10 | 2009-07-22 | Penwest Pharmaceuticals Co | Formulaciones robustas de liberacion sostenida. |
GB0624880D0 (en) | 2006-12-14 | 2007-01-24 | Johnson Matthey Plc | Improved method for making analgesics |
WO2008079404A2 (en) | 2006-12-22 | 2008-07-03 | Combinatorx, Incorporated | Pharmaceutical compositions for treatment of parkinson's disease and related disorders |
DE102006062120A1 (de) | 2006-12-22 | 2008-06-26 | Grünenthal GmbH | Pharmazeutische Zusammensetzung zur Aknebehandlung |
EP2104493A2 (en) | 2007-01-16 | 2009-09-30 | Egalet A/S | Use of i) a polyglycol and n) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse |
WO2008094877A2 (en) | 2007-01-30 | 2008-08-07 | Drugtech Corporation | Compositions for oral delivery of pharmaceuticals |
CN100579525C (zh) | 2007-02-02 | 2010-01-13 | 东南大学 | 盐酸尼卡地平缓释制剂及其制备方法 |
BRPI0807157A2 (pt) | 2007-02-08 | 2014-04-29 | Kempharm Inc | Pró-farmacos hidrófilos polares de anfetamina e outros estimulantes e processos para fabricação e uso dos mesmos |
CN101057849A (zh) | 2007-02-27 | 2007-10-24 | 齐齐哈尔医学院 | 含有盐酸二甲双胍和格列吡嗪的缓释制剂及其制备方法 |
ATE476176T1 (de) | 2007-03-02 | 2010-08-15 | Farnam Co Inc | Wachsähnliches material enthaltende tabletten mit verzögerter freisetzung |
DE102007011485A1 (de) * | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Darreichungsform mit erschwertem Missbrauch |
EP1980245A1 (en) | 2007-04-11 | 2008-10-15 | Cephalon France | Bilayer lyophilized pharmaceutical compositions and methods of making and using same |
US20080260836A1 (en) | 2007-04-18 | 2008-10-23 | Thomas James Boyd | Films Comprising a Plurality of Polymers |
CA2685118C (en) | 2007-04-26 | 2016-11-01 | Sigmoid Pharma Limited | Manufacture of multiple minicapsules |
US20110020408A1 (en) | 2007-05-17 | 2011-01-27 | Ranbaxy Laboratories Limited | multilayered modified release formulation comprising amoxicillin and clavulanate |
US8202542B1 (en) | 2007-05-31 | 2012-06-19 | Tris Pharma | Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings |
EP2155167A2 (en) | 2007-06-04 | 2010-02-24 | Egalet A/S | Controlled release pharmaceutical compositions for prolonged effect |
US20100035886A1 (en) | 2007-06-21 | 2010-02-11 | Veroscience, Llc | Parenteral formulations of dopamine agonists |
EP2170051A1 (en) | 2007-07-01 | 2010-04-07 | Joseph Peter Habboushe | Combination tablet with chewable outer layer |
CN101917977B (zh) | 2007-07-20 | 2013-05-29 | 艾博特股份有限两合公司 | 非阿片样物质和限制的阿片样物质止痛药的制剂 |
WO2009034541A2 (en) | 2007-09-11 | 2009-03-19 | Ranbaxy Laboratories Limited | Controlled release pharmaceutical dosage forms of trimetazidine |
DK2200593T5 (en) | 2007-09-13 | 2016-12-12 | Cima Labs Inc | Hog-resistant pharmaceutical formulation |
WO2009051819A1 (en) | 2007-10-17 | 2009-04-23 | Axxia Pharmaceuticals, Llc | Polymeric drug delivery systems and thermoplastic extrusion processes for producing such systems |
EP3170494A3 (en) | 2007-11-23 | 2017-09-06 | Grünenthal GmbH | Tapentadol compositions |
WO2009088414A2 (en) | 2007-12-06 | 2009-07-16 | Durect Corporation | Oral pharmaceutical dosage forms |
WO2009074609A1 (de) | 2007-12-12 | 2009-06-18 | Basf Se | Salze von wirkstoffen mit polymeren gegenionen |
AU2008338207A1 (en) | 2007-12-17 | 2009-06-25 | Labopharm (Barbados) Limited | Misuse preventative, controlled release formulation |
US8383152B2 (en) | 2008-01-25 | 2013-02-26 | Gruenenthal Gmbh | Pharmaceutical dosage form |
KR100970665B1 (ko) | 2008-02-04 | 2010-07-15 | 삼일제약주식회사 | 알푸조신 또는 그의 염을 함유하는 서방성 정제 |
AU2009220779A1 (en) | 2008-03-05 | 2009-09-11 | Panacea Biotec Limited | Modified release pharmaceutical compositions comprising mycophenolate and processes thereof |
US8372432B2 (en) | 2008-03-11 | 2013-02-12 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
EP2100598A1 (en) * | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
TWI519322B (zh) | 2008-04-15 | 2016-02-01 | 愛戴爾製藥股份有限公司 | 包含弱鹼性藥物及控制釋放劑型之組合物 |
HUE030803T2 (en) | 2008-05-09 | 2017-06-28 | Gruenenthal Gmbh | Process for the preparation of an intermediate powder formulation and a final solid dosage form using a spraying step \ t |
JP2011526928A (ja) | 2008-07-03 | 2011-10-20 | ノバルティス アーゲー | 溶融造粒方法 |
MX2011001864A (es) | 2008-08-20 | 2011-06-20 | Univ Texas | Extrusion de fusion en caliente de multiples particulas de liberacion modificada. |
FR2936709B1 (fr) | 2008-10-02 | 2012-05-11 | Ethypharm Sa | Comprimes alcoolo-resistants. |
US20100099696A1 (en) | 2008-10-16 | 2010-04-22 | Anthony Edward Soscia | Tamper resistant oral dosage forms containing an embolizing agent |
CA2741751C (en) | 2008-10-27 | 2017-05-09 | Alza Corporation | Extended release oral acetaminophen/tramadol dosage form |
US20100260844A1 (en) * | 2008-11-03 | 2010-10-14 | Scicinski Jan J | Oral pharmaceutical dosage forms |
WO2010057036A2 (en) | 2008-11-14 | 2010-05-20 | Portola Pharmaceuticals, Inc. | Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low ph and methods of use thereof |
ES2414856T3 (es) | 2008-12-12 | 2013-07-23 | Paladin Labs Inc. | Formulaciones de fármaco narcótico con potencial de adicción disminuido |
ES2509497T3 (es) | 2008-12-16 | 2014-10-17 | Paladin Labs Inc. | Formulación de liberación controlada para evitar un uso indebido |
WO2010083843A1 (en) | 2009-01-26 | 2010-07-29 | Egalet A/S | Controlled release formulations with continuous efficacy |
WO2010088911A1 (en) | 2009-02-06 | 2010-08-12 | Egalet A/S | Pharmaceutical compositions resistant to abuse |
US9730899B2 (en) | 2009-03-18 | 2017-08-15 | Evonik Roehm Gmbh | Controlled release pharmaceutical composition with resistance against the influence of ethanol employing a coating comprising neutral vinyl polymers and excipients |
EP2246063A1 (en) | 2009-04-29 | 2010-11-03 | Ipsen Pharma S.A.S. | Sustained release formulations comprising GnRH analogues |
WO2010141505A1 (en) | 2009-06-01 | 2010-12-09 | Protect Pharmaceutical Corporation | Abuse-resistant delivery systems |
GB0909680D0 (en) | 2009-06-05 | 2009-07-22 | Euro Celtique Sa | Dosage form |
NZ603579A (en) * | 2009-06-24 | 2014-02-28 | Egalet Ltd | Controlled release formulations |
WO2011008298A2 (en) | 2009-07-16 | 2011-01-20 | Nectid, Inc. | Novel axomadol dosage forms |
KR101738369B1 (ko) * | 2009-07-22 | 2017-05-22 | 그뤼넨탈 게엠베하 | 핫 멜트 압출된 제어 방출 투여형 |
RU2555531C2 (ru) | 2009-07-22 | 2015-07-10 | Грюненталь Гмбх | Защищенная от применения не по назначению лекарственная форма для чувствительных к окислению опиоидов |
EP3064064A1 (en) | 2009-09-30 | 2016-09-07 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
JP5529884B2 (ja) | 2009-11-13 | 2014-06-25 | 森六ケミカルズ株式会社 | 微粉末の製造方法及び同方法で製造された微粉末 |
EP2506838A1 (en) | 2009-12-01 | 2012-10-10 | Noven Pharmaceuticals, INC. | Transdermal testosterone device and delivery |
US9579285B2 (en) | 2010-02-03 | 2017-02-28 | Gruenenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of an extruder |
US9306723B2 (en) * | 2010-02-20 | 2016-04-05 | Google Technology Holdings LLC | Multi-carrier control signaling in wireless communication system |
GB201003731D0 (en) | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Immediate/delayed drug delivery |
EA029077B1 (ru) | 2010-03-09 | 2018-02-28 | Алкермес Фарма Айэленд Лимитед | Устойчивая к спирту фармацевтическая лекарственная форма |
CA2795158C (en) | 2010-04-02 | 2019-10-22 | Alltranz Inc. | Abuse-deterrent transdermal formulations of opiate agonists and agonist-antagonists |
US9884022B2 (en) * | 2010-04-07 | 2018-02-06 | Lupin Limited | Controlled release pharmaceutical compositions of tapentadol |
GB201006200D0 (en) | 2010-04-14 | 2010-06-02 | Ayanda As | Composition |
US10463633B2 (en) | 2010-04-23 | 2019-11-05 | Kempharm, Inc. | Therapeutic formulation for reduced drug side effects |
US20130059010A1 (en) | 2010-05-14 | 2013-03-07 | Ethypharm | Alcohol-resistant oral pharmaceutical form |
FR2960775A1 (fr) | 2010-06-07 | 2011-12-09 | Ethypharm Sa | Microgranules resistants au detournement |
EP2611426B1 (en) | 2010-09-02 | 2014-06-25 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
AU2011297954B2 (en) | 2010-09-02 | 2014-05-15 | Grunenthal Gmbh | Tamper resistant dosage form comprising an anionic polymer |
AR082862A1 (es) * | 2010-09-02 | 2013-01-16 | Gruenenthal Gmbh | Forma de dosificacion resistente a alteracion que comprende un polimero anionico |
EP2635258A1 (en) | 2010-11-04 | 2013-09-11 | AbbVie Inc. | Drug formulations |
US20120231083A1 (en) | 2010-11-18 | 2012-09-13 | The Board Of Trustees Of The University Of Illinois | Sustained release cannabinoid medicaments |
GB201020895D0 (en) | 2010-12-09 | 2011-01-26 | Euro Celtique Sa | Dosage form |
CN103327969A (zh) | 2010-12-23 | 2013-09-25 | 普渡制药公司 | 抗篡改固体口服剂型 |
MX2013009492A (es) | 2011-02-17 | 2014-07-30 | Qrxpharma Ltd | Tecnologia para prevenir el abuso de formas de dosificacion solidas. |
CN107308108A (zh) | 2011-03-04 | 2017-11-03 | 格吕伦塔尔有限公司 | 用于口服给予的他喷他多含水药物制剂 |
SI2701693T1 (sl) | 2011-04-29 | 2017-11-30 | Gruenenthal Gmbh | Tapentadol za preprečevanje in zdravljenje depresije in anksioznosti |
US8858963B1 (en) | 2011-05-17 | 2014-10-14 | Mallinckrodt Llc | Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia |
CA2837077A1 (en) | 2011-06-01 | 2012-12-06 | Fmc Corporation | Controlled release solid dose forms |
EP2726065A4 (en) | 2011-06-30 | 2014-11-26 | Neos Therapeutics Lp | MISS-BROKEN MEDICINAL PRODUCTS |
AR087359A1 (es) | 2011-07-29 | 2014-03-19 | Gruenenthal Gmbh | Tableta a prueba de alteracion que proporciona liberacion inmediata del farmaco |
EA201400172A1 (ru) | 2011-07-29 | 2014-06-30 | Грюненталь Гмбх | Устойчивая к разрушению таблетка, которая обеспечивает немедленное высвобождение лекарственного средства |
CA2844827A1 (en) | 2011-08-16 | 2013-02-21 | Merck Sharp & Dohme Corp. | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
FR2979242A1 (fr) | 2011-08-29 | 2013-03-01 | Sanofi Sa | Comprime contre l'usage abusif, a base de paracetamol et d'oxycodone |
KR20140075704A (ko) | 2011-10-06 | 2014-06-19 | 그뤼넨탈 게엠베하 | 오피오이드 작용제 및 오피오이드 길항제를 포함하는 변형억제 경구용 약제학적 용량형 |
EA201400590A1 (ru) | 2011-11-17 | 2014-11-28 | Грюненталь Гмбх | Устойчивая к разрушению пероральная фармацевтическая лекарственная форма, содержащая фармакологически активный ингредиент, опиоидный антагонист и/или средство, вызывающее отвращение, полиалкиленоксид и анионный полимер |
TW201336529A (zh) | 2011-12-09 | 2013-09-16 | Purdue Pharma Lp | 包含聚(ε-己內酯)和聚氧化乙烯之藥物劑量型 |
EP2606879A1 (en) | 2011-12-21 | 2013-06-26 | Hexal AG | Multiple unit pellet tablet formulation comprising an opioid |
JP2013155124A (ja) | 2012-01-30 | 2013-08-15 | Moriroku Chemicals Co Ltd | 医薬品の原末及びその製造方法 |
EP2819656A1 (en) | 2012-02-28 | 2015-01-07 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
WO2013127830A1 (en) | 2012-02-28 | 2013-09-06 | Grünenthal GmbH | Tamper-resistant pharmaceutical dosage form comprising nonionic surfactant |
WO2013128276A2 (en) | 2012-03-02 | 2013-09-06 | Rhodes Pharmaceuticals L.P. | Tamper resistant immediate release formulations |
WO2013158810A1 (en) | 2012-04-18 | 2013-10-24 | Mallinckrodt Llc | Immediate release pharmaceutical compositions with abuse deterrent properties |
MX362357B (es) | 2012-04-18 | 2019-01-14 | Gruenenthal Gmbh | Forma de dosificacion farmaceutica resistente a la adulteracion y resistente a la liberacion inmediata de la dosis. |
JP2015516406A (ja) | 2012-05-11 | 2015-06-11 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 亜鉛を含む熱成形された不正使用防止医薬剤形 |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
WO2014022541A1 (en) | 2012-08-01 | 2014-02-06 | Acura Pharmaceuticals, Inc. | Stabilization of one-pot methamphetamine synthesis systems |
BR112015002421B1 (pt) | 2012-08-27 | 2022-01-25 | Evonik Röhm Gmbh | Composição farmacêutica ou nutracêutica com características de liberação sustentada e com resistência contra a influência do etanol, seu uso e seu processo de produção |
CN104507460A (zh) | 2012-08-27 | 2015-04-08 | 赢创工业集团股份有限公司 | 抗乙醇影响的抗胃酸药物或保健品组合物 |
JP5775223B2 (ja) | 2012-09-05 | 2015-09-09 | テイカ製薬株式会社 | 口腔内速崩壊性錠剤用造粒物 |
WO2014059512A1 (en) | 2012-10-15 | 2014-04-24 | Isa Odidi | Oral drug delivery formulations |
US10420729B2 (en) * | 2013-03-15 | 2019-09-24 | R.P. Scherer Technologies, Llc | Abuse resistant capsule |
US9517208B2 (en) * | 2013-03-15 | 2016-12-13 | Purdue Pharma L.P. | Abuse-deterrent dosage forms |
US20140275143A1 (en) | 2013-03-15 | 2014-09-18 | Mallinckrodt Llc | Compositions Comprising An Opioid And An Additional Active Pharmaceutical Ingredient For Rapid Onset And Extended Duration Of Analgesia That May Be Administered Without Regard To Food |
JP6445537B2 (ja) * | 2013-05-29 | 2018-12-26 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 1個または複数の粒子を含有する改変防止(tamper−resistant)剤形 |
AR096439A1 (es) | 2013-05-29 | 2015-12-30 | Gruenenthal Gmbh | Forma de dosificación resistente al uso indebido que contiene una o más partículas |
CA2817728A1 (en) | 2013-05-31 | 2014-11-30 | Pharmascience Inc. | Abuse deterrent immediate release formulation |
EA032465B1 (ru) | 2013-07-12 | 2019-05-31 | Грюненталь Гмбх | Защищенная от применения не по назначению пероральная фармацевтическая лекарственная форма, содержащая этиленвинилацетатный полимер, и способ ее изготовления |
US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US9770514B2 (en) | 2013-09-03 | 2017-09-26 | ExxPharma Therapeutics LLC | Tamper-resistant pharmaceutical dosage forms |
WO2015048597A1 (en) | 2013-09-30 | 2015-04-02 | Daya Drug Discoveries, Inc. | Prevention of illicit methamphetamine manufacture from pseudoephedrine using food flavor excipients |
US20150118300A1 (en) | 2013-10-31 | 2015-04-30 | Cima Labs Inc. | Immediate Release Abuse-Deterrent Granulated Dosage Forms |
US10744131B2 (en) | 2013-12-31 | 2020-08-18 | Kashiv Biosciences, Llc | Abuse-resistant drug formulations |
US10632113B2 (en) * | 2014-02-05 | 2020-04-28 | Kashiv Biosciences, Llc | Abuse-resistant drug formulations with built-in overdose protection |
US20160089439A1 (en) | 2014-09-28 | 2016-03-31 | Satara Pharmaceuticals, LLC | Prevention of Illicit Manufacutre of Methamphetamine from Pseudoephedrine Using Food Flavor Excipients |
EP3285745A1 (en) | 2015-04-24 | 2018-02-28 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
US20170112766A1 (en) * | 2015-04-24 | 2017-04-27 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
JP2018526414A (ja) | 2015-09-10 | 2018-09-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 乱用抑止性の即放性製剤を用いた経口過剰摂取に対する保護 |
US20170296476A1 (en) * | 2016-04-15 | 2017-10-19 | Grünenthal GmbH | Modified release abuse deterrent dosage forms |
-
2004
- 2004-07-01 DE DE102004032049A patent/DE102004032049A1/de not_active Withdrawn
- 2004-07-14 US US10/890,763 patent/US20060002860A1/en not_active Abandoned
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2005
- 2005-06-29 MX MX2007000009A patent/MX2007000009A/es active IP Right Grant
- 2005-06-29 ES ES05769988T patent/ES2402192T5/es active Active
- 2005-06-29 PT PT57699886T patent/PT1765303E/pt unknown
- 2005-06-29 DK DK05769988.6T patent/DK1765303T4/da active
- 2005-06-29 SI SI200531671T patent/SI1765303T2/sl unknown
- 2005-06-29 CN CN2005800292367A patent/CN101027044B/zh active Active
- 2005-06-29 RU RU2007103707/15A patent/RU2396944C2/ru not_active IP Right Cessation
- 2005-06-30 PE PE2005000760A patent/PE20060523A1/es not_active Application Discontinuation
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2006
- 2006-12-31 IL IL180470A patent/IL180470A0/en active IP Right Grant
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2007
- 2007-09-28 HK HK07110602.2A patent/HK1107930A1/xx unknown
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2008
- 2008-06-17 US US12/140,470 patent/US20080248113A1/en not_active Abandoned
-
2013
- 2013-03-26 CY CY20131100249T patent/CY1113847T1/el unknown
- 2013-05-20 US US13/897,746 patent/US20130251643A1/en not_active Abandoned
- 2013-12-30 US US14/143,487 patent/US20140112989A1/en not_active Abandoned
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2015
- 2015-07-10 US US14/795,900 patent/US20150313845A1/en not_active Abandoned
-
2016
- 2016-03-01 US US15/057,161 patent/US20170209378A9/en not_active Abandoned
- 2016-03-03 US US15/059,730 patent/US20160184295A1/en not_active Abandoned
- 2016-09-02 US US15/255,534 patent/US20160367549A1/en not_active Abandoned
-
2018
- 2018-01-24 US US15/878,524 patent/US20180147149A1/en not_active Abandoned
-
2019
- 2019-08-16 US US16/542,808 patent/US20200038330A1/en not_active Abandoned
-
2020
- 2020-09-02 US US17/010,106 patent/US11844865B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997033566A2 (en) * | 1996-03-12 | 1997-09-18 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US20030068392A1 (en) * | 2001-08-06 | 2003-04-10 | Richard Sackler | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
DE10250083A1 (de) * | 2002-06-17 | 2003-12-24 | Gruenenthal Gmbh | Gegen Missbrauch gesicherte Darreichungsform |
WO2004037260A1 (de) * | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen missbrauch gesicherte darreichungsform |
WO2004037230A1 (de) * | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen missbrauch gesicherte darreichungsform |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8114383B2 (en) | 2003-08-06 | 2012-02-14 | Gruenenthal Gmbh | Abuse-proofed dosage form |
US8192722B2 (en) | 2003-08-06 | 2012-06-05 | Grunenthal Gmbh | Abuse-proof dosage form |
US8309060B2 (en) | 2003-08-06 | 2012-11-13 | Grunenthal Gmbh | Abuse-proofed dosage form |
US8420056B2 (en) | 2003-08-06 | 2013-04-16 | Grunenthal Gmbh | Abuse-proofed dosage form |
US8114384B2 (en) | 2004-07-01 | 2012-02-14 | Gruenenthal Gmbh | Process for the production of an abuse-proofed solid dosage form |
US8323889B2 (en) | 2004-07-01 | 2012-12-04 | Gruenenthal Gmbh | Process for the production of an abuse-proofed solid dosage form |
US8722086B2 (en) | 2007-03-07 | 2014-05-13 | Gruenenthal Gmbh | Dosage form with impeded abuse |
US8383152B2 (en) | 2008-01-25 | 2013-02-26 | Gruenenthal Gmbh | Pharmaceutical dosage form |
US9161917B2 (en) | 2008-05-09 | 2015-10-20 | Grünenthal GmbH | Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet |
Also Published As
Publication number | Publication date |
---|---|
US20150313845A1 (en) | 2015-11-05 |
US20180147149A1 (en) | 2018-05-31 |
DK1765303T4 (da) | 2023-01-30 |
SI1765303T2 (sl) | 2023-03-31 |
MX2007000009A (es) | 2007-03-07 |
SI1765303T1 (sl) | 2013-03-29 |
US20060002860A1 (en) | 2006-01-05 |
DK1765303T3 (da) | 2013-03-25 |
US20160175256A1 (en) | 2016-06-23 |
US20160367549A1 (en) | 2016-12-22 |
CY1113847T1 (el) | 2016-07-27 |
PT1765303E (pt) | 2013-04-02 |
ES2402192T5 (es) | 2023-04-12 |
US20160184295A1 (en) | 2016-06-30 |
RU2007103707A (ru) | 2008-11-20 |
IL180470A0 (en) | 2007-06-03 |
DE102004032049A1 (de) | 2006-01-19 |
US20200397704A1 (en) | 2020-12-24 |
US20080248113A1 (en) | 2008-10-09 |
ES2402192T3 (es) | 2013-04-29 |
CN101027044A (zh) | 2007-08-29 |
US11844865B2 (en) | 2023-12-19 |
HK1107930A1 (en) | 2008-04-25 |
US20140112989A1 (en) | 2014-04-24 |
RU2396944C2 (ru) | 2010-08-20 |
US20130251643A1 (en) | 2013-09-26 |
US20170209378A9 (en) | 2017-07-27 |
PE20060523A1 (es) | 2006-08-25 |
US20200038330A1 (en) | 2020-02-06 |
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