CN101111232B - 防止滥用的给药剂型的制备方法 - Google Patents
防止滥用的给药剂型的制备方法 Download PDFInfo
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Abstract
本发明涉及用于制备防滥用的给药剂型的方法,所述剂型除了含有一种或多种有滥用倾向的试剂以及任选的生理可接受助剂之外,还含有至少一种最低断裂强度为500N的合成或者天然聚合物(C)。向该制剂混合物中加入针对聚合物(C)的溶剂,加入量使得所述制剂混合物被至少均匀润湿,所述至少被润湿的物质任选被分成部分物质,干燥,并成形为给药剂型。
Description
本发明涉及用于制备防止滥用的固态剂型的方法,其中向除了一种或多种具有滥用可能性的活性成分(A)和任选的生理可接受辅助物质(B)之外还含有至少一种合成或者天然聚合物(C)(所述聚合物的断裂强度为至少500N)的制剂混合物中加入
a)针对聚合物(C)的溶剂,其量至少使得所述制剂混合物被均匀润湿,
b)已经被以此方式至少润湿的所述组合物被任选地分成亚部分,
c)所述部分(一个或多个)被干燥,并
d)成形以获得所述剂型。
许多药用活性成分除了在其合适应用中具有优异的活性之外,还具有被滥用的可能性,即,它们可以被滥用者使用,以带来除了预期效果以外的那些影响。
例如,鸦片剂(opiate)在对抗严重疼痛到极严重疼痛上高度有效,但常常被滥用者使用来诱发麻醉或者陶醉感。
为了能够滥用,相应的剂型,比如片剂或者胶囊,被滥用者粉碎,例如在研钵中研磨,采用优选的水性液体将活性成分从所得粉末中提取出来,得到的溶液任选在通过脱脂棉或者纤维素填絮过滤后肠胃外给药,尤其是静脉给药。和滥用性的口服给药相比,这种给药的另外现象是活性成分水平进一步加速增加,从而赋予滥用者所需的效果,即“兴奋(kick)”或者“激动(rush)”。如果粉末化的剂型经鼻给药,即用鼻子吸入,则也会产生兴奋感。
由于含有具有滥用可能性的活性成分的延迟释放性口服剂型即使在以滥用性大量口服时,通常也不会产生滥用者所需要的兴奋感,所以这种剂型也经过粉碎和提取。
US-A-4070494提出为了防止滥用在剂型中加入膨胀剂。当加入水来提取活性成分时,膨胀剂膨胀,确保和凝胶分离的滤液仅仅含有少量活性成分。
WO95/20947中描述的多层片剂基于和防止肠胃外滥用相似的方法,所述片剂含有具有滥用可能性的活性成分和至少一种凝胶形成物,其中所述活性成分和所述凝胶形成物各自在不同的层中。
WO03/015531A2公开了另一种防止肠胃外滥用的方法。其中描述了含有止痛药阿片样物质和作为厌恶剂的染料的剂型。破坏剂型时释放的颜色旨在使滥用者放弃使用已经被破坏的剂型。
另一种使滥用变得不容易的选择包括向剂型加入针对活性成分的拮抗剂,例如对于阿片样物质而言是纳洛酮或者纳屈酮,或者导致生理防御性响应的化合物,比如例如吐根树(吐根)的根。
但是,如同在过去一样,由于在大多数情况下,为了滥用需要使剂型粉碎,所以本发明的目标是提供制备下述剂型的方法:该剂型含有具有滥用可能性的活性成分,当该剂型被正确给药时确保产生所需的、优选的治疗作用,而且通过该剂型活性成分不会被仅仅通过粉碎而转变成适合滥用的形式。
通过提供用于制备具有至少降低了的滥用可能性的固态剂型的本发明方法,实现了所述目标,所述方法的特征在于:
a)向含有至少一种具有滥用可能性的活性成分(A)和至少一种合成或天然的聚合物(C)的制剂混合物中加入用于聚合物(C)的溶剂,加入量是至少使得所述制剂混合物被均匀润湿的量:所述聚合物的断裂强度为至少500N,
b)已经被以此方式至少润湿的组合物任选地被分成亚部分,
c)所述(一个或多个)部分被干燥,并
d)成形以获得所述剂型。
通过使用具有上述最小断裂强度(测量方法如同在本申请中所述)的聚合物,优选加入量使得该剂型也具有至少为500N,优选至少为1000N的所述最小断裂强度,则可以防止通过常规手段使该剂型粉碎,从而使任何后续滥用变得显著地复杂化或者被防止。
如果粉碎不充分,那么肠胃外给药,尤其是静脉给药,实际上不能安全进行,或者从中提取活性成分将花费滥用者太长时间,或者当口服滥用时由于不是即刻释放地所以不产生“兴奋”效果。
根据本发明,粉碎是指通过通常而言滥用者易得的常规手段施加力来破碎剂型,所述手段比如例如研钵和研杵、锤子、棒槌或者其它通常用于粉碎的装置,其中可以形成的细粉(颗粒尺寸等于或者小于0.3mm)的百分比不得超过5%。
根据本发明制备的剂型在低温下,例如低于-25℃、-40℃或者甚至在液氮中,也不能通过这些方法粉碎。
根据本发明制备的剂型优选是药用剂型,因此适于防止具有滥用可能性的活性成分,优选药用活性成分,的肠胃外、经鼻和/或经口滥用。
具有滥用可能性的活性成分,优选药用活性成分,是本领域技术人员公知的,其用量和制备方法同样是公知的,并且在根据本发明制备的剂型中以如下形式存在:比如,其相应的衍生物形式,尤其是酯类、醚类或酰胺类,或者在每种情况下以相应的生理可接受化合物的形式,尤其是其相应的盐或溶剂化物的形式,作为外消旋物或者立体异构体形式。根据本发明制备的剂型可以含有两种或多种药用活性成分。根据本发明制备的剂型优选含有仅仅一种特异性活性成分。
本发明的剂型特别适于防止滥用阿片类物质、安定剂或者选自下列的另一种麻醉药:N-{1-[2-(4-乙基-5-氧代-2-四唑啉-1-基)乙基]-4-甲氧基甲基-4-哌啶基}-N-丙酰苯胺(阿芬太尼)、5,5-二烯丙基巴比妥酸(阿洛巴比妥)、烯丙罗定、阿法罗定、8-氯-1-甲基-6-苯基-4H-[1,2,4]三唑并[4,3-a][1,4]-苯并二氮杂(阿普唑仑)、2-乙基氨基苯基·乙基(甲)酮(安非拉酮)、(±)-α-甲基苯乙基胺(苯丙胺)、2-(α-甲基苯乙基氨基)-2-苯基乙腈(苯丙胺苄氰)、5-乙基-5-异戊基巴比妥酸(异戊巴比妥)、阿尼利定、阿朴可待因、5,5-二乙基巴比妥酸(巴比妥)、苄基吗啡、氰苯咪呱啶、7-溴-5-(2-吡啶基)-1H-1,4-苯并二氮杂-2(3H)-酮(溴西泮)、2-溴-4-(2-氯苯基)-9-甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂(溴替唑仑)、17-环丙基甲基-4,5α-环氧-7α[(S)-1-羟基-1,2,2-三甲基-丙基]-6-甲氧基-6,14-内-桥亚乙基吗啡烷-3-醇(丁丙诺啡)、5-丁基-5-乙基巴比妥酸(丁巴比妥)、布托啡诺、(7-氯-1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂-3-基)二甲基氨基甲酸酯(卡马西泮)、(1S,2S)-2-氨基-1-苯基-1-丙醇(去甲伪麻黄碱/D-去甲伪麻黄碱)、7-氯-N-甲基-5-苯基-3H-1,4-苯并二氮杂-2-基胺4-氧化物(氯氮卓)、7-氯-1-甲基-5-苯基-1H-1,5-苯并二氮杂-2,4(3H,5H)-二酮(氯巴占)、5-(2-氯苯基)-7-硝基-1H-1,4-苯并二氮杂-2(3H)-酮(氯硝西泮)、氯尼他秦、7-氯-2,3-二氢-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-羧酸(氯氮卓)、5-(2-氯苯基)-7-乙基-1-甲基-1H-噻吩并[2,3-e][1,4]二氮杂2(3H)-酮(氯噻西泮)、10-氯-11b-(2-氯苯基)-2,3,7,11b-四氢噁唑并[3,2-d][1,4]苯并二氮杂-6(5H)-酮(氯噁唑仑)、(-)-甲基-[3β-苯甲酰基氧基-2β(1αH,5αH)-托烷羧酸酯](可卡因)、4,5α-环氧基-3-甲氧基-17-甲基-7-吗啡烷-6α-醇(可待因)、5-(1-环己烯基)-5-乙基巴比妥酸(环巴比妥)、环丙甲吗喃醇、环丙诺啡、7-氯-5-(2-氯苯基)-1H-1,4-苯并二氮杂-2(3H)-酮(地洛西泮)、地索吗啡、右吗拉胺、(+)-(1-苄基-3-二甲基氨基-2-甲基-1-苯基丙基)丙酸酯(右丙氧芬)、地佐辛、地恩丙胺、海洛因(diamorphone)、7-氯-1-甲基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(地西泮)、4,5α-环氧基-3-甲氧基-17-甲基-6α-吗啡烷醇(双氢可待因)、4,5α-环氧基-17-甲基-3,6a-吗啡烷二醇(二氢吗啡)、苯醋胺乙酯、美沙醇(dimephetamo1)、二甲噻丁、吗苯丁酯、地匹哌酮、(6aR,10aR)-6,6,9-三甲基-3-戊基-6a,7,8,10a-四氢-6H-苯并[c]色原烯-1-醇(屈大麻酚)、氢溴酸依他佐辛、8-氯-6-苯基-4H-[1,2,4]三唑并[4,3-(a)][1,4]二氮杂(三唑氯安定)、氢氮革乙酯、乙基甲基噻吩丁烯胺、[7-氯-5-(2-氟苯基)-2,3-二氢-2-氧代-1H-1,4-苯并二氮杂-3-羧酸]乙酯(西泮酸乙酯)、4,5α-环氧基-3-乙氧基-17-甲基-7-吗啡烷-6α-醇(乙基吗啡)、依托尼秦、4,5α-环氧基-7α-(1-羟基-1-甲基丁基)-6-甲氧基-17-甲基-6,14-内-亚乙烯基-吗啡烷-3-醇(埃托芬)、N-乙基-3-苯基-8,9,10-三降冰片烷-2-基胺(芬坎法明)、7-[2-(α-甲基苯乙基氨基)乙基]-茶碱)(苯丙胺乙茶碱)、3-(α-甲基苯乙基氨基)丙腈(美芬雷司)、N-(1-苯乙基-4-哌啶基)丙酰苯胺(芬太尼)、7-氯-5-(2-氟苯基)-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(氟安定)、5-(2-氟苯基)-1-甲基-7-硝基-1H-1,4-苯并二氮杂-2(3H)-酮(氟硝基安定)、7-氯-1-(2-二乙基氨基乙基)-5-(2-氟苯基)-1H-1,4-苯并二氮杂-2(3H)-酮(氟胺安定)、7-氯-5-苯基-1-(2,2,2-三氟乙基)-1H-1,4-苯并二氮杂-2(3H)-酮(哈拉西泮)、10-溴-11b-(2-氟苯基)-2,3,7,11b-四氢[1,3]噁唑并[3,2-d][1,4]苯并二氮杂-6(5H)-酮(溴氟唑仑)、海洛因、4,5α-环氧基-3-甲氧基-17-甲基-6-吗啡烷酮(二氢可待因酮)、4,5α-环氧基-3-羟基-17-甲基-6-吗啡烷酮(氢吗啡酮)、羟基哌替啶、异美沙酮、羟基甲基吗啡烷、11-氯-8,12b-二氢-2,8-二甲基-12b-苯基-4H-[1,3]噁嗪并[3,2-d][1,4]二氮杂-4,7(6H)-二酮(凯他唑仑)、1-[4-(3-羟基苯基)-1-甲基-4-哌啶基]-1-丙酮(酚哌丙酮)、(3S,6S)-6-二甲基氨基-4,4-二苯基庚烷-3-基乙酸酯(左旋醋美沙朵(LAAM))、(-)-6-二甲基氨基-4,4-二苯酚-3-庚酮(左旋美沙酮)、(-)-17-甲基-3-吗啡烷醇(左啡诺)、苯左啡烷、洛芬太尼、6-(2-氯苯基)-2-(4-甲基-1-哌嗪基亚甲基)-8-硝基-2H-咪唑并[1,2-a][1,4]-苯并二氮杂-1(4H)-酮(氯普唑仑)、7-氯-5-(2-氯苯基)-3-羟基-1H-1,4-苯并二氮杂-2(3H)-酮(劳拉西泮)、7-氯-5-(2-氯苯基)-3-羟基-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(氯甲西泮)、5-(4-氯苯基)-2,5-二氢-3H-咪唑并[2,1-a]异吲哚-5-醇(氯苯咪吲哚)、7-氯-2,3-二氢-1-甲基-5-苯基-1H-1,4-二氮杂(去氧安定)、N-(3-氯丙基)-α-甲基苯乙基胺(氯丙苯丙胺)、麦啶、2-甲基-2-丙基三亚甲基二氨基甲酸酯(甲丙氨酯)、甲氮草酚、间唑辛、甲基吗啡、N,α-二甲基苯乙基胺(甲基苯(异)丙胺)、(±)-6-二甲基氨基-4,4-二苯酚-3-庚酮(美沙酮)、2-甲基-3-邻-甲苯基-4(3H)-喹唑啉酮(甲喹酮)、[2-苯基-2-(2-哌啶基)乙酸]甲酯(苯哌啶醋酸甲酯)、5-乙基-1-甲基-5-苯基巴比妥酸(甲苯比妥)、3,3-二乙基-5-甲基-2,4-哌啶二酮(甲乙哌酮)、美托酮、8-氯-6-(2-氟苯基)-1-甲基-4H-咪唑并[1,5a][1,4]苯并二氮杂(咪达唑仑)、2-(二苯甲基亚硫酰基)乙酰胺(莫达非尼)、4,5α-环氧基-17-甲基-7-吗啡(morphinen)-3,6α-二醇(吗啡)、苄吗啡十四酸酯、(±)-反式-3-(1,1-二甲基庚基)-7,8,10,10α-四氢-1-羟基-6,6-二甲基-6H-二苯并-[b,d]吡喃-9(6αH)-酮(大麻隆)、纳布啡、烯丙吗啡、罂粟碱、二烟酰吗啡、1-甲基-7-硝基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(硝基去氯安定)、7-硝基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(硝西泮)、7-氯-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(去甲安定)、去甲左啡诺、6-二甲基氨基-4,4-二苯基-3-己酮(去甲美沙酮)、去甲吗啡、二苯哌己酮、从属于罂粟物种的植物中渗出物(鸦片)、7-氯-3-羟基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(奥沙西泮)、(顺-反)-10-氯-2,3,7,11b-四氢-2-甲基-11b-苯基噁唑并[3,2-d][1,4]苯并二氮杂6-(5H)-酮(甲噁安定)、4,5α-环氧基-14-羟基-3-甲氧基-17-甲基-6-吗啡烷酮(羟氢可待酮)、氧吗啡酮、属于罂粟物种(包括亚物种汤饭子(setigerum))的植物和植物部分(罂粟)、阿片金碱、2-亚氨基-5-苯基-4-噁唑啉酮(pernoline)、1,2,3,4,5,6-六氢-6,11-二甲基-3-(3-甲基-2-丁烯基)-2,6-亚甲基-3-苯并吖辛因(benzazocin)-8-醇(戊唑星)、5-乙基-5-(1-甲基丁基)-巴比妥酸(戊巴比妥)、乙基-(1-甲基-4-苯基-4-哌啶羧酸酯)(哌替啶)、苯吗庚酮、苄啡烷、非那佐辛、苯哌利定、匹米诺定、福尔可定、3-甲基-2-苯吗啡啉(苯甲吗啉)、5-乙基-5-苯基巴比妥酸(苯巴比妥)、α,α-二甲基苯乙基胺(苯(叔)丁胺)、7-氯-5-苯基-1-(2-丙炔基)-1H-1,4-苯并二氮杂-2(3H)-酮(丙炔安定)、α-(2-哌啶基)二苯甲醇(哌苯甲醇)、1′-(3-氰基-3,3-二苯基丙基)[1,4′-联哌啶]-4′-甲酰胺(氰苯双哌酰胺)、7-氯-1-(环丙基甲基)-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(普拉西泮)、普罗法朵、丙庚嗪、二甲哌替啶、异丙哌替啶、丙氧吩、N-(1-甲基-2-哌啶并乙基)-N-(2-吡啶基)丙酰胺、{3-[4-甲氧基羰基-4-(N-苯基丙酰胺基)哌啶子基]丙酸}甲酯(雷米芬太尼)、5-仲丁基-5-乙基巴比妥酸(仲丁比妥)、5-烯丙基-5-(1-甲基丁基)-巴比妥酸(司可巴比妥)、N-{4-甲氧基甲基-1-[2-(2-噻酚基)乙基]-4-哌啶基}-N-丙酰苯胺(舒芬太尼)、7-氯-2-羟基-甲基-5-苯基-1H-1,4-苯并二氮杂-2(3H)-酮(羟基安定)、7-氯-5-(1-环己烯基)-1-甲基-1H-1,4-苯并二氮杂-2(3H)-酮(四氢安定)、(2-二甲基氨基-1-苯基-3-环己烯-1-羧酸)乙酯(替利定(顺式和反式))、曲马多、8-氯-6-(2-氯苯基)-1-甲基-4H-[1,2,4]三唑并[4,3-a][1,4]苯并二氮杂(三唑仑)、5-(1-甲基丁基)-5-乙烯基巴比妥酸(乙烯比妥)、(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、(1R,2R,4S)-2-(二甲基氨基)甲基-4-(对-氟苄基氧基)-1-(间-甲氧基苯基)环己醇、(1R,2R)-3-(2-二甲基氨基甲基-环己基)苯酚、(1S,2S)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、(2R,3R)-1-二甲基氨基-3(3-甲氧基苯基)-2-甲基-戊-3-醇、(1RS,3RS,6RS)-6-二甲基氨基甲基-1-(3-甲氧基苯基)-环己烷-1,3-二醇、优选作为外消旋化合物、3-(2-二甲基氨基甲基-1-羟基-环己基)苯基·2-(4-异丁氧基-苯基)-丙酸酯、3-(2-二甲基氨基甲基-1-羟基-环己基)苯基·2-(6-甲氧基-萘-2-基)-丙酸酯、3-(2-二甲基氨基甲基-环己-1-烯基)-苯基·2-(4-异丁基-苯基)-丙酸酯、3-(2-二甲基氨基甲基-环己-1-烯基)-苯基·2-(6-甲氧基-萘-2-基)-丙酸酯、(RR-SS)-2-乙酰氧基-4-三氟甲基-苯甲酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR-SS)-2-羟基-4-三氟甲基-苯甲酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR-SS)-4-氯-2-羟基-苯甲酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR-SS)-2-羟基-4-甲基-苯甲酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR-SS)-2-羟基-4-甲氧基-苯甲酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR-SS)-2-羟基-5-硝基-苯甲酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯、(RR-SS)-2’,4’-二氟-3-羟基-联苯基-4-羧酸·3-(2-二甲基氨基甲基-1-羟基-环己基)-苯基酯,以及相应的立体异构化合物,在每种情况下其相应的衍生物,尤其是酰胺、酯或者醚,以及在每种情况下其生理上可接受的化合物,尤其是其盐和溶剂化物,特别优选氢氯化物。
根据本发明制备的剂型特别适于选自下列的阿片样活性成分被滥用:羟氢可待酮、氢吗啡酮、吗啡、曲马多和其生理可接受的衍生物或者化合物,优选其盐和溶剂化物,优选其氢氯化物。
根据本发明制备的剂型另外特别适用于防止选自下列的阿片样活性成分被滥用:(1R,2R)-3-(3-二甲基氨基-1-乙基-2-甲基-丙基)苯酚、(2R,3R)-1-二甲基氨基-3-(3-甲氧基苯基)-2-甲基-戊-3-醇、(1RS,3RS,6RS)-6-二甲基氨基甲基-1-(3-甲氧基苯基)-环己烷-1,3-二醇、(1R,2R)-3-(2-二甲基氨基乙基-环己基)苯酚、其生理上可接受的盐,优选氢氯化物、生理上可接受的对映体、立体异构体、非对映体和外消旋化合物,及其生理上可接受的衍生物,优选醚、酯或者酰胺。
这些化合物及其制备方法分别在EP-A-693475和EP-A-780369中进行了描述。相应的描述在此引入作为参考,并认定为本公开的一部分。
为了获得所需的断裂强度,在本发明的方法中采用了至少一种断裂强度为至少500N的合成或天然聚合物(C),所述断裂强度采用本申请公开的方法测量。优选至少一种选自下列的聚合物用于此目的:聚环氧烷、优选聚甲醛、聚环氧乙烷、聚环氧丙烷;聚乙烯、聚丙烯、聚氯乙烯、聚碳酸酯、聚苯乙烯、聚丙烯酸酯、其共聚物、以及所述聚合物的至少两种的混合物。优选高分子量的热塑性聚环氧烷。特别优选分子量为至少50万,优选至少100万-1500万的高分子量聚环氧乙烷,所述分子量通过流变学测量方法来确定。这些聚合物在25℃的粘度当采用RVF Brookfield粘度计(2号心轴/转速为2rpm)对5重量%的水溶液进行测量时为4500-17600cP,当采用所述粘度计(1号心轴或者3号心轴/转速10rpm)对2重量%水溶液进行测量时是400-4000cP,当采用所述粘度计(2号心轴/转速2rpm)对1重量%水溶液进行测量时是1650-10000cP。
所述聚合物优选以粉末形式使用。它们应该溶于水。
为了利用本发明的方法获得必须的断裂强度,进一步可能的是另外使用至少一种断裂强度至少500N的天然或合成蜡(D),所述断裂强度采用本申请公开的方法测量。优选软化点为至少60℃的蜡。特别优选棕榈蜡和蜂蜡。极其优选棕榈蜡。棕榈蜡是得自棕榈树叶、软化点至少80℃的天然蜡。当另外使用蜡组分时,它和至少一种聚合物(C)一起使用,用量使得根据本发明制备的剂型的断裂强度至少为500N。
组分(C)的用量优选是20-99.9重量%,特别优选至少30重量%,及其优选至少40重量%,相对于剂型的总重量而言。
可以使用的辅助物质(B)是那些公知的对于固态剂型制剂而言常规的辅助物质。优选是增塑剂,比如甘油三乙酸酯和聚乙二醇、影响活性成分释放的辅助物质,优选疏水性的或者亲水性的,优选亲水性聚合物,特别优选羟丙基甲基纤维素或者羟丙基纤维素和/或抗氧化剂。聚合物,特别优选纤维素醚、纤维素酯和/或丙烯酸树脂被优选用作亲水性基质材料。乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、聚(甲基)丙烯酸和/或其衍生物,比如其盐、酰胺或者酯被特别优选用作基质材料。合适的抗氧化剂是抗坏血酸、丁基羟基茴香醚、丁基羟基甲苯、抗坏血酸的盐、单硫代丙三醇、磷酸、维生素C、维生素E和其衍生物、亚硫酸氢钠、特别优选丁基羟基甲苯(BHT)或者丁基羟基茴香醚(BHA)和α-生育酚。
抗氧化剂的优选用量是0.01-10重量%,优选0.03-5重量%,相对于剂型的总重量而言。
为了执行本发明的方法,对至少一种具有滥用可能性的活性成分(A)、至少一种聚合物(C)和任选的蜡(D)、任选的至少一种下面列出的其它任选存在的防滥用组分(a)-(f)、以及任选存在的辅助物质(B)比如抗氧化剂、增塑剂和/或延迟释放辅助物质,通过加入针对聚合物(C)的溶剂进行处理,以形成所述剂型。
为此,将组分(A)、(B)、(C)和任选存在的组分(D)和任选至少一种任选存在的另外的防滥用组分(a)-(f)混合,或者需要时分开混合同时加入组分(C)和任选的组分(D),所得的制剂混合物(一种或多种)在加入溶剂并任选在造粒后,经过成形以获得所述剂型。
组分(A)、(B)、(C)和任选的(D)以及任选存在的其它组分(a)-(f)和组分(C)与任选存在的组分(D)的混合,任选在每种情况下都在本领域技术人员公知的混炼机中进行。所述混炼机可以例如是辊式混炼机、振动式混炼机、剪切式混炼机或者桨叶式混炼机。
针对聚合物(C)的溶剂的加入量至少使得所述制剂混合物被均匀润湿。
适于作为针对聚合物(C)的溶剂的溶剂优选是水性溶剂,比如水、水和脂族醇,优选C1-C6的醇的混合物、酯、醚、烃,特别优选单独蒸馏水或者蒸馏水和短链醇比如甲醇、乙醇、异丙醇、丁醇的混合物以形成水性醇溶液。
溶剂优选通过搅拌加入。然后,干燥该均匀润湿的组合物。干燥优选通过于能够防止组合物出现任何脱色的温度暴露到热量下进行。所述温度可以通过简单的初步测试来建立。
在干燥前或后,组合物可以分成亚部分,其在每种情况下优选和单位剂型的质量相相应。然后,将相应干燥后的部分成形以形成剂型。
这优选通过采用压片机来进行。
制剂混合物可以以如下方式润湿:即,在加入溶剂之前,制剂混合物被划分,优选在模具中划分成亚部分,搅拌分散在液体分散剂中,然后加入溶剂。聚合物组分(C)不溶于所述分散剂,所述分散剂必须与溶剂混溶。
合适的分散剂优选是亲水性分散剂,比如脂族醇、酮、酯。优选使用短链醇。
或者,制剂混合物可以以溶剂可以以泡沫形式结合到制剂混合物中的方式被润湿。所述溶剂泡沫优选通过高速混炼机制备,优选加入常规泡沫稳定剂。合适的稳定剂是例如亲水性聚合物,比如例如羟丙基甲基纤维素。
泡沫也优选在搅拌下结合到制剂混合物中,这样优选获得颗粒化的组合物。
在被分成亚部分之前或者之后,颗粒化的组合物被干燥然后成形成剂型,其中所述亚部分优选和单位剂型质量相对应。
干燥和成形可以优选如上所述进行。
根据本发明的方法也可以以如下方式进行,即溶剂在制剂混合物中的加入量使得获得了可成形的糊。
在干燥(可以如前所述那样进行)之前或之后,所述糊可以划分成亚部分,所述干燥的部分在每种情况下在进一步划分成和单位剂型质量相应的部分之后,经过成形或转变以获得所述剂型。
在此,可以形成条状的亚部分,其可以通过筛子或者条形成器的辅助来制备。干燥的条状物优选经过单分(singulate)和成形,以获得剂型。这种成形优选在压片机的辅助下进行,采用成形辊或者配有辊的成形带。
也可以将糊转变成平板结构,并在其一旦干燥后从中冲压出所述剂型。
所述糊有利地通过挤出机进行处理,其中,取决于挤出模头的构造,制备出条状或者板状结构制品,所述制品通过砍、切或者冲压被单分。单分的亚部分可以如上所述进行成形或者成型,以获得所述剂型。相应的装置是本领域技术人员所公知的。
在此,本发明的方法可以连续或者不连续进行。
也可以在制剂混合物中加入至少溶解聚合物组分(C)的量的溶剂。所述溶液或者分散体/悬浮液优选转变成板状结构,优选使用具有扁平模头的挤出机,或者溶液被流延到平板支撑体上。
如上所述,在干燥后,可以通过冲压或者压延由所述平面结构获得剂型。也可以如上所述将溶液转变成条状物,并优选在其干燥后进行单分和成形,以获得所述剂型。
或者,也可以利用模具将溶液分成部分,使得在干燥后所述部分每个都对应于单位剂型的质量,其中,为此目的优选采用已经和单位剂型的形状相应的模具。
如果溶液被分成任何所需的部分,则所述部分可以在干燥后任选被再次组合,并经过成形以形成所述剂型,所述剂型例如被包装在胶囊里或者经过压模形成片剂。
结合有溶剂的制剂混合物优选在20℃-40℃的温度下处理,其中,除了在用于去除溶剂和任选存在的分散剂的干燥期间以外,没有使用更高的温度。在成形以获得剂型后,可以任选地进行进一步地和上述干燥相应的干燥。
如同已经解释的,根据本发明制备的剂型可以采取多颗粒形式,优选微片剂、微胶囊、微丸粒、颗粒、球状体、珠子或者丸粒形式,任选包装在胶囊中或者经压模形成片剂,优选用于经口给药。多颗粒形式优选的尺寸或者尺寸分布为0.1-3mm,特别优选为0.5-2mm。取决于所需的剂型,所述剂型的制剂也任选使用常规辅助物质(B)。
根据本发明方法获得的剂型的不同之处在于:由于其至少500N的硬度,它们不能通过滥用者可以获得的常规粉碎装置,比如研钵和研杵,来粉碎。这实质上排除了经口、肠胃外,尤其是静脉、或者经鼻滥用。但是,为了防止本发明制备的剂型的任何可能的滥用,在优选实施方案中,本发明的剂型可以进一步含有使滥用不容易或者防止滥用的试剂作为辅助物质(B)。
根据本发明制备的防滥用剂型除了包含一种或多种具有滥用可能性的活性成分(A)、至少一种硬化聚合物(C)和任选的至少一种蜡(D)之外,还可以相应地包含至少一种下列组分(a)-(e)作为辅助物质(B):
(a)至少一种刺激鼻通道和/或咽腔的物质,
(b)至少一种增加粘度的试剂,其在必需的最少量水性液体,优选是从该剂型获得的水性提取物,的帮助下,形成凝胶,所述凝胶在引入到另外量的水性液体中时优选保持视觉上可区分,
(c)至少一种针对每一具有滥用可能性的活性成分的拮抗剂,
(d)至少一种催吐剂,
(e)至少一种染料作为厌恶剂,
(f)至少一种苦味物质。
组分(a)-(f)是另外的、均独立地适于防止滥用根据本发明获得的剂型的物质。相应地,组分(a)优选适于防止剂型经鼻、经口和/或肠胃外,优选经静脉滥用,组分(b)优选适于防止肠胃外滥用,特别优选防止经静脉和/或经鼻滥用,组分(c)优选适于防止经鼻和/或肠胃外滥用,特别优选适于防止经静脉滥用,组分(d)优选适于防止肠胃外滥用,特别优选防止经静脉滥用,和/或经口和/或经鼻滥用,组分(e)适于作为抵抗经口或肠胃外滥用的视觉上的阻止物,组分(f)适于防止经口或经鼻滥用。根据本发明将至少一种上述组分组合使用使其可以更有效地防止滥用根据本发明方法制备的剂型。
例如,根据本发明制备的剂型也可以组合包含两种或多种组分(a)-(f),优选(a)、(b)和任选的(c)和/或(f)和/或(e),或者(a)、(b)和任选的(d)和/或(f)和/或(e)。
在另一实施方案中,根据本发明制备的剂型可以包含所有组分(a)-(f)。
如果根据本发明制备的剂型包含防滥用组分(a),那么根据本发明可以考虑的、刺激鼻通道和/或咽腔的物质,是当经由鼻腔通道和/或咽腔相应给药时带来如下物理反应的物质:所述物理反应或者对滥用者而言是不受欢迎的以至于滥用者不愿意或者不能继续给药,例如,烧灼感,或者例如由于增加鼻腔分泌或者打喷嚏而从生理上抵制摄入相应的活性成分。常规刺激鼻腔通道和/或咽腔的这些物质,当肠胃外给药尤其是静脉给药时,也可能带来非常不受欢迎的感觉或者甚至不能承受的疼痛,使得滥用者不愿意或者不能继续摄入所述物质。
特别合适的刺激鼻腔通道和/或咽腔的物质,是导致烧灼感、刺痛感、刺激打喷嚏、分泌物形成增加、或者至少两种所述刺激的组合的物质。常规使用的合适物质及其用量是本领域普通技术人员公知的,或者可以通过简单的初步试验来确定。
组分(a)的刺激鼻腔通道和/或咽腔的物质优选基于至少一种辣物质药物的一种或多种组分或者一种或多种植物部分。
相应的辣物质药物是本领域技术人员公知的,在例如“Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe″,Prof.Dr.Hildebert Wagner,第二版,修订版,Gustav Fischer Verlag,Stuttgart-New York,1982,第82页起”中进行了描述。该相应的描述在此引入作为参考,并被认定是本公开的一部分。
剂量单位是指分开的或者可分开的给药单位,比如例如片剂或者胶囊。
在本发明的剂型中,可以优选加入至少一种选自下列辣物质药物的一种或多种组分作为组分(a):Allii sativi bulbus(大蒜)、Asarirhizoma cum herba(细辛根和叶)、Calami rhizoma(菖蒲根)、Capsicifructus(辣椒)、Capsici fructus acer(番椒)、Curcumae longae rhizoma(姜黄根)、Curcumae xanthorrhizae rhizoma(爪哇姜黄根)、Galangaerhizoma(高良姜根)、Myristicae semen(肉豆蔻)、Piperis nigri fructus(胡椒)、Sinapis albae semen(白芥菜籽)、Sinapis nigri semen(黑芥菜籽)、Zedoariae rhizoma(片姜黄根)和Zingiberis rhizoma(生姜根),特别优选选自Capsici fructus(辣椒)、Capsici fructus acer(番椒)和Piperis nigri fructus(胡椒)。
辣物质药物的组分优选包含邻甲氧基(甲基)苯酚化合物、酰胺化合物、芥菜油、或者由其衍生的一种或多种硫化物。
特别优选的,辣物质药物的至少一种组分选自肉豆蔻醚、榄香素、异丁子香酚、α-细辛醚、黄樟油精、姜醇、黄根醇(xanthorrhizol)、辣椒素生物碱,优选辣椒素、辣椒素衍生物,比如N-香草基-9E-十八烯酰胺、二氢辣椒素、去甲二氢辣椒素、高辣椒素(homocapsaicin)、去甲辣椒素(norcapsaicin)和nomorcapsaicin、胡椒碱,优选反式-胡椒碱、硫代葡萄糖酸盐,优选基于非挥发性芥菜油,特别优选基于对-羟基苄基芥菜油、甲基巯基芥菜油或者甲基硫酰基芥菜油,以及源自这些组分的化合物。
根据本发明获得的剂型可以优选含有相应辣物质药物的植物部分,在每种情况下基于剂型单位的总重量含量为0.01-30重量%,特别优选0.1-0.5重量%。
如果使用相应辣物质药物的一种或多种组分,其在本发明制备的剂型单位中的量优选是0.001-0.005重量%,相对于剂型单位的总重量。
防止滥用本发明制备的剂型的另一选项是在剂型中加入至少一种增加粘度的试剂作为另外的防滥用组分(b),其在必需的最小量水性液体,优选作为得自该剂型的水性提取物,的辅助下形成凝胶,所述凝胶实质上不能安全地给药,优选当引入到另外量的水性液体中时保持视觉上可以区分。
对于本发明而言,视觉上可区分是指在必需的最小量水性液体的辅助下形成的含活性成分的凝胶,当引入(优选在皮下注射针的辅助下)到另外量的处于37℃的水性液体中时,保持基本不溶的和内聚的,并且不能以直接以如下方式分散:所述方式使得其可以安全地、肠胃外给药,尤其是经静脉给药。所述材料优选保持视觉上可区分至少1分钟,优选至少10分钟。
提取物的增加的粘度使其更难以或者甚至不可能通过针头或者被注射。如果凝胶保持视觉上可区分的,那么这意味着所得的凝胶到引入到另外量的水性液体中时,例如通过注入到血液中引入时,首先保持为主要是内聚性的细线的形式,所述细线尽管实际上可以经机械方式破碎成更小的片段,但是不能以如下方式粉碎或者甚至溶解:所述方式使其可以安全地肠胃外给药,尤其是经静脉给药。当与至少一种任选存在的组分(a)-(e)组合时,这另外增加了不受欢迎的烧灼感、呕吐感、臭味和/或视觉上的阻碍。
静脉给药所述凝胶很有可能导致堵塞血管,伴随着严重损坏滥用者的健康。
为了验证提高粘度的试剂是否适合作为用于本发明制备的剂型中的组分(b),将活性成分和所述提高粘度的试剂混合,并悬浮在25℃的10ml水中。如果这导致形成满足上述条件的凝胶,那么相应的提高粘度的试剂适于另外防止或者避免根据本发明制备的剂型的滥用。
如果组分(b)加入到根据本发明制备的剂型中,那么使用一种或多种选自下列的提高粘度的试剂:具有11重量%羧甲基纤维素钠的微晶纤维素(RC 591)、羧甲基纤维素钠(、CMC-Na、Frimulsion,、Tylose)、聚丙烯酸(980NF、981)、槐豆粉(LA-200、LID/150、LN-1)、果胶,优选源自含果胶的水果和苹果(HM Medium Rapid Set)、蜡状玉米淀粉(C*Gel)、海藻酸钠(Frimulsion ALG)、瓜儿豆粉(FrimulsionPolygum)、阿尔塔角叉菜胶(Frimulsion)、刺梧桐树胶、胶凝糖胶(Kelcogel、Kelcogel)、半乳甘露聚糖(Meyprogat)、tara stone粉(Polygum)、丙二醇海藻酸酯(Protanal-Ester)、透明质酸钠、黄蓍胶、tara胶(Vidogum SP)、发酵的多糖威兰(welan)胶(K1A96)、黄原胶(Xantural)。特别优选黄原胶。括号中给出的名称是材料市售的商品名。通常,相对于剂型的总重量,0.1-20重量%,特别优选0.1-15重量%的所述提高粘度的试剂(一种或多种)就足以满足上述条件。
组分(b),即提高粘度的试剂,当提供时,在本发明制备的剂型中优选存在的量是≥5mg每剂量单位,即,每给药单位。
在本发明的特别优选的实施方案中,用作组分(b)的提高粘度的试剂是在用必需的最少量水性液体从剂型中提取时,形成封闭气泡的凝胶。所得的凝胶通过混浊外观进行区分,这为潜在的滥用者提供了另外的视觉警告并使其放弃肠胃外给药所述凝胶。
组分(C)也可以任选地作为另外的提高粘度的试剂,其在必需的最小量水性液体的辅助下形成凝胶。
也可以以在空间上相互分开的排列形式,来在根据本发明制备的剂型中配制所述提高粘度的试剂和其它组分。
为了放弃和防止滥用,根据本发明制备的剂型可以进一步包括组分(c),即一种或多种针对(一种或多种)具有滥用可能性的活性成分的拮抗剂,其中所述拮抗剂优选和根据本发明制备的剂型的剩余组分在空间上分开,并且当正确使用时不产生任何影响。
用于防止活性成分滥用的合适拮抗剂是本领域技术人员公知的,可以就这样或者以相应衍生物的形式,尤其是酯或者醚,或者在每种情况下以相应生理上可接受的化合物形式,尤其是其盐或者溶剂化物的形式,存在于本发明的剂型中。
如果剂型中存在的活性成分是阿片样物质,那么所用的拮抗剂优选是选自下列的拮抗剂:纳洛酮、纳曲酮、纳美芬、nalid、纳美酮、烯丙吗啡或者naluphine,在每种情况下任选地以其相应生理可接受化合物的形式,尤其是碱、盐或溶剂化物的形式。相应的拮抗剂(在提供组分(c)的情况下),优选用量是每剂型,即每给药单位≥1mg,特别优选3-100mg,极其特别优选5-50mg。
如果根据本发明制备的剂型包括刺激剂作为活性成分,那么拮抗剂优选是精神抑制药,优选是至少一种选自下列的化合物:氟哌啶醇、异丙嗪、羟哌氟丙嗪、奋乃静、甲氧异丁嗪、甲硫达嗪、丙拉嗪、氯丙嗪、氯丙硫蒽、珠氯噻醇、三氟噻吨、氮丙嗪、佐替平、苯哌唑酮、匹泮哌隆、甲哌酮和溴哌利多。
根据本发明制备的剂型优选以本领域技术人员公知的常规治疗剂量,特别优选以每给药单位2倍-3倍的所述常规剂量的量包含这些拮抗剂。
如果所述用以进一步放弃和防止滥用根据本发明制备的剂型的组合也包含组分(d),那么它可以包含至少一种催吐剂,所述催吐剂优选以和根据本发明制备的剂型的其它组分在空间上分开的排列方式存在,并且当正确使用时不会试图对身体产生影响。
用于另外防止滥用活性成分的合适催吐剂是本领域技术人员公知的,可以以原样或者以相应衍生物的形式,尤其是酯或者醚,或者在每种情况下以相应生理上可接受的化合物形式,尤其是其盐或者溶剂化物的形式,存在于根据本发明获得的剂型中。
在根据本发明制备的剂型中可以优选考虑基于吐根树(吐根)根的一种或多种组分,更优选基于组分依米丁的催吐剂,例如在“Pharmazeutische Biologie-Drogen und ihre Inhaltsstoffe″,Prof.Dr.Hildebert Wagner,第二版,修订版,Gustav Fischer Verlag,Stuttgart-New York,1982中进行了描述。该相应的描述在此引入作为参考,并被认定是本公开的一部分。
根据本发明制备的剂型可以优选含有催吐性的依米丁作为组分(d),优选每剂型,即给药单位的含量≥3mg,特别优选≥10mg,极其优选≥20mg。
阿朴吗啡同样可以优选用作催吐剂用于另外防止滥用,优选的用量优选≥3mg,特别优选≥5mg,极其特别优选≥7mg每给药单位。
如果根据本发明制备的剂型包含组分(e)作为另外的防止滥用的辅助物质,那么使用所述染料使相应的水性溶液具有强烈的着色作用,尤其是当试图提取活性成分供肠胃外给药,优选静脉给药时,所述着色可以充当对潜在滥用者的阻止物。经口滥用通常通过水性提取活性成分开始,也可以通过这种着色来防止。所述必需的阻止物所需的合适染料和量可以参见WO03/015531,其中所述相应公开应该视为本公开的一部分,在此引入作为参考。
如果根据本发明制备的剂型含有组分(f)作为另外的防止滥用的辅助物质,那么加入至少一种苦味物质和最终对剂型味道的损害,会另外防止经口和/或经鼻滥用。
合适的苦味物质及其使用有效量可以参见US2003/0064099A1,其相应的公开应该认为是本申请公开的一部分,在此引入作为参考。合适的苦味物质优选是芳族油,优选薄荷油、桉树油、苦杏仁油、薄荷醇、水果芳香物质,优选来自柠檬、桔子、酸橙、葡萄柚的芳香物质,或者其混合物,和/或苯甲酸地那铵()。苯甲酸地那铵是特别优选地。
根据本发明制备的固态剂型不仅仅适于经口给药,而且适于阴道或直肠给药,但是优选经口摄入。剂型优选不是薄膜形式。根据本发明的剂型可以采用多颗粒形式,优选圆柱形式、微片剂、微胶囊、微丸粒、颗粒、球状体、珠子或者丸粒形式,任选的包装在胶囊中或者压模成片剂,优选用于经口给药。多颗粒形式优选的尺寸或者尺寸分布是0.1-3mm,特别优选0.5-2mm。取决于所需的剂型,常规辅助物质(B)任选也用于配制所述剂型。
在进一步优选的实施方案中,根据本发明制备的剂型采用片剂、胶囊形式,或者是经口渗透治疗系统(OROS)的形式,优选也存在至少一种另外的防滥用组分(a)-(f)。
如果组分(c)和/或(d)和/或(f)存在于根据本发明制备的剂型中,则必须小心确保它们以如下方式配制或者以如下低剂量存在:即,所述方式或者所述剂量使得当正确给药时,所述剂型能够实质上不产生会损坏病人或者活性成分效率的影响。
如果根据本发明制备的剂型含有组分(d)和/或(f),那么剂量必须经选择使得当正确经口给药时,不产生负面影响。但是,如果在滥用情况下超过目标剂量,那么会产生恶心或者想呕吐或者臭味。在正确经口给药的情况下病人可以容忍的组分(d)和/或(f)的具体量可以由本领域技术人员通过简单的初步试验来确定。
但是,如果不考虑根据本发明制备的进一步剂型实质上不可能被粉碎这个事实,而采用组分(c)和/或(d)和/或(f)来保护所述剂型,那么这些组分应该优选以足够高的剂量使用,使得当被滥用性给药时,它们对滥用者产生强烈的负面影响。这优选通过将至少所述活性成分(一种或多种)和组分(c)和/或(d)和/或(f)在空间上分开来实现,其中所述活性成分(一种或多种)存在于至少一个亚单位(X)中,而组分(c)和/或(d)和/或(f)存在于至少一个亚单位(Y)中,以及其中,当剂型被正确给药时,组分(c)、(d)和(f)对摄入和/或在体内不产生影响,所述制剂的其余组分,尤其是组分(C)和任选的(D),是相同的。
如果根据本发明制备的剂型包含组分(c)和(d)或者(f)的至少2种,那么它们每个都可以存在于相同或者不同亚单位(Y)中。优选地,当存在时,所有组分(c)和(d)和(f)都存在于同一个亚单位(Y)中。
对于本发明而言,亚单位是固态制剂,其中在每种情况下,除了本领域技术人员知道的辅助物质以外,含有活性成分(一种或多种)、至少一种聚合物(C)和任选存在的组分(D)、和任选至少一种任选存在的组分(a)和/或(b)和/或(e),或者在每种情况下,至少一种聚合物(C)和任选的(D)和拮抗剂(一种或多种)和/或催吐剂(一种或多种)和/或组分(e)和/或组分(f)以及任选的至少一种任选存在的组分(a)和/或组分(b)。必须小心确保每个上述亚单位都根据本发明的上述方法制备。
将活性成分和组分(c)或者(d)或者(f)在根据本发明制备的剂型的亚单位(X)和(Y)中分开配制的一个显著优点在于,当正确给药时,组分(c)和/或(d)和/或(f)在摄入时和/或在体内时几乎不释放,或者释放小量以至于不会产生损害病人或者治疗成功性的效果,或者,在通过病人身体时,它们仅仅在不能被充分吸收以至于有效的位置处释放。当剂型被正确给药时,优选几乎没有组分(c)和/或(d)和/或(f)被释放到病人身体内,或者不会被病人注意到。
本领域技术人员将理解,上述条件可以随着所用的具体组分(c)、(d)和/或(f)以及亚单位或者剂型的配制而变。特殊剂型的最优配制可以由简单的初步测试来确定。重要的是每个亚单位包含聚合物(C)和任选的组分(D),并且是根据上述方式配制和根据本发明制备。
如果和预期的相反,滥用者为了滥用活性成分而成功粉碎了根据本发明制备的剂型,所述剂型在亚单位(Y)中含有组分(c)和/或(e)和/或(d)和/或(f),并获得了通过合适提取剂提取的粉末,那么不仅活性成分而且特殊组分(c)和/或(e)和/或(f)和/或(d)将以如下形式获得:在该形式中,它不能容易地和活性成分分离,使得当所述已经被改动的剂型在被给药时,尤其是通过经口和/或肠胃外给药时,它将对摄入产生影响和/或在身体内产生影响,并且和对滥用者产生的、与组分(c)和/或(d)和/或(f)相应的负面影响相结合,或者,当试图提取活性成分时,着色充当阻止物并因而防止滥用剂型。
其中活性成分(一种或多种)和组分(c)、(d)和/或(e)在空间上分离(优选通过在不同亚单位中配制)的剂型,可以根据本发明以许多不同方式配制,其中在剂型中的相应亚单位各自可以互相以任何所需的空间排列形式存在,前提是满足用于释放组分(c)和/或(d)的上述条件。
本领域技术人员将理解,任选也存在的(一种或多种)组分(a)和/或(b)优选可以在根据本发明制备的剂型中在特殊亚单位(X)和(Y)中存在,以及以和亚单位(X)和(Y)相应的独立亚单位的形式存在,前提是防止滥用或者在正确给药的情况下活性成分的释放都不会受到制剂本质的损害,聚合物(C)和任选的(D)优选包括在制剂中,并且所述配制是根据上述方法进行的以便获得所需的硬度。
在根据本发明制备的剂型的优选实施方案中,亚单位(X)和(Y)以多颗粒形式存在,其中优选微片剂、微胶囊、微丸粒、颗粒、球形体、珠子或者丸粒,对亚单位(X)和亚单位(Y)选择同样的形式,即形状,以使不可能例如通过机械选择将亚单位(X)和亚单位(Y)分离。优选多颗粒形式的尺寸为0.1-3mm,优选0.5-2mm。
多颗粒形式中的亚单位(X)和(Y)也可以优选包装在胶囊中或者压模成片剂,其中在每种情况下最终配制都以亚单位(X)和(Y)也都保留在最终剂型中的方式进行。
形状相同的多颗粒亚单位(X)和(Y)也不应互相在视觉上可以区分开,从而使得滥用者不能通过简单分拣而将它们彼此分离。这可以例如通过施加相同的涂层来实现,所述涂层除了这个伪装功能以外,也还可以结合其它的功能,比如例如,延迟释放一种或多种活性成分,或者为胃液对颗粒亚单位的作用提供最后一道屏障。
多颗粒亚单位也可以配制成如同在药用安全的悬浮介质中的浆料或者悬浮液一样的经口剂型。
在本发明的进一步优选实施方案中,在每种情况下亚单位(X)和(Y)互相成层排列。
为此,层状的亚单位(X)和(Y)优选在根据本发明制备的剂型中互相成水平或者垂直排列,其中在每种情况下,一种或多个层状亚单位(X)和一个或多个层状亚单位(Y)可以存在于剂型中,从而除了优选的层顺序(X)-(Y)或者(X)-(Y)-(X)外,可以考虑任何所需的其它层顺序,并任选的和含有组分(a)和/或(b)的层组合。
根据本发明制备的另一种优选剂型是其中亚单位(Y)形成完全被亚单位(X)封闭的芯的剂型,其中在所述层之间可以存在分隔层(Z)。所述结构也优选适用于上述多颗粒形式,其中亚单位(X)和(Y)以及任选存在的分隔层(Z)被配制在同一多颗粒形式中,其中所述分隔层(Z)必须满足本发明的硬度要求。
在根据本发明制备的剂型的进一步优选实施方案中,亚单位(X)形成芯,所述芯被亚单位(Y)封闭,其中后者包含至少一条从芯导向剂型表面的通道。
根据本发明制备的剂型在每种情况下在一层亚单位(X)和一层亚单位(Y)之间可以包含一个或者多个,优选一个,任选的可溶胀分隔层(Z),所述分隔层起到将亚单位(X)和(Y)在空间上分隔的作用。
如果根据本发明制备的剂型包含至少部分垂直或者水平排列形式的层状亚单位(X)和(Y)以及任选存在的分隔层(Z),那么该剂型优选采用片剂或者层压体的形式。
在一个特别优选的实施方案中,亚单位(Y)的全部自由表面、任选的亚单位(X)(一个或多个)的至少部分自由表面以及任选的任选存在的分隔层(Z)(一个或多个)的至少部分自由表面,可以涂有至少一个阻挡层(Z’),以防组分(c)和/或(e)和/或(d)和/或(f)的释放。阻挡层(Z’)也必须满足本发明的硬度条件。
根据本发明制备的剂型的另一特别优选的实施方案包含呈水平或者垂直排列的亚单位(X)和(Y)的层以及至少一个设置在其间的推进层(push layer)(p)以及任选的分隔层(Z),在所述剂型中,由亚单位(X)和(Y)、推进层和任选存在的分隔层(Z)的全部自由表面被设置有半渗透性的涂层(E),所述涂层对于释放介质,即,常规生理液体,是可渗透的,但是对于活性成分和组分(c)和/或(d)和/或(f)而言基本不可渗透,而且其中所述涂层(E)包含至少一个在亚单位(X)区域中的用于释放活性成分的开口。
相应的剂型是本领域技术人员公知的,例如以经口渗透性治疗系统(OROS)的名义,用于制备所述剂型的合适材料和方法等等同样也是公知的,请参见US4612008、US4765989和US4783337。相应的描述在此引入作为参考并认定为本公开的一部分。
在进一步优选的实施方案中,根据本发明制备的剂型的亚单位(X)是片剂形式,其边缘面和任选的两个主表面之一覆盖有含有组分(c)和/或(d)和/或(f)的阻挡层(Z’)。
本领域技术人员会理解,在根据本发明剂型配制中所用的(一个或多个)亚单位(X)或者(Y)以及任选存在的分隔层(一个或多个)(Z)和/或阻挡层(一个或多个)(Z’)的辅助物质,将随着其在剂型中排列的功能、给药模式、以及任选存在的组分(a)和/或(b)和/或(e)的特定活性成分以及组分(c)和/或(d)和/或(f)的特定活性成分而变。具有所需性质的材料在每种情况下对于本领域技术人员而言本身都是公知的。
如果通过该覆盖层,优选阻挡层,的作用,阻止了组分(c)和/或(d)和/或(f)从根据本发明制备的剂型的亚单位(Y)中的释放,那么该亚单位可以由本领域公知的常规材料制备,前提是它含有至少一个聚合物(C)和任选(D)以满足硬度条件,并且已经根据本发明制备。
如果没有提供相应的阻挡层(Z’)来在阻止组分(c)和/或(d)和/或(f)的释放,那么亚单位的材料应该经过选择以使实质上消除了特定组分组分(c)和/或(d)从亚单位(Y)的释放。下述适于制备阻挡层的材料可以优选用于本目的。
优选的材料是选自下列的材料:烷基纤维素、羟基烷基纤维素、葡聚糖、硬葡聚糖、甘露聚糖、黄原胶、聚[双(对羧基苯氧基)丙烷]和癸二酸的共聚物(优选摩尔比为20∶80,市售名称为Polifeprosan20)、羧甲基纤维素、纤维素醚、纤维素酯、硝基纤维素、基于(甲基)丙烯酸和其酯的聚合物、聚酰胺、聚碳酸酯、聚亚烷基、聚(氧化亚烷基二醇)、聚环氧烷、聚对苯二甲酸亚烷基酯、聚乙烯基醇、聚乙烯基醚、聚乙烯基酯、卤化聚乙烯基、聚乙醇酸交酯、聚硅氧烷和聚氨酯及其共聚物。
特别合适的材料可以选自下列:甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、乙酸纤维素、丙酸纤维素(低、中或者高分子量)、纤维素乙酸丙酸酯、纤维素乙酸丁酸酯、纤维素乙酸邻苯二甲酸酯、羧甲基纤维素、纤维素三乙酸酯、纤维素硫酸钠、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸丁酯、聚甲基丙烯酸异丁酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸酯、聚甲基丙烯酸月桂酯、聚甲基丙烯酸苯基酯、聚丙烯酸甲酯、聚丙烯酸异丙酯、聚丙烯酸异丁酯、聚丙烯酸十八烷基酯、聚乙烯、低密度聚乙烯、高密度聚乙烯、聚丙烯、聚乙二醇、聚环氧乙烷、聚对苯二甲酸乙二醇酯、聚乙烯醇、聚乙烯基异丁基醚、聚乙酸乙烯酯和聚氯乙烯。
特别合适的共聚物可以选自下列:甲基丙烯酸丁酯和甲基丙烯酸异丁酯的共聚物、大分子量的甲基乙烯基醚和马来酸的共聚物、甲基乙烯基醚和马来酸单乙酯的共聚物、甲基乙烯基醚和马来酸酐的共聚物、以及乙烯醇和乙酸乙烯酯的共聚物。
特别适于配制阻挡层的其它材料是淀粉填充的聚己内酯(WO98/20073)、脂族聚酯酰胺(DE19753534A1、DE19800698A1、EP0820698A1)、脂族和芳香族聚酯尿烷(DE19822979)、聚羟基烷羧酸酯,尤其是聚羟基丁酸酯、聚羟基戊酸酯、酪蛋白(DE4309528)、聚丙交酯和共聚丙交酯(EP0980894A1)。相应的描述在此引入作为参考并认定为本公开的一部分。
上述材料可以任选地与本领域公知的其它常规辅助物质掺混,所述辅助物质优选选自下列:单硬脂酸甘油酯、半合成甘油三酸酯衍生物、半合成甘油酯、氢化的蓖麻油、棕榈硬脂酸甘油酯、二十二烷酸甘油酯、聚乙烯基吡咯烷酮、白明胶、硬脂酸镁、硬脂酸、硬脂酸钠、滑石、苯甲酸钠、硼酸和胶态氧化硅、脂肪酸、取代的三甘油酯、甘油酯、聚亚烷基二醇、和其衍生物。
如果根据本发明制备的剂型包括分隔层(Z’),那么所述层和未覆盖的亚单位(Y)一样,优选可以由上述针对阻挡层描述的材料组成。本领域技术人员可以理解可以通过分隔层的厚度来控制活性成分或者组分(c)和/或(d)从特定亚单位的释放。
根据本发明制备的剂型显示出对活性成分的受控释放。优选适于每日两次给药给病人。
根据本发明制备的剂型可以含有一种或多种至少部分处于其它延迟释放形式的、具有滥用可能性的活性成分,其中延迟释放可以通过本领域普通技术人员公知的常规材料和方法来实现,例如通过将活性成分嵌入在延迟释放基质中,或者通过施加一个或多个延迟释放涂层。但是,活性成分释放必须受控,以使在每种情况下上述条件得以满足,例如,在正确给药所述剂型的情况下,在任选存在的组分(c)和/或(d)可以产生损害效果之前,一种或多种活性成分实质上完全释放。而且,能对受控释放有影响的材料的加入也必须不损害所需的硬度。
优选,通过将活性成分嵌入在基质中,实现从根据本发明制备的剂型中的受控释放。充当基质材料的辅助物质控制着活性成分的释放。基质材料可以例如是亲水性的凝胶形成材料,活性成分通过所述材料的释放主要是通过扩散进行;或者,是疏水性材料,活性成分通过所述材料的释放主要是通过从基质中的孔扩散来进行。
本领域公知的、生理上可接受的疏水性材料可以用作基质材料。聚合物,特别优选纤维素醚、纤维素酯和/或丙烯酸树脂,优选用作亲水性基质材料。乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、聚(甲基)丙烯酸和/或其衍生物,比如其盐、酰胺或酯,特别优选用作基质材料。
也优选由疏水性材料,比如疏水性聚合物、蜡、脂肪、长链脂肪酸、脂肪醇或者其相应的酯或醚或混合物,制备的基质材料。特别优选C12-C30脂肪酸的单或者二甘油酯和/或C12-C30脂肪醇和/或蜡或者其混合物用作疏水性材料。
也可以采用上述亲水性和疏水性材料的混合物作为基质材料。
用于获得根据本发明必须的至少500N的断裂强度的组分(C)和任选存在的组分(D),可以进一步自身作为另外的基质材料。
如果根据本发明制备的剂型打算用于经口给药,那么也可以优选包含抗胃液的、并且随着释放环境pH值的变化而溶解的涂层。由于所述涂层,可以确保根据本发明制备的剂型不溶解地通过胃,活性成分仅仅在肠中释放。抗胃液的涂层优选在pH为5-7.5之间时溶解。
用于延迟释放活性材料以及用于实现抗胃液涂层的相应材料和方法,是本领域技术人员公知的,例如,参见“Coated PharmaceuticalDosage Forms-Fundamentals,Manufacturing Techniques,Biopharmaceutical Aspects,Test Methods and Raw Materials”,KurtH.Bauer,K.Lehmann,Hermann P.Osterwald,Rothgang,Gerhart,第一版,1998,MedpharmScientific Publishers。相应的文献描述在此引入作为参考,并认定为本公开的一部分。
确定断裂强度的方法
为了验证材料是否可以用作组分(C)或者(D),在片剂模具中利用针对组分(C)或者(D)的溶剂将该材料溶解,一旦在低于该材料软化点的温度将溶剂去除后,采用150N的力将该材料压成直径10mm、高度5mm的片剂。
采用以此方式制备的片剂,利用下述装置根据EuropeanPharmacopoeia 1997,第143,144,方法no.2.9.8公布的确定片剂断裂强度的方法来确定断裂强度。用于该测量的装置是“Zwick Z 2.5”材料测试机,Fmax=2.5kN,最大拉伸距离为1150mm,该测试机应该配有1个柱和1个心轴,后间隙(clearance behind)为100mm,测试速度在0.1-800mm/min之间可调,以及配有testControl软件。采用具有拧入式插件和汽缸(直径10mm)的压力活塞、力传感器(Fmax为1kN,直径=8mm,根据ISO 7500-1,从10N开始为0.5级,从2N开始为1级)进行测量,所述装置具有根据DIN 55350-18的制造商测试证书M(Zwick的力总量Fmax=1.45kN)(所有装置来自Zwick GmbH&Co.KG,Ulm,Germany),其中测试机的型号为BTC-FR 2.5TH.D09,力传感器的型号为BTC-LC 0050N.P01,对中设备的型号为BO70000S06。
图1示出了片剂的断裂强度测量,具体而言,在测量前和测量中为此目的采用了片剂(4)调整设备(6)。为此,在两个2-部分夹持设备的帮助下,将片剂(4)保持在施力装置(未示出)的上压板(1)和下压板(3)之间,一旦已经建立了需要容纳待测量片剂并将所述片剂居中设置所需的间隔(5)时,则在每种情况下将所述夹持设备用上压板和下压板牢固地固定(未示出)。可以通过在每种情况下将所述2-部分夹持设备在安装它的压力板上向内或向外水平移动,来建立所述间隔(5)。
被认定在特定载荷下能抵抗断裂的片剂,不仅仅包括那些没有破裂的片剂,也包括那些在力用作可能已经发生塑性变形的片剂。
根据本发明制备的制剂的断裂强度通过用于确定断裂强度的所述测量方法来确定,还测量了除了片剂以外的剂型。
下面将参考实施例描述本发明。这些解释仅仅通过实施例来给出,不是限制本发明的范围。
实施例
实施例1
每片剂 | 全批次 | |
盐酸曲马多 | 100.0mg | 1495.0g |
聚环氧乙烷MW7000000(来自Dow的Polyox WSR 303) | 167.8mg | 2508.6g |
羟丙基甲基纤维素(羟丙甲纤维素100000mPa) | 33.5mg | 500.8g |
丁基羟基甲苯(BHT) | 0.2mg | 3.0g |
总质量 | 300.5mg | 4507.4g |
将所述量的BHT溶解在乙醇(96%)中,从而得到7.7%(质量/质量)的乙醇溶液。该溶液首先和150g聚环氧乙烷在高速混合机中混合30分钟,然后,加入剩余量的聚环氧乙烷,继续搅拌30分钟。将组合物在40℃干燥12小时。
在自由下落式混合机中加入所有其它组分,并混合15分钟。将粉末混合物在模具之间分配,每个模具的直径为13mm,深度为6mm。采用具有套管的注射器,将混合物在每种情况下悬浮在0.5ml的96%乙醇中,然后在每种情况下与0.5ml蒸馏水合并。在24小时溶胀之后,将溶胀的组合物在40℃干燥24小时。
采用型号为EK0的偏心压床,将分配好的、干燥的部分各自压模形成片剂。制造片剂的工具的直径是10mm,曲率半径是8mm。
采用上述方法确定片剂的断裂强度。当施加500N力时,没有发生破裂。片剂不能用锤子粉碎,也不能用研钵和研杵粉碎。
根据Pharm.Eur.在具有冲钻(sinker)的桨式搅拌装置中,确定在体外活性成分从片剂的释放。释放介质温度是37℃,搅拌器的旋转速度是75min-1。所用释放介质是600ml的肠液,pH为6.8。在每种情况下在任何一次释放到溶解介质中的活性成分量通过光谱法确定。
时间 | 释放的活性成分量 |
30分 | 20% |
240分 | 43% |
480分 | 83% |
720分 | 90% |
实施例2
粉末混合物 | 全批次 | 每片剂 |
盐酸曲马多 | 100.1g | 100mg |
聚环氧乙烷MW5000000(来自Dow的Polyox WSR促凝剂) | 300.0g | 299.7mg |
羟丙基甲基纤维素(羟丙甲纤维素100000mPa) | 50.05g | 50.0mg |
丁基羟基甲苯(BHT) | 0.25g | 0.25mg |
泡沫羟丙基甲基纤维(羟丙甲纤维素100000mPa) | 0.250g | 0.25mg |
蒸馏水 | 49.8g |
首先如实施例1所述制备粉末混合物。
通过将所述量的羟丙甲纤维素溶解在蒸馏水中制备泡沫。然后,采用高性能均化器(IKA Ultraturrax25Basic)通过首先在水平1搅拌2分钟,然后在水平2用混合机/造粒机搅拌2分钟,最后在水平3搅拌3分钟,制备泡沫。在混合机(Kenwood Major Classic25Basic)中,将粉末混合物缓慢加入到泡沫中,并一直搅拌。
然后,将颗粒化的混合物在40℃干燥24小时,在通过孔隙为1mm的筛子(得自Frewitt,型号GLA-A-ORV)后,以450.2mg的重量将其压模成片剂。为此目的,采用了具有圆形的、制备片剂的工具的EKO型偏心压床,其中所述制备片剂的工具直径为10mm,曲率半径为8mm。将这些片剂在70℃干燥1小时。
采用上述方法确定片剂的断裂强度。当施加500N力时,没有发生破裂。片剂不能用锤子粉碎,也不能用研钵和研杵粉碎。
根据Pharm.Eur.在具有冲钻的桨式搅拌装置中,确定在体外活性成分从片剂的释放。释放介质温度是37℃,搅拌器的旋转速度是75min-1。所用释放介质是600ml的肠液,pH为6.8。在每种情况下在任何一次释放到溶解介质中的活性成分量通过光谱法确定。
时间 | 释放的活性成分量 |
30分 | 12% |
240分 | 47% |
480分 | 71% |
720分 | 84% |
Claims (9)
1.用于制备具有至少降低的滥用可能性的固态剂型的方法,特征在于
a)向含有至少一种具有滥用可能性的活性成分A和至少一种合成或天然聚合物C的制剂混合物中,加入针对所述聚合物C的溶剂,加入量是至少使得所述制剂混合物被均匀润湿的量,其中所述聚合物C为具有分子量为至少100万-1500万的高分子量的热塑性聚环氧乙烷,
c)将经均匀润湿的混合物干燥,和
d)经成形以获得所述剂型,
聚合物C的用量使得所述剂型具有至少500N的最低断裂强度。
2.权利要求1的方法,特征在于在加入溶剂之前,所述制剂混合物已经分散在液体分散剂中,所述聚合物组分C不溶于所述液体分散剂。
3.权利要求2的方法,特征在于在所述制剂组合物分散之前或者之后,在每种情况下它都已经被分成和单位所述剂型的质量相一致的亚部分。
4.权利要求2的方法,特征在于所述溶剂和所述分散剂互相混溶。
5.权利要求1的方法,特征在于所述溶剂作为泡沫引入到所述制剂混合物中。
6.权利要求5的方法,特征在于所述泡沫在泡沫稳定剂的辅助下得以稳定。
7.权利要求5或6的方法,特征在于用所述溶剂泡沫颗粒化的组合物被干燥。
8.权利要求7的方法,特征在于所述干燥的、颗粒化的组合物被分成亚部分,并成形以获得所述剂型,其中所述亚部分在每种情况下和单位所述剂型的质量相一致。
9.权利要求1的方法,特征在于所述溶剂以使得得到可成形糊的量加入到制剂混合物中。
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Cited By (7)
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US8309060B2 (en) | 2003-08-06 | 2012-11-13 | Grunenthal Gmbh | Abuse-proofed dosage form |
US8323889B2 (en) | 2004-07-01 | 2012-12-04 | Gruenenthal Gmbh | Process for the production of an abuse-proofed solid 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 |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
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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 |
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AU2010265213B2 (en) | 2009-06-24 | 2012-08-23 | Egalet Ltd. | Controlled release formulations |
EP2456427B1 (en) | 2009-07-22 | 2015-03-04 | Grünenthal GmbH | Hot-melt extruded controlled release dosage form |
AU2010275754B2 (en) | 2009-07-22 | 2014-05-15 | Grünenthal GmbH | Tamper-resistant dosage form for oxidation-sensitive opioids |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
WO2011079074A1 (en) * | 2009-12-24 | 2011-06-30 | Acura Phamaceuticals, Inc. | Pharmaceutical compositions for deterring misuse, abuse, and diversion |
WO2011095314A2 (en) | 2010-02-03 | 2011-08-11 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of an extruder |
WO2012028319A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
KR20130097201A (ko) | 2010-09-02 | 2013-09-02 | 그뤼넨탈 게엠베하 | 음이온성 중합체를 포함하는 내변조성 투여형 |
MX2013002293A (es) | 2010-09-02 | 2013-05-09 | Gruenenthal Gmbh | Forma de dosificacion resistente a alteracion que comprende un polimero anionico. |
WO2012085656A2 (en) | 2010-12-22 | 2012-06-28 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
KR20140075807A (ko) | 2010-12-23 | 2014-06-19 | 퍼듀 퍼머 엘피 | 탬퍼 저항성 고체 경구 투여 형태 |
EP2704889B1 (en) * | 2011-05-03 | 2016-05-25 | SHL Group AB | Mold assembly and method for manufacturing a syringe container |
BR112014002022A2 (pt) | 2011-07-29 | 2017-02-21 | Gruenenthal Gmbh | comprimido resistente à violação proporcionando liberação de fármaco imediata |
LT2736497T (lt) | 2011-07-29 | 2017-11-10 | Grünenthal GmbH | Sugadinimui atspari tabletė, pasižyminti greitu vaisto atpalaidavimu |
PE20141171A1 (es) | 2011-10-06 | 2014-09-21 | Gruenenthal Chemie | Forma de dosificacion farmaceutica oral resistente a alteracion comprendiendo agonista opioide y antagonista opioide |
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 |
EP2819657A1 (en) | 2012-02-28 | 2015-01-07 | Grünenthal GmbH | Tamper-resistant pharmaceutical dosage form comprising nonionic surfactant |
US20130225697A1 (en) | 2012-02-28 | 2013-08-29 | Grunenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
AU2013248351B2 (en) | 2012-04-18 | 2018-04-26 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
ES2650945T3 (es) | 2012-05-11 | 2018-01-23 | Grünenthal GmbH | Forma de dosificación farmacéutica termoconformada resistente a la manipulación que contiene zinc |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
MX362838B (es) | 2012-07-12 | 2019-02-19 | SpecGx LLC | Composiciones farmacéuticas de liberación prolongada para disuadir el abuso de opioides que comprenden un plastómero, un elastómero y un plastificante delicuescente. |
MX2015010041A (es) | 2013-02-05 | 2015-10-30 | Purdue Pharma Lp | Formulacion farmaceuticas resistentes a la alteracion. |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
ES2764445T3 (es) | 2013-03-15 | 2020-06-03 | Inspirion Delivery Sciences Llc | Productos farmacéuticos que comprenden un componente dependiente de pH y un agente de aumento del pH |
CA2907950A1 (en) | 2013-05-29 | 2014-12-04 | Grunenthal Gmbh | Tamper-resistant dosage form containing one or more particles |
JP6466417B2 (ja) | 2013-05-29 | 2019-02-06 | 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 | 二峰性放出プロファイルを有する改変防止(tamper−resistant)剤形 |
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 |
AU2014356581C1 (en) | 2013-11-26 | 2020-05-28 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
MX2016007848A (es) | 2013-12-16 | 2016-09-07 | Gruenenthal Gmbh | Forma de dosificacion resistente a alteraciones con perfil de liberacion bimodal fabricado mediante co-extrusion. |
CA2938699A1 (en) | 2014-02-05 | 2015-08-13 | Kashiv Pharma Llc | Abuse-resistant drug formulations with built-in overdose protection |
CN106572980A (zh) | 2014-05-12 | 2017-04-19 | 格吕伦塔尔有限公司 | 包含他喷他多的防篡改即释胶囊制剂 |
CN106456550A (zh) | 2014-05-26 | 2017-02-22 | 格吕伦塔尔有限公司 | 避免乙醇剂量倾泻的多颗粒 |
EP3253376A1 (en) | 2015-02-03 | 2017-12-13 | Grünenthal GmbH | Tamper-resistant dosage form comprising a polyethylene glycol graft copolymer |
CA2983640A1 (en) | 2015-04-24 | 2016-10-27 | Grunenthal Gmbh | Tamper-resistant fixed dose combination providing fast release of two drugs from different particles |
WO2016170094A1 (en) | 2015-04-24 | 2016-10-27 | Grünenthal GmbH | Tamper-resistant fixed dose combination providing fast release of two drugs from particles |
AU2016251854A1 (en) | 2015-04-24 | 2017-10-19 | Grunenthal Gmbh | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
JP2018513864A (ja) | 2015-04-24 | 2018-05-31 | 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 | 粒子及びマトリックスから2種の薬物の急速放出をもたらすタンパレジスタントな固定用量組合せ |
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 |
WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
CA3029869A1 (en) | 2016-07-06 | 2018-01-11 | Grunenthal Gmbh | Reinforced pharmaceutical dosage form |
CA3032598A1 (en) | 2016-08-01 | 2018-02-08 | Grunenthal Gmbh | Tamper resistant dosage form comprising an anionic polysaccharide |
AU2017310006A1 (en) | 2016-08-12 | 2019-01-31 | Grünenthal GmbH | Tamper resistant formulation of ephedrine and its derivatives |
CA2941315C (en) * | 2016-08-12 | 2018-03-06 | Api Labs Inc. | High thebaine poppy and methods of producing the same |
JP6131379B1 (ja) * | 2016-12-28 | 2017-05-17 | 森下仁丹株式会社 | 4,5−エポキシモルヒナン誘導体含有製剤 |
EP3438133A1 (en) | 2017-08-04 | 2019-02-06 | Basell Polyolefine GmbH | Polymerization process including discharging polyolefin particles from a gas-phase polymerization reactor |
CN111465390A (zh) | 2017-10-13 | 2020-07-28 | 格吕伦塔尔有限公司 | 调释防滥用剂型 |
EP3473246A1 (en) | 2017-10-19 | 2019-04-24 | Capsugel Belgium NV | Immediate release abuse deterrent formulations |
TW202002957A (zh) | 2018-02-09 | 2020-01-16 | 德商歌林達有限公司 | 包含轉化抑制劑之麻黃素及其衍生物之抗損壞調配物 |
EP3698776A1 (en) | 2019-02-19 | 2020-08-26 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
WO2021219577A1 (en) | 2020-04-27 | 2021-11-04 | Grünenthal GmbH | Dosage form comprising hot-melt extruded pellets containing eva copolymer and gliding agent |
WO2021219576A1 (en) | 2020-04-27 | 2021-11-04 | Grünenthal GmbH | Multiparticulate dosage form containing eva copolymer and additional excipient |
Family Cites Families (577)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2524855A (en) | 1950-10-10 | Process for the manufacture of | ||
CA722109A (en) | 1965-11-23 | W. Mock Henry | Extrusion of ethylene oxide polymers | |
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 |
US4215104A (en) | 1979-03-26 | 1980-07-29 | Mead Johnson & Company | Multi-fractionable tablet structure |
US4258027A (en) | 1979-03-26 | 1981-03-24 | 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 |
CH648754A5 (en) | 1979-08-16 | 1985-04-15 | Ciba Geigy Ag | Pharmaceutical slow release tablet |
US4353887A (en) | 1979-08-16 | 1982-10-12 | Ciba-Geigy Corporation | Divisible tablet having controlled and delayed release of the active substance |
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 |
US5082668A (en) * | 1983-05-11 | 1992-01-21 | Alza Corporation | Controlled-release system with constant pushing source |
US4612008A (en) | 1983-05-11 | 1986-09-16 | Alza Corporation | Osmotic device with dual thermodynamic activity |
US4783337A (en) | 1983-05-11 | 1988-11-08 | Alza Corporation | Osmotic system comprising plurality of members for dispensing drug |
US4765989A (en) | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
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 |
US4690814A (en) * | 1985-06-17 | 1987-09-01 | The Standard Oil Company | Process for the production of hydrogen |
AU583639B2 (en) | 1985-06-24 | 1989-05-04 | Pitman-Moore Australia Limited | Ingestible capsules |
DE3665262D1 (en) | 1985-06-28 | 1989-10-05 | Carrington Lab 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 |
EP0226061B1 (en) | 1985-12-17 | 1994-02-16 | United States Surgical Corporation | High molecular weight bioresorbable polymers and implantation devices thereof |
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 |
BR8701434A (pt) | 1986-03-31 | 1987-12-29 | Union Carbide Corp | Processo para a producao de uma dispersao,processo para a producao de um catalisador;processo para a producao de oxidos de polialquileno;e processo para a producao de polimeros solidos de oxido de alquileno em condicoes de pressao relativamente baixas |
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 |
JP2962731B2 (ja) | 1986-11-10 | 1999-10-12 | バイオピュアー、コーポレーション | 超純枠半合成代用血液 |
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 |
EP0277092B1 (de) * | 1987-01-14 | 1992-01-29 | Ciba-Geigy Ag | Therapeutisches System für schwerlösliche 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 |
KR900700071A (ko) | 1987-12-17 | 1990-08-11 | 로버어트 에이 아미테이지 | 트리-스코어(Tri-scored) 약 정제 |
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 |
US5139790A (en) | 1988-10-14 | 1992-08-18 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
US5004601A (en) | 1988-10-14 | 1991-04-02 | 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 |
SU1759445A1 (ru) | 1990-06-15 | 1992-09-07 | Ленинградский Технологический Институт Им.Ленсовета | Способ получени капсулированных гидрофобных веществ |
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 |
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 |
DK0662320T3 (da) | 1991-08-30 | 2001-09-24 | Showa Pharm Chem Ind | Tør gelsammensætning |
WO1993006821A1 (en) | 1991-10-04 | 1993-04-15 | Yoshitomi Pharmaceutical Industries, Ltd. | Sustained-release tablet |
AU2670292A (en) | 1991-10-04 | 1993-05-03 | Olin Corporation | Fungicide tablet |
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 |
ES2090714T3 (es) | 1991-12-05 | 1996-10-16 | Mallinckrodt Veterinary Inc | Matriz de vidrio de carbohidrato para la liberacion prolongada de un agente terapeutico. |
DK0617612T3 (da) | 1991-12-18 | 1998-04-14 | Warner Lambert Co | Fremgangsmåde til fremstilling af en fast dispersion |
US5200194A (en) | 1991-12-18 | 1993-04-06 | Alza Corporation | Oral osmotic device |
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 |
ES2086229T3 (es) | 1992-05-22 | 1996-06-16 | Goedecke Ag | Procedimiento para la obtencion de preparados medicinales de accion retardada. |
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 |
ATE219933T1 (de) * | 1992-09-18 | 2002-07-15 | Yamanouchi Pharma Co Ltd | Hydrogelzubereitung mit verzögerter freisetzung |
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 |
DE69326163T2 (de) | 1992-12-23 | 2000-05-04 | Saitec Srl | Verfahren zur herstellung von arzneiformen und kontrollierte freigabe und die soerhaltenen arzneiformen |
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 |
NZ260408A (en) | 1993-05-10 | 1996-05-28 | Euro Celtique Sa | Controlled release preparation 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 |
DK0654263T3 (da) | 1993-11-23 | 2002-04-29 | Euro Celtique Sa | Fremgangsmåde til fremstilling af et præparat med langvarig frigivelse |
AU1266895A (en) | 1993-12-20 | 1995-07-10 | Procter & Gamble Company, The | 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 |
PT744941E (pt) | 1994-02-16 | 2003-10-31 | Abbott Lab | Processo para preparar formulacoes farmaceuticas de particulas finas |
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 |
CZ292360B6 (cs) | 1994-05-06 | 2003-09-17 | Pfizer Inc. | Dávkovací forma s řízeným uvolňováním obsahující azithromycin a způsob její výroby |
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. |
JP3285452B2 (ja) | 1994-08-11 | 2002-05-27 | サンスター株式会社 | 歯磨組成物 |
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 |
US5908850A (en) | 1995-12-04 | 1999-06-01 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
US6355656B1 (en) * | 1995-12-04 | 2002-03-12 | Celgene Corporation | Phenidate drug formulations having diminished abuse potential |
DE19547766A1 (de) | 1995-12-20 | 1997-06-26 | Gruenenthal Gmbh | 1-Phenyl-2-dimethylaminomethyl-cyclohexan-1-ol-verbindungen als pharmazeutische Wirkstoffe |
AU2059297A (en) * | 1996-03-12 | 1997-10-01 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US6461644B1 (en) * | 1996-03-25 | 2002-10-08 | Richard R. Jackson | Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods |
US6096339A (en) | 1997-04-04 | 2000-08-01 | Alza Corporation | Dosage form, process of making and using same |
US20020114838A1 (en) * | 1996-04-05 | 2002-08-22 | Ayer Atul D. | Uniform drug delivery therapy |
CZ297941B6 (cs) | 1996-04-05 | 2007-05-02 | Takeda Pharmaceutical Company Limited | Farmaceutický prípravek obsahující slouceninu s antagonickým úcinkem k angiotensinu II |
US5817343A (en) | 1996-05-14 | 1998-10-06 | Alkermes, Inc. | Method for fabricating polymer-based controlled-release devices |
EP0952824B1 (en) | 1996-06-06 | 2004-09-29 | Bifodan A/S | Enteric coating, comprising alginic acid, for an oral preparation |
DK1014941T3 (da) | 1996-06-26 | 2009-07-27 | Univ Texas | Ekstruderbar farmaceutisk hot-melt-formulering |
US6093420A (en) | 1996-07-08 | 2000-07-25 | 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. |
DK0950689T3 (da) | 1996-11-05 | 2005-02-07 | Novamont Spa | Biologisk nedbrydelige polymersammensætninger omfattende stivelse og en termoplastisk polymer |
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 |
ES2248908T7 (es) | 1997-06-06 | 2014-11-24 | Depomed, Inc. | Formas de dosificación de fármacos por vía oral y retención gástrica para liberación continuada de fármacos altamente solubles |
US6635280B2 (en) | 1997-06-06 | 2003-10-21 | Depomed, Inc. | Extending the duration of drug release within the stomach during the fed mode |
AU8293498A (en) | 1997-07-02 | 1999-01-25 | Euro-Celtique S.A. | Stabilized sustained release tramadol formulations |
IE970588A1 (en) | 1997-08-01 | 2000-08-23 | Elan Corp Plc | Controlled release pharmaceutical compositions containing tiagabine |
EP1027305A1 (en) | 1997-09-10 | 2000-08-16 | AlliedSignal Inc. | 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 |
CA2310847C (en) * | 1997-11-28 | 2007-03-13 | Knoll Aktiengesellschaft | Method for producing solvent-free non-crystalline biologically active substances |
DE19753534A1 (de) | 1997-12-03 | 1999-06-10 | Bayer Ag | Schnell kristallisierende, biologisch abbaubare Polyesteramide |
CA2312479A1 (en) * | 1997-12-03 | 1999-06-10 | Bayer Aktiengesellschaft | Polyether ester amides |
JP2001526229A (ja) | 1997-12-22 | 2001-12-18 | ユーロ−セルティーク,エス.エイ. | オピオイド投薬剤形の乱用を防止する方法 |
US6375957B1 (en) * | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
DE19800698A1 (de) | 1998-01-10 | 1999-07-15 | Bayer Ag | Biologisch abbaubare Polyesteramide mit blockartig aufgebauten Polyester- und Polyamid-Segmenten |
DE19800689C1 (de) | 1998-01-10 | 1999-07-15 | Deloro Stellite Gmbh | Formkörper aus einem verschleißfesten Werkstoff |
US6251430B1 (en) | 1998-02-04 | 2001-06-26 | Guohua Zhang | Water insoluble polymer based sustained release formulation |
CA2319353A1 (en) | 1998-02-06 | 1999-08-12 | Surendra Kumar Verma | 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 |
US20010055613A1 (en) | 1998-10-21 | 2001-12-27 | Beth A. Burnside | 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 |
AU3469100A (en) | 1999-01-05 | 2000-07-24 | 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 |
US20030118641A1 (en) | 2000-07-27 | 2003-06-26 | Roxane Laboratories, Inc. | Abuse-resistant sustained-release opioid formulation |
EP1204406A2 (en) | 1999-07-29 | 2002-05-15 | Roxane Laboratories, Inc. | Opioid sustained-released formulation |
US6562375B1 (en) | 1999-08-04 | 2003-05-13 | Yamanouchi Pharmaceuticals, Co., Ltd. | Stable pharmaceutical composition for oral use |
ATE324909T1 (de) | 1999-08-04 | 2006-06-15 | Astellas Pharma Inc | Stabile medizinische zusammensetzungen zur oralen verabreichung unter verwendung von eisenoxiden |
KR100345214B1 (ko) | 1999-08-17 | 2002-07-25 | 이강춘 | 생체적합성 고분자가 수식된 펩타이드의 비점막 전달 |
US6198226B1 (en) * | 1999-08-18 | 2001-03-06 | Astronics Corporation | Low-noise drive circuit for electroluminescent lamp, and electroluminescent lamp assembly comprising same |
DE19940944B4 (de) * | 1999-08-31 | 2006-10-12 | Grünenthal GmbH | Retardierte, orale, pharmazeutische Darreichungsformen |
CA2388560A1 (en) | 1999-08-31 | 2001-03-08 | Grunenthal Gmbh | Sustained-release form of administration containing tramadol saccharinate |
DE19940740A1 (de) * | 1999-08-31 | 2001-03-01 | Gruenenthal Gmbh | Pharmazeutische Salze |
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 |
OA12215A (en) | 2000-02-08 | 2006-05-09 | Euro Celtique Sa | Tamper-resistant oral opioid agonist formulations. |
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 |
JP5324732B2 (ja) * | 2000-05-23 | 2013-10-23 | スネス ファーマシューティカルズ インコーポレイテッド | Nrg−2核酸分子、ポリペプチド、ならびに診断および治療法 |
JP4696210B2 (ja) * | 2000-06-07 | 2011-06-08 | トーアエイヨー株式会社 | イソソルビド‐5‐モノニトレートを有効成分とする徐放性錠剤及びその製造方法 |
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 |
EP1322189A1 (en) | 2000-09-27 | 2003-07-02 | 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 |
CN101317825A (zh) | 2000-10-30 | 2008-12-10 | 欧罗赛铁克股份有限公司 | 控释氢可酮制剂 |
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 |
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 |
EP1241110A1 (en) | 2001-03-16 | 2002-09-18 | Pfizer Products Inc. | Dispensing unit for oxygen-sensitive drugs |
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 |
ATE328028T1 (de) | 2001-05-01 | 2006-06-15 | Union Carbide Chem Plastic | Pharmazeutische zusammensetzung enthaltend polyalkylenoxide mit verringerten mengen an ameisensäure und ameisensäurederivaten |
UA81224C2 (uk) | 2001-05-02 | 2007-12-25 | Euro Celtic S A | Дозована форма оксикодону та її застосування |
US6852891B2 (en) | 2001-05-08 | 2005-02-08 | The Johns Hopkins University | Method of inhibiting methaphetamine synthesis |
EP1389092B1 (en) | 2001-05-11 | 2006-11-15 | Endo Pharmaceuticals Inc. | Abuse-resistant opioid dosage form |
ES2361148T3 (es) | 2001-05-11 | 2011-06-14 | Endo Pharmaceuticals Inc. | Forma de dosificación de opioides de liberación controlada resistente al abuso. |
US6623754B2 (en) | 2001-05-21 | 2003-09-23 | Noveon Ip Holdings Corp. | Dosage form of N-acetyl cysteine |
AU2002339378A1 (en) | 2001-05-22 | 2002-12-03 | Euro-Celtique | Compartmentalized dosage form |
US20030064122A1 (en) | 2001-05-23 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse resistant pharmaceutical composition containing capsaicin |
WO2003002100A1 (en) | 2001-06-26 | 2003-01-09 | 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 |
US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
KR20030048026A (ko) | 2001-07-06 | 2003-06-18 | 펜웨스트 파머슈티칼즈 컴파니 | 옥시모르폰의 서방형 제제 |
WO2003004031A1 (en) | 2001-07-06 | 2003-01-16 | Endo Pharmaceuticals, Inc. | Parenteral 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 |
DE60230632D1 (de) * | 2001-07-18 | 2009-02-12 | Euro Celtique Sa | Pharmazeutische kombinationen von oxycodon und naloxon |
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 |
US7144587B2 (en) * | 2001-08-06 | 2006-12-05 | Euro-Celtique S.A. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
AU2002324624A1 (en) | 2001-08-06 | 2003-02-24 | Euro-Celtique S.A. | Sequestered antagonist formulations |
US7141250B2 (en) * | 2001-08-06 | 2006-11-28 | Euro-Celtique S.A. | Pharmaceutical formulation containing bittering agent |
CA2455420A1 (en) | 2001-08-06 | 2003-02-20 | Euro-Celtique, S.A. | Compositions and methods to prevent abuse of opioids |
US7842307B2 (en) * | 2001-08-06 | 2010-11-30 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent |
US7332182B2 (en) * | 2001-08-06 | 2008-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and 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 |
AU2002319774B2 (en) | 2001-08-06 | 2005-04-21 | 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 |
US20030044458A1 (en) * | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
JP3474870B2 (ja) * | 2001-08-08 | 2003-12-08 | 菱計装株式会社 | 昇降機 |
US20030049272A1 (en) | 2001-08-30 | 2003-03-13 | Yatindra Joshi | Pharmaceutical composition which produces irritation |
US6691698B2 (en) | 2001-09-14 | 2004-02-17 | Fmc Technologies Inc. | Cooking oven having curved heat exchanger |
US20030059467A1 (en) | 2001-09-14 | 2003-03-27 | Pawan Seth | Pharmaceutical composition comprising doxasozin |
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 |
DE60224293T2 (de) | 2001-09-21 | 2008-12-11 | Egalet A/S | Feste dispersionen mit kontrollierter freisetzung von carvedilol |
WO2003024430A1 (en) | 2001-09-21 | 2003-03-27 | Egalet A/S | Morphine polymer release system |
AU2002342755A1 (en) | 2001-09-26 | 2003-04-14 | Klaus-Jurgen Steffens | Method and device for producing granulates that comprise at least one pharmaceutical active substance |
EP1429730A4 (en) | 2001-09-26 | 2010-06-16 | Penwest Pharmaceuticals Compan | OPIOID FORMULATIONS WITH REDUCED ABUSE POTENTIAL |
US6837696B2 (en) | 2001-09-28 | 2005-01-04 | Mcneil-Ppc, Inc. | Apparatus for manufacturing dosage forms |
BR0212950A (pt) | 2001-09-28 | 2004-10-26 | Mcneil Ppc Inc | Formas de dosagens compósitas tendo uma porção inserida |
EP1434837B1 (en) | 2001-10-09 | 2006-03-29 | The Procter & Gamble Company | Aqueous compositions for treating a surface |
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 |
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 |
US20030104052A1 (en) | 2001-10-25 | 2003-06-05 | Bret Berner | 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 |
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 |
CA2464653C (en) | 2001-10-29 | 2011-10-18 | Therics, Inc. | 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 |
JP2005508372A (ja) | 2001-11-02 | 2005-03-31 | エラン コーポレーシヨン ピーエルシー | 薬剤組成物 |
WO2003049689A2 (en) | 2001-12-06 | 2003-06-19 | Nutraceutix, Inc. | 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 |
EP2425823A1 (en) | 2002-04-05 | 2012-03-07 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
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 |
US20040010000A1 (en) | 2002-04-29 | 2004-01-15 | Ayer Atul D. | Methods and dosage forms for controlled delivery of oxycodone |
US20050106249A1 (en) | 2002-04-29 | 2005-05-19 | Stephen Hwang | Once-a-day, oral, controlled-release, oxycodone dosage forms |
US20060073102A1 (en) | 2002-05-13 | 2006-04-06 | Huaihung Kao D | Abuse-resistant opioid solid dosage form |
JP2005528423A (ja) | 2002-05-31 | 2005-09-22 | アルザ・コーポレーシヨン | オキシコドンの変動性投薬用量の浸透圧的送達のための剤形および組成物 |
DE10250083A1 (de) | 2002-06-17 | 2003-12-24 | Gruenenthal Gmbh | Gegen Missbrauch gesicherte Darreichungsform |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
WO2004004693A1 (en) | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | 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 |
AR040680A1 (es) | 2002-07-25 | 2005-04-13 | Pharmacia Corp | Composicion de tabletas de liberacion sostenida |
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 |
CA2496110A1 (en) | 2002-08-21 | 2004-03-04 | Phoqus Pharmaceuticals Limited | Use of an aqueous solution of citric acid and a water-soluble sugar like lactitol as granulation liquid in the manufacture of tablets |
US20040052844A1 (en) * | 2002-09-16 | 2004-03-18 | Fang-Hsiung Hsiao | Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins |
DE60324609D1 (de) | 2002-09-17 | 2008-12-18 | Wyeth Corp | GRANULIERTE FORMULIERUNG DES RAPAMYCINESTERS CCl-779 |
US7815924B2 (en) | 2002-09-20 | 2010-10-19 | Fmc Corporation | Cosmetic composition containing microcrystalline cellulose |
EP1555022B1 (en) | 2002-09-21 | 2008-02-20 | Shuyi Zhang | Sustained release formulation of acetaminophen and tramadol |
WO2004026262A2 (en) * | 2002-09-23 | 2004-04-01 | 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 |
DE10250087A1 (de) | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
US20050191244A1 (en) | 2002-10-25 | 2005-09-01 | Gruenenthal Gmbh | Abuse-resistant pharmaceutical dosage form |
DE10250088A1 (de) | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
RU2328275C2 (ru) | 2002-10-25 | 2008-07-10 | Лабофарм Инк. | Композиции трамадола пролонгированного высвобождения с 24-часовым действием |
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 |
MXPA05009757A (es) | 2003-03-13 | 2005-12-05 | Controlled Chemicals Inc | Conjugados de oxicodona con menor potencial de abuso y duracion de accion extendida. |
DE602004031096D1 (de) | 2003-03-26 | 2011-03-03 | Egalet As | Morphin-system mit kontrollierter freisetzung |
DE602004014747D1 (de) | 2003-03-26 | 2008-08-14 | Egalet As | Matrixzubereitungen für die kontrollierte darreichung von arzneistoffen |
TWI347201B (en) | 2003-04-21 | 2011-08-21 | Euro Celtique Sa | Pharmaceutical products,uses thereof and methods for preparing the same |
WO2004093819A2 (en) | 2003-04-21 | 2004-11-04 | Euro-Celtique, S.A. | Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same |
MY141815A (en) | 2003-04-30 | 2010-06-30 | Purdue Pharma Lp | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer |
JP2004354981A (ja) | 2003-05-06 | 2004-12-16 | Fuji Photo Film Co Ltd | 画像パターン記録方法 |
US8906413B2 (en) | 2003-05-12 | 2014-12-09 | Supernus Pharmaceuticals, Inc. | Drug formulations having reduced abuse potential |
CN1473562A (zh) | 2003-06-27 | 2004-02-11 | 辉 刘 | 儿用口腔速溶、速崩冻干片及其制备方法 |
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 |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
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 |
BRPI0413361B8 (pt) | 2003-08-06 | 2021-05-25 | Gruenenthal Gmbh | comprimido seguro contra abuso termo-moldado por extrusão sem descoramento |
RU2339365C2 (ru) | 2003-08-06 | 2008-11-27 | Грюненталь Гмбх | Защищенная от применения не по назначению лекарственная форма |
DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
DE102004032051A1 (de) | 2004-07-01 | 2006-01-19 | 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 |
DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
US20050063214A1 (en) * | 2003-09-22 | 2005-03-24 | Daisaburo Takashima | Semiconductor integrated circuit device |
CA2539027C (en) | 2003-09-25 | 2010-02-23 | Euro-Celtique S.A. | Pharmaceutical combinations of hydrocodone and naltrexone |
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 |
KR20060108690A (ko) | 2003-10-29 | 2006-10-18 | 알자 코포레이션 | 1일 1회 경구용의 서방성 옥시코돈 제형 |
US7201920B2 (en) | 2003-11-26 | 2007-04-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of opioid containing dosage forms |
BRPI0417348A (pt) | 2003-12-04 | 2007-03-13 | Pfizer Prod Inc | processo de gelatinização por spray com utilização de uma extrusora para preparação de composições de droga cristalina multiparticulada contendo preferencialmente um poloxámero e um glicerìdeo |
ES2281851T3 (es) | 2003-12-09 | 2007-10-01 | Euro-Celtique S.A. | Forma de dosis co-extruida resistente a la manipulacion conteniendo un agente activo y un agente adverso y proceso para preparar el mismo. |
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 |
MXPA06007509A (es) | 2003-12-29 | 2007-10-18 | Johnson & Johnson | Composiciones de farmaco y formas de dosis novedosas. |
US20070196396A1 (en) | 2004-02-11 | 2007-08-23 | 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 |
US20080233178A1 (en) | 2004-02-23 | 2008-09-25 | Euro-Celtique S.A. | Abuse Resistant Opioid Transdermal Delivery Device Containing Opioid Antagonist Microspheres |
TWI483944B (zh) * | 2004-03-30 | 2015-05-11 | Euro Celtique Sa | 含有小於25ppm14-羥可待因酮之羥可酮鹽酸鹽組成物、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 |
TWI428271B (zh) * | 2004-06-09 | 2014-03-01 | Smithkline Beecham Corp | 生產藥物之裝置及方法 |
EP1612203B1 (en) | 2004-06-28 | 2007-08-01 | Grünenthal GmbH | Crystalline forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride |
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 |
CA2572491A1 (en) | 2004-07-01 | 2006-01-12 | Gruenenthal Gmbh | Oral dosage form safeguarded against abuse |
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 |
AR049839A1 (es) | 2004-07-01 | 2006-09-06 | Gruenenthal Gmbh | Procedimiento para la produccion deuna forma farmaceutica solida, protegida frente al abuso |
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. |
EP1771152B1 (en) | 2004-07-27 | 2008-05-28 | Unilever Plc | Hair care compositions |
GB2418854B (en) | 2004-08-31 | 2009-12-23 | Euro Celtique Sa | Multiparticulates |
US20060068009A1 (en) | 2004-09-30 | 2006-03-30 | Scolr Pharma, Inc. | Modified release ibuprofen dosage form |
US20070077297A1 (en) | 2004-09-30 | 2007-04-05 | 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 |
US20070231268A1 (en) | 2004-11-24 | 2007-10-04 | 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 |
US20060177380A1 (en) | 2004-11-24 | 2006-08-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of orally administered pharmaceutical products |
CA2594713A1 (en) | 2005-01-26 | 2006-08-03 | Taiho Pharmaceutical Co., Ltd. | Anticancer drug containing .alpha.,.alpha.,.alpha.-trifluorothymidine and thymidine phosphorylase inhibitor |
JP5704789B2 (ja) | 2005-01-28 | 2015-04-22 | ユーロ−セルティーク エス.エイ. | 耐アルコール性剤形 |
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 |
KR20070104447A (ko) | 2005-02-10 | 2007-10-25 | 라이프사이클 파마 에이/에스 | 페노피브레이트 및 HMG-CoA 리덕타제 억제제의 고정용량 배합물을 포함하는 안정한 약학 조성물 |
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 |
PL2112153T3 (pl) | 2005-03-04 | 2011-04-29 | Euro Celtique Sa | Sposób zmniejszania ilości alfa, beta-nienasyconych ketonów w kompozycjach opioidowych |
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 |
JP5256425B2 (ja) | 2005-04-08 | 2013-08-07 | リングアル コンセグナ ピーティーワイ エルティーディー | 口腔送達システム |
EP1881819A1 (en) | 2005-05-10 | 2008-01-30 | Novartis AG | Extrusion process for making compositions with poorly compressible therapeutic compounds |
CN101188999B (zh) | 2005-06-03 | 2012-07-18 | 尹格莱特股份有限公司 | 用于递送分散在分散介质中的活性物质的药物传递系统 |
WO2007005716A2 (en) | 2005-06-30 | 2007-01-11 | Cinergen, Llc | Methods of treatment and compositions for use thereof |
EP1917000A2 (en) | 2005-07-07 | 2008-05-07 | Farnam Companies, Inc. | Sustained release pharmaceutical compositions for highly water soluble drugs |
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 |
EP1909769A2 (en) | 2005-08-01 | 2008-04-16 | Alpharma, Inc. | Alcohol resistant pharmaceutical formulations |
JP2009503071A (ja) | 2005-08-03 | 2009-01-29 | イーストマン ケミカル カンパニー | トコフェリルポリエチレングリコールスクシネート粉末及びその製造方法 |
US20070048373A1 (en) | 2005-08-30 | 2007-03-01 | Cima Labs Inc. | Dried milled granulate and methods |
ATE513842T1 (de) | 2005-10-14 | 2011-07-15 | Kitasato Inst | Neue dihydropseudoerythromycinderivate |
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 |
US9125833B2 (en) | 2005-11-02 | 2015-09-08 | Relmada Therapeutics, Inc. | Multimodal abuse resistant and extended release opioid formulations |
US8329744B2 (en) | 2005-11-02 | 2012-12-11 | Relmada Therapeutics, Inc. | Methods of preventing the serotonin syndrome and compositions for use thereof |
FR2892937B1 (fr) | 2005-11-10 | 2013-04-05 | Flamel Tech Sa | Forme pharmaceutique orale microparticulaire anti-mesusage |
US8652529B2 (en) | 2005-11-10 | 2014-02-18 | Flamel Technologies | Anti-misuse microparticulate oral pharmaceutical form |
DE102005058569B4 (de) | 2005-12-08 | 2010-07-15 | Lts Lohmann Therapie-Systeme Ag | Schaumwafer mit Polyvinylalkohol-Polyethylenglycol-Pfropfcopolymer |
US20090317355A1 (en) | 2006-01-21 | 2009-12-24 | Abbott Gmbh & Co. Kg, | Abuse resistant melt extruded formulation having reduced alcohol interaction |
US20100172989A1 (en) | 2006-01-21 | 2010-07-08 | Abbott Laboratories | Abuse resistant melt extruded formulation having reduced alcohol interaction |
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 |
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 |
FR2898056B1 (fr) | 2006-03-01 | 2012-01-20 | Ethypharm Sa | Comprimes resistant a l'ecrasement destines a eviter le detournement illicite |
CA2644095A1 (en) | 2006-03-02 | 2007-09-13 | Mallinckrodt Inc. | Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds |
WO2007103286A2 (en) | 2006-03-02 | 2007-09-13 | Spherics, Inc. | Rate-controlled bioadhesive oral dosage formulations |
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 |
US20070224637A1 (en) | 2006-03-24 | 2007-09-27 | Mcauliffe Joseph C | Oxidative protection of lipid layer biosensors |
NZ572207A (en) | 2006-03-24 | 2012-02-24 | Auxilium Int 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 |
EP2526932B1 (en) | 2006-06-19 | 2017-06-07 | Alpharma Pharmaceuticals LLC | Pharmaceutical composition |
CN101091721A (zh) | 2006-06-22 | 2007-12-26 | 孙明 | 阿胶新剂型的制备方法 |
WO2008008120A1 (en) | 2006-07-14 | 2008-01-17 | 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 |
EP2049087A2 (en) * | 2006-07-21 | 2009-04-22 | 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 |
JP5422388B2 (ja) | 2006-10-10 | 2014-02-19 | ペンウェスト ファーマシューティカルズ カンパニー | ロバスト性持続放出製剤 |
US20080085304A1 (en) | 2006-10-10 | 2008-04-10 | Penwest Pharmaceuticals Co. | Robust sustained release formulations |
GB0624880D0 (en) | 2006-12-14 | 2007-01-24 | Johnson Matthey Plc | Improved method for making analgesics |
DE102006062120A1 (de) | 2006-12-22 | 2008-06-26 | Grünenthal GmbH | Pharmazeutische Zusammensetzung zur Aknebehandlung |
CA2673511A1 (en) | 2006-12-22 | 2008-07-03 | Combinatorx, Incorporated | Pharmaceutical compositions for treatment of parkinson's disease and related disorders |
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 |
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 |
EP2061587A1 (en) | 2007-04-26 | 2009-05-27 | Sigmoid Pharma Limited | Manufacture of multiple minicapsules |
WO2008142627A2 (en) | 2007-05-17 | 2008-11-27 | 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 |
AU2008258596B2 (en) | 2007-06-04 | 2013-02-14 | Egalet Ltd | Controlled release pharmaceutical compositions for prolonged effect |
US20100035886A1 (en) | 2007-06-21 | 2010-02-11 | Veroscience, Llc | Parenteral formulations of dopamine agonists |
JP2010532358A (ja) | 2007-07-01 | 2010-10-07 | ピーター ハバウシ,ジョセフ | 咀嚼可能外層を有する配合剤 |
RU2477995C2 (ru) | 2007-07-20 | 2013-03-27 | Эбботт Гмбх Унд Ко.Кг | Составы неопиоидных и ограниченных опиоидных аналгетиков |
EP2200591A2 (en) | 2007-09-11 | 2010-06-30 | 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 |
PT2596784T (pt) | 2007-11-23 | 2017-03-29 | Gruenenthal Gmbh | Composições de tapentadol |
WO2009088414A2 (en) | 2007-12-06 | 2009-07-16 | Durect Corporation | Oral pharmaceutical dosage forms |
CA2707282A1 (en) | 2007-12-12 | 2009-06-18 | Basf Se | Salts of active ingredients with polymeric counterions |
AU2008338207A1 (en) | 2007-12-17 | 2009-06-25 | Labopharm (Barbados) Limited | Misuse preventative, controlled release formulation |
BRPI0906467C1 (pt) | 2008-01-25 | 2021-05-25 | Gruenenthal Gmbh | forma de dosagem farmacêutica com formato exterior modificado resistente à ruptura e com liberação controlada |
KR100970665B1 (ko) | 2008-02-04 | 2010-07-15 | 삼일제약주식회사 | 알푸조신 또는 그의 염을 함유하는 서방성 정제 |
BRPI0909030A2 (pt) | 2008-03-05 | 2018-03-13 | Panacea Biotec Ltd | composições farmacêuticas de liberação modificada compreendendo micofenolato e processos para as mesmas. |
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 |
LT2273983T (lt) | 2008-05-09 | 2016-10-25 | Grünenthal GmbH | Tarpinės miltelių kompozicijos gamybos būdas ir galutinė kieta dozavimo forma naudojant purškalo kietinimo stadija |
ES2393949T3 (es) * | 2008-07-03 | 2013-01-02 | Novartis Ag | Proceso de granulación en estado fundido |
JP2010062141A (ja) * | 2008-08-04 | 2010-03-18 | Komatsu Ltd | 極端紫外光源装置 |
CN102271661A (zh) | 2008-08-20 | 2011-12-07 | 德克萨斯州立大学董事会 | 缓释多颗粒的热熔挤出 |
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 |
KR20110119845A (ko) * | 2008-10-27 | 2011-11-02 | 알자 코퍼레이션 | 지속 방출형 경구용 아세트아미노펜/트라마돌 제형 |
CA2743639A1 (en) | 2008-11-14 | 2010-05-20 | Patheon 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 |
CA2746888C (en) | 2008-12-16 | 2015-05-12 | Labopharm (Barbados) Limited | Misuse preventative, controlled release formulation |
US20100203129A1 (en) | 2009-01-26 | 2010-08-12 | Egalet A/S | Controlled release formulations with continuous efficacy |
ES2607209T3 (es) | 2009-02-06 | 2017-03-29 | Egalet Ltd. | Composiciones farmacéuticas resistentes al abuso |
CN102355893A (zh) | 2009-03-18 | 2012-02-15 | 赢创罗姆有限公司 | 采用含有中性乙烯基聚合物和赋形剂的包衣的具有耐乙醇影响的控释药物组合物 |
EP2246063A1 (en) | 2009-04-29 | 2010-11-03 | Ipsen Pharma S.A.S. | Sustained release formulations comprising GnRH analogues |
GB0909680D0 (en) | 2009-06-05 | 2009-07-22 | Euro Celtique Sa | Dosage form |
AU2010265213B2 (en) | 2009-06-24 | 2012-08-23 | Egalet Ltd. | Controlled release formulations |
WO2011008298A2 (en) | 2009-07-16 | 2011-01-20 | Nectid, Inc. | Novel axomadol dosage forms |
AU2010275754B2 (en) | 2009-07-22 | 2014-05-15 | Grünenthal GmbH | Tamper-resistant dosage form for oxidation-sensitive opioids |
EP2456427B1 (en) * | 2009-07-22 | 2015-03-04 | Grünenthal GmbH | Hot-melt extruded controlled release dosage form |
ES2569925T3 (es) | 2009-09-30 | 2016-05-13 | Acura Pharmaceuticals, Inc. | Métodos y composiciones de disuasión del abuso |
US9044758B2 (en) | 2009-11-13 | 2015-06-02 | Moriroku Chemicals Company, Ltd. | Method for producing fine powder and the fine powder produced by the same |
WO2011068722A1 (en) | 2009-12-01 | 2011-06-09 | Noven Pharmaceuticals, Inc. | Transdermal testosterone device and delivery |
WO2011095314A2 (en) | 2010-02-03 | 2011-08-11 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of an extruder |
GB201003731D0 (en) | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Immediate/delayed drug delivery |
HUE042593T2 (hu) | 2010-03-09 | 2019-07-29 | Alkermes Pharma Ireland Ltd | Alkoholnak ellenálló enterális gyógyszerkészítmények |
ES2592277T3 (es) | 2010-04-02 | 2016-11-29 | Buzzz Pharmaceuticals Limited | Formulaciones transdérmicas disuasorias del abuso de agonistas y agonistas-antagonistas opiáceos |
WO2011124953A2 (en) | 2010-04-07 | 2011-10-13 | Lupin Limited | Controlled release pharmaceutical compositions of tapentadol |
GB201006200D0 (en) | 2010-04-14 | 2010-06-02 | Ayanda As | Composition |
PL2560624T3 (pl) | 2010-04-23 | 2019-01-31 | Kempharm, Inc. | Formulacja terapeutyczna do zmniejszania skutków ubocznych leku |
FR2959935B1 (fr) | 2010-05-14 | 2013-02-08 | Ethypharm Sa | Forme pharmaceutique orale alcoolo-resistante |
FR2960775A1 (fr) | 2010-06-07 | 2011-12-09 | Ethypharm Sa | Microgranules resistants au detournement |
KR20130097201A (ko) * | 2010-09-02 | 2013-09-02 | 그뤼넨탈 게엠베하 | 음이온성 중합체를 포함하는 내변조성 투여형 |
WO2012028319A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
MX2013002293A (es) | 2010-09-02 | 2013-05-09 | Gruenenthal Gmbh | Forma de dosificacion resistente a alteracion que comprende un polimero anionico. |
WO2012061779A1 (en) | 2010-11-04 | 2012-05-10 | Abbott Gmbh & Co. Kg | 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 |
KR20140075807A (ko) | 2010-12-23 | 2014-06-19 | 퍼듀 퍼머 엘피 | 탬퍼 저항성 고체 경구 투여 형태 |
MX2013009492A (es) | 2011-02-17 | 2014-07-30 | Qrxpharma Ltd | Tecnologia para prevenir el abuso de formas de dosificacion solidas. |
SI2680832T1 (sl) | 2011-03-04 | 2019-11-29 | Gruenenthal Gmbh | Vodna farmacevtska formulacija tapentadola za peroralno dovajanje |
RS56523B1 (sr) | 2011-04-29 | 2018-02-28 | Gruenenthal Gmbh | Tapentadol za sprečavanje i lečenje depresije i 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 |
DK2714015T3 (en) | 2011-06-01 | 2017-06-19 | Fmc Corp | Fixed controlled release dosage forms |
WO2013003845A1 (en) | 2011-06-30 | 2013-01-03 | Neos Therapeutics, Lp | Abuse resistant drug forms |
BR112014002022A2 (pt) * | 2011-07-29 | 2017-02-21 | Gruenenthal Gmbh | comprimido resistente à violação proporcionando liberação de fármaco imediata |
LT2736497T (lt) | 2011-07-29 | 2017-11-10 | Grünenthal GmbH | Sugadinimui atspari tabletė, pasižyminti greitu vaisto atpalaidavimu |
IN2014CN00827A (zh) | 2011-08-16 | 2015-04-03 | Merck Sharp & Dohme | |
FR2979242A1 (fr) | 2011-08-29 | 2013-03-01 | Sanofi Sa | Comprime contre l'usage abusif, a base de paracetamol et d'oxycodone |
PE20141171A1 (es) | 2011-10-06 | 2014-09-21 | Gruenenthal Chemie | Forma de dosificacion farmaceutica oral resistente a alteracion comprendiendo agonista opioide y antagonista opioide |
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 |
AU2012327231B2 (en) | 2011-12-09 | 2015-09-24 | Purdue Pharma L.P. | Pharmaceutical dosage forms comprising poly(epsilon-caprolactone) and polyethylene oxide |
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 |
US20130225697A1 (en) | 2012-02-28 | 2013-08-29 | Grunenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
EP2819657A1 (en) | 2012-02-28 | 2015-01-07 | Grünenthal GmbH | Tamper-resistant pharmaceutical dosage form comprising nonionic surfactant |
AR090218A1 (es) | 2012-03-02 | 2014-10-29 | Rhodes Pharmaceuticals Lp | Formulaciones de liberacion inmediata resistentes a la manipulacion |
JP6103785B2 (ja) | 2012-04-18 | 2017-03-29 | マリンクロッド エルエルシー | 乱用抑止特性を有する即放性医薬組成物 |
AU2013248351B2 (en) | 2012-04-18 | 2018-04-26 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
ES2650945T3 (es) | 2012-05-11 | 2018-01-23 | Grünenthal GmbH | Forma de dosificación farmacéutica termoconformada resistente a la manipulación que contiene zinc |
EP2880011A4 (en) | 2012-08-01 | 2016-03-23 | Acura Pharmaceuticals Inc | STABILIZATION OF SYNTHESIS SYSTEMS OF METHAMPHETAMINE IN SINGLE PREGNANCY |
SI2887925T1 (sl) | 2012-08-27 | 2017-06-30 | Evonik Roehm Gmbh | Na želodčne tekočine odporen farmacevtski ali nutracevtski sestavek z odpornostjo na vpliv etanola |
ES2600860T3 (es) | 2012-08-27 | 2017-02-13 | Evonik Röhm Gmbh | Composición farmacéutica o nutracéutica con característica de liberación retardada y con resistencia contra la influencia de etanol |
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 |
EP2906202A4 (en) | 2012-10-15 | 2016-04-27 | Isa Odidi | DRUG FORMULATIONS FOR ORAL ADMINISTRATION |
US10420729B2 (en) | 2013-03-15 | 2019-09-24 | R.P. Scherer Technologies, Llc | Abuse resistant capsule |
BR112015022567A2 (pt) | 2013-03-15 | 2017-07-18 | Mallinckrodt Llc | composições compreendendo um opioide e um ingrediente farmacêutico ativo adicional para início rápido e duração prolongada de analgesia que podem ser administradas sem alimento |
US9517208B2 (en) | 2013-03-15 | 2016-12-13 | Purdue Pharma L.P. | Abuse-deterrent dosage forms |
JP6466417B2 (ja) | 2013-05-29 | 2019-02-06 | 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 | 二峰性放出プロファイルを有する改変防止(tamper−resistant)剤形 |
CA2907950A1 (en) | 2013-05-29 | 2014-12-04 | Grunenthal Gmbh | Tamper-resistant dosage form containing one or more particles |
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 |
WO2015023675A2 (en) | 2013-08-12 | 2015-02-19 | 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 |
WO2015065547A1 (en) | 2013-10-31 | 2015-05-07 | 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 |
CA2938699A1 (en) | 2014-02-05 | 2015-08-13 | Kashiv Pharma 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 |
AU2016251854A1 (en) | 2015-04-24 | 2017-10-19 | Grunenthal 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 |
US20170296476A1 (en) | 2016-04-15 | 2017-10-19 | Grünenthal GmbH | Modified release abuse deterrent dosage forms |
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2005
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2006
- 2006-02-06 WO PCT/EP2006/001025 patent/WO2006082097A1/de active Application Filing
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- 2006-02-06 TW TW095103888A patent/TWI449540B/zh not_active IP Right Cessation
- 2006-02-06 CA CA002595979A patent/CA2595979A1/en not_active Abandoned
- 2006-02-06 JP JP2007553555A patent/JP5265201B2/ja not_active Expired - Fee Related
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- 2006-02-06 US US11/348,276 patent/US20060188447A1/en not_active Abandoned
- 2006-02-06 CN CN2006800038549A patent/CN101111232B/zh not_active Expired - Fee Related
- 2006-02-06 EP EP06706680.3A patent/EP1845955B1/de not_active Not-in-force
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2007
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- 2007-12-13 HK HK07113637.5A patent/HK1108370A1/zh not_active IP Right Cessation
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2008
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2014
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2015
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2016
- 2016-09-02 US US15/255,312 patent/US10729658B2/en active Active
- 2016-09-02 US US15/255,218 patent/US20160367485A1/en not_active Abandoned
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
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US20080311197A1 (en) | 2008-12-18 |
PE20061204A1 (es) | 2006-12-15 |
EP1845955B1 (de) | 2015-05-27 |
TW200640500A (en) | 2006-12-01 |
US20150091201A1 (en) | 2015-04-02 |
CA2595979A1 (en) | 2006-08-10 |
JP2008528653A (ja) | 2008-07-31 |
US20150283086A1 (en) | 2015-10-08 |
AR054222A1 (es) | 2007-06-13 |
JP5265201B2 (ja) | 2013-08-14 |
WO2006082097A1 (de) | 2006-08-10 |
US20160367486A1 (en) | 2016-12-22 |
IL185017A0 (en) | 2007-12-03 |
CN101111232A (zh) | 2008-01-23 |
EP1845955A1 (de) | 2007-10-24 |
DE102005005449A1 (de) | 2006-08-10 |
US20160367485A1 (en) | 2016-12-22 |
US10729658B2 (en) | 2020-08-04 |
TWI449540B (en) | 2014-08-21 |
IL185017A (en) | 2016-05-31 |
HK1108370A1 (zh) | 2008-05-09 |
US20060188447A1 (en) | 2006-08-24 |
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