CN107595793B - 活性药物成分的自调节释放 - Google Patents
活性药物成分的自调节释放 Download PDFInfo
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- CN107595793B CN107595793B CN201711090908.6A CN201711090908A CN107595793B CN 107595793 B CN107595793 B CN 107595793B CN 201711090908 A CN201711090908 A CN 201711090908A CN 107595793 B CN107595793 B CN 107595793B
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Abstract
活性药物成分的自调节释放。防止滥用的药物组合物，其包含药物活性成分；酸溶性成分；和缓冲成分；其中当以预期剂量的过量摄入所述组合物时，所述酸溶性成分和所述缓冲成分延迟所述活性药物成分的释放。
Description
相关申请的交叉引用
本申请是国际申请日为2013年11月27日的发明名称为“活性药物成分的自调节释放”的PCT/US2013/072249号发明专利申请的分案申请，原申请进入中国国家阶段获得的国家申请号为201380062421.0，其要求2012年11月30日提交的标题为“Methods andCompositions for Self-Regulating Release of Active Pharmaceutical Ingredient”的美国临时专利申请号61/731,901的权益，其通过引用以其全部内容并入本文中。
背景技术
表现出阿片或吗啡样性质的药物种类被称作阿片样物质(opioid)，或阿片样物质激动剂。作为激动剂，某些药物的特征为与脑和其它身体组织和器官中的立体特异性的和可饱和的结合位点相互作用。内源性的阿片样物质样的肽存在于中枢神经系统的区域中，推测所述区域与下列因素有关：对疼痛的感知；运动、情绪和行为；以及神经内分泌功能的调节。三种经典的阿片受体类型，mu (μ)，delta (δ)，和kappa (κ)已经被广泛地研究。这些受体中的每个在脑、脊髓和外周具有独特的解剖学分布。大多数临床使用的阿片样物质是对μ受体具有相对选择性的，这反映了它们与吗啡的相似之处。然而，在标准治疗剂量下对特定受体亚型具有相对选择性的含阿片样物质的药物，当其在足够高的剂量给予时，将通常与多种受体亚型相互作用，这导致它们的药理学作用可能会改变。这在阿片样物质剂量被逐渐升高以克服耐受性时尤为如此。
反复的阿片样物质使用所发展的耐受性、身体和/或心理依赖(即成瘾)的潜在可能性是大多数含有阿片样物质镇痛剂的药物的独特的特征。发展成瘾的可能性是使用阿片样物质来处理疼痛中的主要考虑之一。与对阿片样物质的使用相关的另一个主要考虑是这些药物从处于合法疼痛中的病人，转移到其他个体(非病人)以用于娱乐性目的。
药物滥用者和/或成瘾者通常可获得旨在用于口服给药的含有一种或多种阿片样物质镇痛剂的固体剂型，并碾碎、剪切、研磨、咀嚼、溶解和/或加热、提取或以其它方式擅改或破坏剂量单元，以使活性药物的显著部分或甚至整个量变得可用于通过以超过此类药物的通常治疗剂量的量1)注射，2)吸入，和/或3)口服来进行给药。
存在导致阿片样物质滥用的三种基本行为模式。第一种涉及这样的个体，其阿片样物质药物使用在合法医学治疗的背景下开始且其经由来自合适的具有执照的卫生保健提供者的处方来获得他们起初的药物供给。经由不知不觉的过程这些个体可能最终开始从多个卫生保健提供者和/或药房和/或从由其它合法药物分配渠道转变的违法来源寻求远超出他们合法医学需要的处方药供给。第二种滥用模式起始于寻求“兴奋(high)”的实验或“娱乐性”的没有要被滥用的药物的合法医学适应症的药物使用者。第三种滥用模式涉及起始于前述方式的一种或另一种，并最终转变为口服给药获自有组织的和合法的成瘾治疗项目的药物的使用者。
滥用者可通常采用各种给药途径来滥用含有阿片样物质的药物制剂。最常见的方法包括：1)胃肠外(例如静脉注射)，2)鼻内(例如嗅吸法)，和3)反复的过量口服摄入，例如摄入口服给药的片剂或胶囊。一种口服固体药物的滥用的模式涉及从剂型中提取阿片样物质组分，其通过以下步骤进行：首先将剂型与合适的溶剂(例如水)混合，并随后从混合物中提取阿片样物质组分以用在适合于静脉注射阿片样物质的溶液中来达到“兴奋”。
已经对减少口服给药的药物的滥用的潜在可能性进行了尝试。这些尝试通常集中于在口服剂型中包含拮抗剂，所述拮抗剂不是口服活性的，但如果某人尝试溶解药物并对其胃肠外给药的话，所述拮抗剂将基本上阻断药物的作用。
尽管进行了所有的尝试，但药物产品的误用和滥用仍持续增长。明显地存在对阻止药物产品(例如口服给药的药物产品)的滥用的新型和有效的方法和组合物的增长的需求，所述药物产品包括但不限于要被滥用的药物的立即释放、缓释或延长释放和迟释制剂。特别地，对寻求药物疗法的病人来说，此类方法和组合物将会是对阿片样物质镇痛剂而言有用的，其阻止了滥用并最小化或降低了身体或心理依赖性的潜在可能性。
发明概述
根据本发明的一些实施方案，防止滥用的药物组合物包含药物活性成分；酸溶性成分；以及缓冲成分。在一些实施方案中，当超出预期剂量摄入组合物时，酸溶性成分和缓冲成分延迟了药物活性成分的释放。
在一些实施方案中，药物活性成分为易被滥用的药物。在一些实施方案中，药物活性成分为具有窄治疗指数的药物。
在一些实施方案中，酸溶性成分可包括碳酸钙、阳离子共聚物，或它们的组合。在某些实施方案中，酸溶性成分包括基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。酸溶性成分的存在量可为药物组合物的约1wt%至约40wt%。
在一些实施方案中，药物活性成分包含在酸溶性成分的基质之中。
在某些实施方案中，缓冲成分可包括碳酸钙、碳酸氢钠、氧化镁、磷酸三钠，或它们的组合。缓冲成分的存在量可为约45 wt%至约95 wt%。
附图简要说明
通过检查以下的阐明本发明特定性质的附图，将更好地理解本发明，其中：
附图1显示了随时间经过的碳酸钙对溶出介质的pH的影响。
附图2显示了溶出介质对活性成分从碳酸钙颗粒中释放的影响。
附图3显示了活性成分从阳离子共聚物颗粒中的释放。
附图4显示了当添加多个片剂时溶出介质的pH的变化。
附图5显示了从单个和多个片剂给药的体外活性成分释放之间的对比。
对于附图，用相同的参考号来指示附图之间的相同的特征。
发明详述
在一些实施方案中，将本发明的制剂设计为阻断或阻碍由对药物产品的有意或无意的过量摄入所导致的作用。在正常的定药量配条件下，本发明的制剂可允许所需药物剂量的完全的和/或生物等效的(bioequivalent)口服输送。然而当无论是有意还是无意地摄入过量的剂量时，本发明的制剂可起到减缓或阻断过量剂量的释放和后续的吸收的作用。因此，在有意的过量摄入的情况下(其中药物滥用者将服用被滥用的药物的过量的剂量来体验欣快的作用)，与自由释放过量的滥用药物的剂量相比，对本发明的制剂来说该作用将被显著地降低。以这种方式，本发明的制剂可起到对出于实现欣快作用的目的而滥用本发明的制剂的抑制剂的作用。而按照指示使用本发明的病人将得到所需的治疗处理。
通常，且如本文更为详细地描述的，可将本发明的药物制剂设计为具有控制活性药物成分的释放和/或吸收的一种或多种组分。在一些实施方案中，可将药物制剂设计为具有pH调节特征和/或pH依赖性溶解度特征。pH调节特征可通过基于药物组合物是以合适的剂量还是过量摄取而调节胃环境的pH来影响活性成分的释放和/或吸收。可通过在药物组合物中包含一种或多种缓冲和/或抗酸成分来提供pH调节特征。pH依赖性溶解度特征可通过取决于胃环境的pH包含或释放活性药物成分来影响活性成分的释放和/或吸收。可通过在药物组合物中包含一种或多种酸溶性成分来提供pH依赖性溶解度特征。
组分
活性药物成分
任何药物、治疗上可接受的药物盐、药物衍生物、药物类似物、药物同系物，或多晶形物可用于本发明中。用于同本发明一起使用的合适的药物可在Physician’s DeskReference, 第59版中找到，其内容特此通过引用并入。在一种实施方案中，所述药物为口服给药的药物。
在某些实施方案中，使用易被滥用的药物。常见的易被滥用的药物包括精神治疗药物和镇痛剂，包括但不限于阿片样物质、阿片制剂、兴奋剂、安定剂、镇静剂、抗焦虑药、麻醉剂以及可导致心理和/或身体依赖性的药物。在一种实施方案中，用于在本发明中使用的药物可包括苯丙胺类、苯丙胺样的化合物、苯并二氮杂䓬类，和哌醋甲酯或它们的组合。在另一种实施方案中，本发明可包括本文描述的药物和/或其盐的经拆分的异构体中的任一种。
可易被滥用的用于在本发明中使用的药物可为以下的一种或多种：阿芬太尼、苯丙胺类、丁丙诺啡、布托啡诺、卡芬太尼、可待因、地佐辛、二乙酰吗啡、二氢可待因、二氢吗啡、地芬诺酯、二丙诺啡、埃托啡、芬太尼、氢可酮、氢吗啡酮、β-羟基-3-甲基芬太尼、左旋-α-乙酰基地美庚醇、左啡诺、洛芬太尼、哌替啶、美沙酮、哌醋甲酯、吗啡、纳布啡、纳美芬、羟考酮、氧吗啡酮、喷他佐辛、哌替啶、丙氧吩、雷米芬太尼、舒芬太尼、替利定和曲马多、其盐、其衍生物、其类似物、其同系物、其多晶型物，以及前述任何药物的混合物。
在另一个实施方案中，用于与本发明一起使用的可易被滥用的药物包括以下的一种或多种：右美沙芬(3-甲氧基-17-甲基-9a, 13a, 1 4a-吗啡喃 氢溴酸盐一水合物)，N-{1-[2-(4-乙基-5-氧基-2-四唑啉-1-基)-乙基]-4-甲氧基甲基-4-哌啶基}N-丙酰苯胺(阿芬太尼)，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]-苯并二氮杂䓬(阿普唑仑)，2-二乙基氨基苯丙酮(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)，氨苄哌替啶，阿朴可待因，5,5-二乙基巴比妥酸(巴比妥)，苄基吗啡，贝齐米特，7-溴-5-(2-吡啶基)-1H-1,4-苯并二氮杂䓬-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]二氮杂䓬(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-内型-桥亚乙基吗啡喃-3-醇(丁丙诺啡)，5-丁基-5-乙基巴比妥酸(丁巴比妥)，布托啡诺，(7-氯-1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂䓬-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-苯并二氮杂䓬-2-基胺-4氧化物(氯氮䓬)，7-氯-1-甲基-5-苯基-1H-1,5-苯并二氮杂䓬-2,4(3H,5H)-二酮(氯巴占)，5-(2-氯苯基)-7-硝基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(氯硝西泮)，氯尼他秦，7-氯-2,3-二氢-2-氧基-5-苯基-1H-1,4-苯并二氮杂䓬-3-甲酸(氯拉䓬酸)，5-(2-氯苯基)-7-乙基-1-甲基-1H-噻吩并[2,3-e][1,4]-二氮杂䓬-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]苯并二氮杂䓬-6(5H)-酮(氯噁唑仑)，(-)-甲基-[3β-苯甲酰基氧基-2β(1αH,5αH)-托品烷甲酸酯(可卡因)，4,5α-环氧-3-甲氧基-17-甲基-7-吗啡烯-6α-醇(可待因)，5-(1-环己烯基)-5-乙基巴比妥酸(环巴比妥)，赛克罗酚，环丙诺啡，7-氯-5-(2-氯苯基)-1H-1,4-苯并二氮杂䓬-2(3H)-酮(地洛西泮)，二氢去氧吗啡，右旋吗拉迈得，(+)-(1-苄基-3-二甲基氨基-2-甲基-1-苯基丙基)丙酸酯(右旋丙氧芬)，地佐辛，地恩丙胺，diamorphone，7-氯-1-甲基-5-苯基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(安定)，4,5α-环氧-3-甲氧基-17-甲基-6α-吗啡喃醇(二氢可待因)，4,5α-环氧-17-甲基-3,6a-吗啡喃二醇(二氢吗啡)，地美沙多，地美庚醇[sic - Tr.Ed.]，二甲基噻吩丁烯胺，吗苯丁酯，地匹哌酮，(6aR,10aR)-6,6,9-三甲基-3-戊基-6a,7,8,10a-四氢-6H-苯并[c]苯并吡喃-1-醇(屈大麻酚)，依他佐辛，8-氯-6-苯基-4H-[1,2,4]三唑并[4,3-a][1,4]苯并二氮杂䓬(艾司唑仑)，乙庚嗪，乙基甲基噻吩丁烯胺，乙基-[7-氯-5-(2-氟苯基)-2,3-二氢-2-氧基-1H-1,4-苯并二氮杂䓬-3-甲酸酯](氯氟䓬乙酯)， 4,5α-环氧-3-乙氧基-17-甲基-7-吗啡烯-6α-醇(乙基吗啡)，依托尼秦(etonitrazene)，4,5α-环氧-7α-(1-羟基-1-甲基丁基)-6-甲氧基-17-甲基-6,14-内型-亚乙烯基-吗啡喃-3-醇(埃托啡)，N-乙基-3-苯基-8,9,10-三降冰片烷-2-基胺(芬坎法明)，7-[2-(α-甲基苯乙基氨基)-乙基]茶碱(芬乙茶碱)，3-(α-甲基苯乙基氨基)丙腈(芬普雷司)，N-(1-苯乙基-4-哌啶基)N-丙酰苯胺(芬太尼)，7-氯-5-(2-氟苯基)-1-甲基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(氟地西泮)，5-(2-氟苯基)-1-甲基-7-硝基-1H-1,4-苯并二氮杂䓬-2-(3H)-酮(氟硝西泮)，7-氯-1-(2-二乙基氨基乙基)-5-(2-氟苯基)-1H-1,4-苯并二氮杂䓬-2(3H)-酮(氟胺安定)，7-氯-5-苯基-1-(2,2,2-三氟乙基)-1H-1,4-苯并二氮杂䓬-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]苯并二氮杂䓬-6(5H)-酮(卤噁唑仑)，海洛因，4,5α-环氧-3-甲氧基-17-甲基-6-吗啡烷酮(氢可酮)，4,5α-环氧-3-羟基-17-甲基-6-吗啡烷酮(氢吗啡酮)，羟哌替啶，异美沙酮，羟基甲基吗啡喃，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]苯并二氮杂䓬-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(凯托米酮)，(3S,6S)-6-二甲基氨基-4,4-二苯基庚烷-3-基乙酸酯(左醋美沙朵(LAAM))，(-)-6-二甲基氨基-4,4-二苯基-3-庚酮(左美沙酮), (-)-17-甲基-3-吗啡喃醇(羟甲左吗喃)，左芬啡烷，洛芬太尼，6-(2-氯苯基)-2-(4-甲基-1-哌嗪基亚甲基)-8-硝基-2H-咪唑并[1,2a][1,4]苯并二氮杂䓬-1(4H)-酮(氯普唑仑)，7-氯-5-(2-氯苯基)-3-羟基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(劳拉西泮)，7-氯-5-(2-氯苯基)-3-羟基-1-甲基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(氯甲西泮)，5-(4-氯苯基)-2,5-二氢-3H-咪唑并[2,1-a]异吲哚-5-醇(马吲哚)，7-氯-2,3-二氢-1-甲基-5-苯基-1H-1,4-苯并二氮杂䓬(美达西泮)， N-(3-氯丙基)-α-甲基乙氧苯基胺(美芬雷司)，哌替啶，二氨基甲酸2-甲基-2-丙基三亚甲酯(眠尔通)，美普他酚，美他佐辛，甲基吗啡，N,α-二甲基苯乙基胺(脱氧麻黄碱)，(±)-6-二甲基氨基-4,4-二苯基-3-庚酮(美沙酮)，2-甲基-3-邻-甲苯基-4(3H)-喹唑啉酮(安眠酮)，甲基-[2-苯基-2-(2-哌啶基)乙酸酯](派醋甲酯)，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)，麦托朋，8-氯-6-(2-氟苯基)-1-甲基-4H-咪唑并[1,5-a][1,4]苯并二氮杂䓬(咪达唑仑)，2-(二苯甲基亚磺酰基)乙酰胺(莫达非尼)，4,5α-环氧-17-甲基-7-吗啡烯-3,6α-二醇(吗啡)，麦罗啡，(±)-反式-3-(1,1-二甲基庚基)-7,8,10,10α-四氢-1-羟基-6,6-二甲基-6H-二苯并[b,d]吡喃-9(6αH)-酮(大麻隆)，纳布啡(nalbuphen)，纳洛芬，罂粟碱， 尼可吗啡，1-甲基-7-硝基-5-苯基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(硝甲西泮)，7-硝基-5-苯基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(硝基安定)，7-氯-5-苯基-1H-1,4-苯并二氮杂䓬-2-(3H)-酮(去甲西泮)，去甲左啡诺，6-二甲基氨基-4,4-二苯基-3-己酮(去甲美沙酮)，去甲吗啡，二苯哌己酮，属于罂粟(Papaver somniferum)物种的植物的凝结的汁液(阿片)，7-氯-3-羟基-5-苯基-1H-1,4-苯并二氮杂䓬-2-(3H)-酮(去甲羟基安定)，(顺式-反式)-10-氯-2,3,7,11b-四氢-2-甲基-11b-苯基噁唑并[3,2-d][1,4]苯并二氮杂䓬-6-(5H)-酮(奥沙唑仑)，4,5α-环氧-14-羟基-3-甲氧基-17-甲基-6-吗啡烷酮(羟考酮)，羟吗啡酮，属于罂粟(Papaver somniferum)物种(包括setigerum亚种)的植物的植物和植物部分(Papaver somniferum)，阿片全碱，2-亚氨基-5-苯基-4-噁唑烷酮(pernoline), 1,2,3,4,5,6-六氢-6,11-二甲基-3-(3-甲基-2-丁烯基)-2,6-桥亚甲基-3-苯并吖辛因(benzazocin)-8-醇(喷他佐辛)，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-甲酸酯)(哌替啶)，苯吗庚酮，非诺吗烷，非那佐辛，苯哌利定，匹米诺定，福尔可定，3-甲基-2-苯基吗啉(芬美曲嗪)，5-乙基-5-苯基巴比妥酸(苯巴比妥)，α,α-二甲基苯乙基胺(芬特明)，7-氯-5-苯基-1-(2-丙炔基)-1H-1,4-苯并二氮杂䓬-2(3H)-酮(匹那西泮)，α-(2-哌啶基)二苯甲基醇(哌苯甲醇)，1'-(3-氰基-3,3-二苯基丙基)[1,4'-联哌啶]-4'-甲酰胺(哌腈米特)，7-氯-1-(环丙基甲基)-5-苯基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(普拉西泮)，普罗法多，普罗庚嗪，三甲利定，异丙哌替啶，丙氧芬，N-(1-甲基-2-哌啶子基乙基)-N-(2-吡啶基)丙酰胺，甲基-{3-[4-甲氧基羰基-4-(N-苯基丙酰氨基)哌啶子基]丙酸酯} (瑞芬太尼)，5-仲丁基-5-乙基巴比妥酸(仲丁巴比妥)，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-噻吩基)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-苯并二氮杂䓬-2-(3H)-酮(替马西泮)，7-氯-5-(1-环己烯基)-1-甲基-1H-1,4-苯并二氮杂䓬-2(3H)-酮(四氢西泮)，乙基-(2-二甲基氨基-1-苯基-3-环己烷-1-甲酸酯) (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]苯并二氮杂䓬(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-氟苄氧基)-1-(间-甲氧基苯基)环己醇，任选地其各自为相应的立体异构的化合物以及相应的衍生物，尤其是酯或醚的形式，且其全部为生理相容性的化合物，尤其是盐和溶剂化物。
在一种实施方案中，本发明的药物组合物包括一种或多种阿片样物质，例如氢可酮、氢吗啡酮、吗啡和羟考酮和/或它们的盐，来作为治疗上的活性成分。通常当被加工为合适的剂型时，正如下面更为详细地描述的，所述药物可以通常规定的量存在于此类剂型中，通常以干重计为基于制剂的总重量的约0.5%至约25%。
对于在单位剂量形式中的镇痛剂，此类药物可以药学上可接受的量存在；此类药物的标准剂量通常是在本领域中已知的且为公开的，例如，公开在United States Pharmacopeia and National Formulary (USP 36-NF 31). Rockville, MD: UnitedStates Pharmacopeia Convention; 2013，其通过引用以其全部内容并入于本文中。在一些实施方案中，此类药物的存在量可为约5, 25, 50, 75, 100, 125, 150, 175或200 mg。在一些实施方案中，所述药物的存在量可为约5至约500 mg或约5至约200 mg。在一些实施方案中，剂型含有合适量的药物以提供治疗的效果。
在一些实施方案中，药物活性成分可包括具有窄治疗指数的药物。具有窄治疗指数的药物包括但不限于：氨茶碱、卡马西平、氯林可霉素、氯压定、地高辛、达舒平、dyphylinne、胍乙啶、异他林甲磺酸盐(isoetharine mesylate)、异丙肾上腺素(isoproterenol)、左旋甲状腺素、碳酸锂、奥西那灵、米诺地尔、茶碱胆碱、苯妥英、pasosin、普里米酮、普鲁卡因胺、葡糖酸奎尼定、茶碱、丙戊酸、丙戊酸钠和华法林钠等。对于在单位剂量形式中的具有窄治疗剂量的药物，此类药物可以药学上可接受的量存在；此类药物的标准剂量通常是在本领域中已知的且为公开的，例如公开在United States Pharmacopeia and National Formulary (USP 36-NF 31). Rockville, MD: UnitedStates Pharmacopeia Convention; 2013中，其通过引用以其全部内容并入于本文中。在一些实施方案中，此类药物的存在量可为约 0.025, 0.05, 0.1, 0.2, 0.3, 0.5, 1, 2,2.5, 3, 4, 5, 6, 7.5, 10, 25, 50, 75, 100, 125, 150, 175, 200, 和250 mg。在一些实施方案中，所述药物的存在量可为约 0.01至约1000 mg或约0.05至约500 mg。在一些实施方案中，剂型含有合适量的药物以提供治疗的效果。
在酸性溶液中可溶的组分
在一些实施方案中，本发明的药物组合物包含在酸性溶液中可溶的一种或多种组分。酸性溶液可被认为是pH为约1至约4的那些溶液。在一些实施方案中，酸溶性组分在略微酸性、中性和/或碱性溶液，即pH大于约4的那些溶液中的可溶性较小。
在一些实施方案中，酸溶性组分以具有活性药物成分的颗粒基质的形式包含在药物组合物中。酸溶性成分可以足以形成该基质的量包含在药物组合物中。在一些实施方案中，活性成分被隔离在酸溶性组分中。酸溶性组分可影响活性药物成分的释放，这取决于环境的pH，所述pH通过作为被摄入的药物组合物的量的函数的缓冲和/或抗酸成分来升高或保持：当以合适剂量摄入药物组合物时，pH缓冲成分不以改变或足以升高胃肠pH的量存在，且酸溶性组分溶解并释放活性药物成分；当过量摄入药物组分时，pH缓冲成分以升高胃肠pH的量存在，由此阻止了酸溶性成分溶解并释放活性药物成分。
在一些实施方案中，酸溶性组分包含在药物组合物中的量为：约1 wt% 至约50wt%; 约1 wt%至约 48 wt%; 约1 wt%至约46 wt%; 约1 wt%至约44 wt%; 约1wt%至约42wt%; 约1wt%至约40wt%; 约2wt%至约38wt%; 约4wt%至约36wt%; 约6wt%至约34 wt%; 约8wt%至约32 wt%; 约10wt%至约30 wt%; 约12wt%至约28wt%; 约14wt%至约26wt%; 约16wt%至约24wt%; 约18 wt%至约22wt%; 约1wt%; 约2wt%; 约4wt%; 约6wt%; 约8wt%; 约10wt%; 约12wt%; 约14wt%; 约16wt%; 约18wt%; 约20wt%; 约22wt%; 约24wt%; 约26wt%; 约28wt%; 约30wt%; 约32wt%; 约34wt%; 约36wt%; 约38wt%; 约40wt%; 约42wt%; 约44wt%; 约46wt%; 约48wt%; 或约50wt%。
合适的酸溶性组分的例子包括碳酸钙，壳聚糖，甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物，例如，举例来说Eudragit® E POEudragit® E100和Eudragit® E 12.5，磷酸氢钙和磷酸钙，和氢氧化镁。
缓冲和/或抗酸成分
在一些实施方案中，本发明的药物组合物包含一种或多种缓冲和/或抗酸成分。如果药物组合物以足够的量被服用，此类成分可导致胃pH的升高。在一些实施方案中，当药物组合物以足够的量被服用时，此类成分可导致胃pH的快速和持续的升高至大于约4的pH。
在一些实施方案中，可以使得当以合适的治疗量摄取药物组合物时胃pH不受影响，但当过量摄入药物组合物时胃pH可被升高的量包含缓冲和/或抗酸成分。在一些实施方案中，包含在药物组合物中的缓冲和/或抗酸成分的量为约45wt%至约95 wt%; 约50wt%至约90 wt%; 约55 wt%至约85wt%; 约60wt%至约80 wt%; 约65wt%至约75wt%; 约45wt%; 约50 wt%; 约55 wt%; 约60wt%; 约65wt%; 约70wt%; 约75wt%; 约80wt%; 约85wt%; 约90wt%; 或约95wt%。
合适的缓冲和/或抗酸成分的例子包括但不限于氢氧化铝、铝酸铋、碳酸铋、碱式碳酸铋、碱式没食子酸铋、碱式硝酸铋、碳酸钙、磷酸钙、磷酸氢钙、氨基乙酸二羟铝、碳酸二羟铝钠、甘氨酸、甘氨酸镁、氢氧化镁、氧化镁、碳酸氢钾、碳酸氢钠、酒石酸钠钾、磷酸钠和磷酸钙。
在一些实施方案中，一种成分可充当酸溶性成分和缓冲和/或抗酸成分两者。此类合适成分的例子包括碳酸钙、磷酸氢钙和磷酸钙，以及氢氧化镁。
附加成分
本发明还可任选地包含其它成分以增强由本发明的药物组合物的剂型制造和/或改变包含本发明的组合物的剂型的释放特性(release profile)。
本发明的一些实施方案包含一种或多种药学上可接受的填充剂/稀释剂。在一些实施方案中，Avicel PH (微晶纤维素)是在制剂中使用的填充剂。Avicel PH的平均粒度可为20至约200 μm，优选约100 μm。其密度为1.512-1.668 g/ cm3。Avicel PH的分子量应为约36,000。当Avicel PH的存在量以固体重量计为制剂的约10%-65%时，其效力为最优的。典型的填充剂的存在量可以为以干重重量计为总的组合物的10%-65%。其它成分可包括糖和/或多元醇。也可包含粒度为约20至约400微米和密度为约0.3至约0.9 g/ml的乳糖。
在本发明的一些实施方案中，可以干重重量计在约10%-65%下存在的填充剂也可作为粘合剂起作用，因为它们不仅赋予制剂内的材料粘合的性质，还可增加可直接压缩的制剂(如下面所讨论的)的散重以达到对于直接压缩来说可接受的制剂重量。在一些实施方案中，附加的填充剂不需要提供与所选择的填充剂一样水平的粘合性质，但可以能够为制剂均质性做出贡献且一旦共混时能够阻止制剂的离析(segregation)。进一步地，优选的填充剂不具有对组合物的流动性或形成的片剂的溶出特性的有害影响。
在一种实施方案中，本发明可包含一种或多种药学上可接受的崩解剂。此类崩解剂是技术人员已知的。在本发明中，崩解剂可包括但不限于：淀粉羟乙酸钠(Explotab®)，其粒度为约104微米且密度为约0.756 g/ ml，淀粉(例如Starch 21)，其粒度为约2-约32微米，且密度为约0.462 g/ ml，Crospovidone®，其粒度为约400微米且密度为约1.22 g/ml，以及交联羧甲基纤维素钠(Ac-Di-Sol)，其粒度为约37-约73.7微米，且密度为约0.529 g/ml。所选择的崩解剂应对制剂的可压缩性、流动性和均质性做出贡献。进一步地，所述崩解剂可使离析最小化并为制剂提供立即释放特性。在一些实施方案中，崩解剂(一种或多种)的存在量以固体重量计为可直接压缩的制剂的约2%-约25%。更进一步地，当将片剂引入到低pH环境中时，添加到制剂的抗酸剂可通过抗酸成分的泡腾(effervescense)而有助于片剂崩解，由此潜在地降低对额外的崩解剂的需求。
在一种实施方案中，本发明可包含一种或多种药学上可接受的助流剂，其包括但不限于胶体二氧化硅。在一种实施方案中，可使用密度为约0.029-约 0.040 g/ ml的胶体二氧化硅(Cab-O-Sil®)以改进制剂的流动特性。可以固体计为制剂重量的约0.1%-约1%的量来提供此类助流剂。然而，将理解的是，基于本发明，尽管胶体二氧化硅是一种特定的助流剂，但也可使用其它已知的或待开发的具有相似性质的助流剂，只要它们与制剂中的其它赋形剂和活性成分相容且不显著地影响制剂的流动性、均质性和可压缩性即可。
在一种实施方案中，本发明可包含一种或多种药学上可接受的润滑剂，其包括但不限于硬脂酸镁。在一种实施方案中，硬脂酸镁的粒度为约450-约550微米且密度为约1.00-约1.80 g/ml。在一种实施方案中，硬脂酸镁可在压缩过程中为降低模具的壁与本发明的药物组合物之间的摩擦做出贡献，且可使得片剂的弹出更容易，由此促进了加工。在一些实施方案中，润滑剂阻止了粘附至冲头和模具和/或有助于粉末在料斗中和/或至模具中的流动。在本发明的一种实施方案中，在药物组合物中使用粒度为约5-约50微米且密度为约0.1至约1.1 g/ml的硬脂酸镁，在某些实施方案中，润滑剂应占制剂重量的约0.1%-约2%(以固体计)。合适的润滑剂是稳定的且一旦组合时不在制剂中聚合。本领域中已知的或待开发的表现出可接受的或可比得上的性质的其它润滑剂包括硬脂酸、氢化油、硬脂酰富马酸钠、聚乙二醇、以及Lubritab®。
在某些实施方案中，选择赋形剂的最重要的标准是，赋形剂应达到良好的含量均匀性，且按照需要来释放活性成分。通过具有优异的粘结性质和均质性，以及良好的可压缩性，以共混形式时的粘合性和流动性，所述赋形剂在压缩过程中使料斗中的粉末的离析最小化。
受控的药物释放的剂型
如本文描述的，可将本发明的药物制剂配置为减慢或阻断过量剂量的活性药物成分的释放和随后的吸收。在一些实施方案中，可将药物组合物设计为具有pH调节特征和/或pH依赖性溶解度特征。pH调节特征可通过基于药物组合物是以合适的剂量还是过量摄取而调节胃环境的pH来影响活性成分的释放和/或吸收。可通过在药物组合物中包含一种或多种缓冲和/或抗酸成分来提供pH调节特征。pH依赖性溶解度特征可通过取决于胃肠环境的pH包含或释放活性药物成分来影响活性成分的释放和/或吸收。可通过在药物组合物中包含一种或多种pH可溶性成分来提供pH依赖性溶解度特征。
在一些实施方案中，可如此配制药物组合物，使得当以合适的量摄取组合物时，pH调节特征具有最小的影响(即胃环境的pH基本上不被调节或被保持在所需的水平)，且pH依赖性溶解度特征具有最大的影响(即活性药物成分被释放)，由此允许活性成分的释放和/或吸收。然而，当过量摄入药物组合物时，在一些实施方案中将所述组合物如此配制，使得pH调节特征具有最大影响(即胃环境的pH被升高)，且pH依赖性溶解度特征具有最小的影响(即酸溶解性成分是不可溶的并因此不溶解)，由此阻碍了活性成分的释放和/或吸收。
在一些实施方案中，可通过使活性药物成分与酸溶性成分(一种或多种)紧密混合来制备药物组合物，所述混合可通过任何合适的方法(即干法或湿法造粒，热熔挤出等)进行，使得以微粒形式形成微粒基质。然后可通过当摄入药物组合物时基质周围的即时的pH环境来控制药物从该基质的释放。在低pH环境(即pH为1-4)中，基质可倾向于快速溶解并释放药物；然而，在较高的pH环境(即pH> 4)中，基质倾向于不可溶且药物的释放将被延迟且可能不完全，由此降低了吸收的药物的水平。
在一些实施方案中，对于单个剂量单位，进一步将所需量的酸溶性药物基质与缓冲和/或抗酸成分(一种或多种)混合，所述缓冲和/或抗酸成分(一种或多种)的量足以使得当摄入单个剂量单位时，缓冲和/或抗酸成分(一种或多种)将中和胃pH至胃pH保持在pH为1-4范围内的点。酸溶性药物基质/抗酸剂/缓冲剂的共混物可形成为口服固体剂型例如片剂或胶囊，但不限于所述的剂型。
因此，可将药物组合物配制为具有pH调节特征和pH依赖性溶解度特征，使得在正常定药量配条件(即一片或两片片剂)下，当摄入单个剂量时，缓冲/抗酸成分(一种或多种)中和部分的胃酸，然而胃酸保持在pH为1-4的范围。在这些条件下，酸溶性药物基质在酸性的胃环境中是可溶的且药物可在胃中被迅速地释放并吸收至血流中。
在其中有意或无意地摄入过量的剂量(即三片片剂或更多)的条件下，来自过量摄入的缓冲和/或抗酸成分(一种或多种)的量此刻可足以导致胃pH的快速和可持续的增加(pH>4)。因此酸溶性药物基质在较高pH的胃环境中的可溶性可能较小，且药物从基质的释放可能被抑制。在一些实施方案中，对药物从酸溶性基质的抑制进一步受助于胃肠传输，其可将酸溶性基质颗粒转移到肠和下胃肠道(其具有生物学控制的高pH环境(即pH为5.5-8))之中。当与在正常胃pH(即pH为1-4)中释放药物的等量口服剂量相比时，对来自过量摄入的药物释放的总的抑制导致药物动力学曲线的Tmax升高和Cmax降低。
本发明的合适的制剂和剂型包括但不限于由本发明的药物组合物制造的粉末、小胶囊、丸剂、栓剂、凝胶、软胶胶囊，胶囊和压缩片剂。剂型可为任何形状，包括规则或不规则的形状，这取决于技术人员的需要。
包含本发明的药物组合物的压缩片剂可为直接压缩片剂或非直接压缩片剂。在一种实施方案中，可通过湿法造粒，和干法造粒(例如击压法(slugging)或碾压法(rollercompaction))来制备本发明的剂型。选择制备方法和赋形剂的类型以给予片剂制剂所需的允许片剂的快速压缩的物理特性。在压缩后，片剂必须具有许多额外的属性，例如外观、硬度、崩解能力，和可接受的溶出特性。
对填充剂和其它赋形剂的选择通常取决于药物的化学和物理性质，在加工过程中混合物的行为，以及最终片剂的性质。将对此类参数的调整理解为在相关领域技术人员的通常理解的范围内。合适的填充剂和赋形剂在上面被更为详细地描述了。
本发明的剂型的制造可涉及直接压缩以及湿法和干法造粒方法，其包括击压法和碾压法。
在一些实施方案中，一种或多种组分可为被隔离的，如在美国专利申请公开号2012/0202839中描述的，其通过引用以其全部内容并入于本文中。
可使用本发明来制造立即释放和受控药物释放的制剂。受控释放制剂可包括延迟释放、双峰型(bi-modal)和三峰型(tri-modal)释放、延长释放和缓释口服固体剂量制剂。
如本文使用的，将术语“约”理解为表示所引用的值的 +10%。例如。将“约45%”理解为字面上表示40.5%-49.5%。
如本文使用的，将术语“生物等效性”理解为表示药物的 Cmax、Tmax或浓度曲线“AUC”下的面积中的一个或多个在参考药物的相同标记的75%-120%以内。
本发明的某些方面可以如以下实施例所举例说明的那样被更好地理解，所述实施例旨在举例说明而不是限制。
实施例1
准备两个溶出容器：一个容器含有25 mEq的HCl和单个市售碳酸钙抗酸片剂(Tums®)，且另外的容器含有25 mEq的HCl和五片碳酸钙抗酸片剂。监控在每个容器中的pH且结果在图1中显示。对于单个的片剂，片剂在约30分钟内完全反应，且单个片剂的溶出显示pH没有变化。然而，五片片剂的引入导致了pH在10分钟内相对快速的升高至大于4.5，且在90分钟后，在容器中观察到相当大量的未溶解的固体。因此，这已经显示出了低水平(500 mg)的碳酸钙可在对pH几乎不影响的情况下完全溶解，然而使用过量的量的碳酸钙时发生了pH的快速增加，产生了高pH环境，其中碳酸钙表现出低溶解度。碳酸钙已经显示出作为pH调节剂的能力和pH依赖性溶解度。
实施例2
在设计自调节剂型中所面临的挑战是当摄取单个剂量时，在升高的pH下建立调节(即较慢的或不完全的释放)，而不损失与立即释放片剂有关的所需的快速释放速率。在含有阿普唑仑的直接共混基质片剂和干法造粒片剂两者中对碳酸钙进行评估，其中所述颗粒含有碳酸钙以控制药物释放和颗粒外面的碳酸钙来影响pH的改变。与低pH(pH为1)相比，在较高pH(pH约为6)下，两种手段均导致在单个片剂中的更缓慢的阿普唑仑的释放，然而，在该情况下释放间隔不如所需要的那样高(图2)。然而，该结果证明了可使用颗粒来基于pH环境控制药物释放。所述颗粒可由药物和功能组分组成，所述功能组分在升高的pH下遏制了溶蚀或崩解，使得观察到药物的较慢的和/或不完全的释放。片剂的颗粒外的部分可主要含有pH控制试剂，其需要被迅速地释放和反应。
实施例3
Eudragit® E PO (EPO)是基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物。技术文献表明该聚合物在酸中，最多至pH为5中是可溶的；在高于5的pH下其溶胀而不溶解。制备在EPO聚合物中含有5%的阿普唑仑的干法造粒，且在-16目和+20目 (16/20) 下和在-20目和+30目(20/30)下收集粒度级份(sizefraction)。在其中EPO是可溶的低pH(pH为1.5)下和在其中EPO可溶性较低的高pH(pH为6)下进行颗粒粒度级份的溶出。结果在图3中显示。在低pH下，与粒度无关，在15分钟内发生阿普唑仑的快速和完全的释放。然而在高pH下，对于两种粒度级份来说阿普唑仑的释放显著的更慢和不完全，但对于较小级分来说稍微升高。必须注意到的是该溶出模拟代表了当按照指示(pH为1)和过量(pH为6)摄取片剂时在潜在的pH极值下的静态的pH条件。下一个实施例考察了在按照指示摄取时不影响pH但当过量摄入时将快速地增加pH的pH调节体系。
实施例4
使用碳酸钙作为主要的pH调节试剂的后续的试验导致了阿普唑仑从5%的阿普唑仑/EPO颗粒中在15分钟内的相对快速的释放(60%)。尽管之前对于碳酸钙观察到在10分钟内pH变为pH=5(图1)已经可被认为是快速的，考虑到阿普唑仑的释放也是快速的且在15分钟内完成，对于阿普唑仑/EPO颗粒来说碳酸钙可能不足够快速地影响pH改变。在更早期的试验中，碳酸氢钠已经显示出具有更为快速的pH影响，在小于2分钟内将酸媒介物从pH为1升高至pH为6。因此，添加碳酸氢钠到原型制剂主要是为了控制快速pH升高，且碳酸钙用于对升高pH的更为持续的控制。本发明的代表性的制剂在下表中显示：
| 组分 | Wt% | Wt (mg) |
| 阿普唑仑(5%)，在Eudragit E PO (20/30)中 | 3.195 | 20.00 |
| 碳酸氢钠 | 79.87 | 500.0 |
| 碳酸钙 DC | 15.97 | 100.0 |
| 硬脂酸镁 | 0.958 | 6.0 |
| 总量 | 100 | 626.0 |
将原型制剂制成片剂并进行动态测试，其中pH调节试剂包含在片剂中且在0.55 NHCl媒介物(pH约为1.6)中动态地反应。测试并比较具有和不具有自调节的多个片剂剂量和具有自调节的单个剂量。监控溶出媒介物的pH和药物释放。如在图4中所显示的，观察到原型多个片剂中pH的快速升高，且在小于两分钟内发生了至pH为6的升高。因此，可通过片剂中含有的pH调节试剂来影响pH的快速升高。
更进一步地，如在图5中所显示的，单个片剂在15分钟内释放阿普唑仑，显示了单个片剂的立即释放特性不受装载(on-board)的、自调节的体系影响。然而，具有自调节的多个片剂显示了大约在15分钟内的单个剂量释放，且在大约2小时的时间内的过量阿普唑仑的延迟释放。通过比较，不具有自调节的多个片剂显示了在大约15分钟内释放了整个的阿普唑仑剂量(大约9 mg)，然而在相同的时间点在具有自调节的多个片剂中仅释放了20%的阿普唑仑。明显地，原型自调节阿普唑仑片剂已经显示了按照预期释放单个剂量的阿普唑仑，但多个片剂与不具有自调节的过量剂量相比显示了对过量剂量的释放的延迟。
本领域技术人员将意识到的是可在不背离正如所广泛描述的本发明的精神和范围的情况下，对在特定实施方案中示出的本发明做出众多变化和/或修饰。更进一步地，通过以如本文阐述其全部内容的方式引用来将上面引用的每一篇参考文献并入于此。
Claims (5)
1.防止滥用的药物组合物，其包含：
a. 药物活性成分；
b. 酸溶性成分，其是基于甲基丙烯酸二甲基氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物；和
c. 缓冲成分，其以当以预期剂量的过量摄入所述组合物时足以增加胃pH至大于4的量存在；
其中当以预期剂量的过量摄入所述组合物时，所述酸溶性成分和所述缓冲成分延迟所述药物活性成分的释放；并且其中所述缓冲成分包含碳酸钙、碳酸氢钠、氧化镁、磷酸三钠，或它们的组合中的一种或多种。
2.权利要求1的组合物，其中所述药物活性成分是易被滥用的药物。
3.权利要求1的组合物，其中所述药物活性成分是具有窄治疗指数的药物。
4.权利要求1的组合物，其中所述药物活性成分包含在所述酸溶性成分的基质之中。
5.权利要求1的组合物，其中所述酸溶性成分以所述药物组合物的1wt%-40wt%的量存在。
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