CN103119435A - 用于检测饮料中的药物的方法和试剂 - Google Patents
用于检测饮料中的药物的方法和试剂 Download PDFInfo
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Abstract
本发明涉及一种防止化学药品投放的方法,所述方法包括:将药剂加入饮料溶液中,所述药剂含有活性物质和至少0.05mg,优选0.2-5mg,更优选0.3-2mg的至少一种水溶性着色剂,所述着色剂选自靛蓝胭脂红或E132、赤藓红或E127、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF;检测所述药剂,所述检测特征在于饮料颜色的即时变化;本发明还涉及所述着色剂用于防止化学药物投放的用途,以及还涉及含有所述着色剂的非薄膜包衣的固体药剂。
Description
技术领域
本发明的主题是一种用于防止暗中给予化学药物的方法。
背景技术
一些年来,违法者一直利用某些物质的催眠性质在人们不知觉的情况下对他们用药。罪犯毫不犹豫地将药剂加入受害者的饮料中以改变其行为或甚至使其完全失忆。一旦受害者丧失了全部意识,罪犯就能够从他们处获取利益:偷窃、强夺或敲诈钱财。而且,这种不考虑规定剂量的药剂摄入可导致严重后果,特别是如果其与一定量的酒精一起吸收的话。该药剂还可与受害者之前已经摄入的其他药物产生有害的相互作用。
从现有技术的状态来看,一种***,氟硝安定,已知因其易于溶解和感觉不到的特性而广泛用于非法目的。已经改变了该药物的制剂以形成外面为绿色和里面为蓝色的薄膜包衣的片剂并因此缓慢溶解而释放蓝颜色。然而,蓝颜色仅在浸入液体一刻钟后才可见;因此,如果受害人立即饮用他们的饮料,就不能够发觉偷偷加入的***。
从现有技术的状态还已知文献WO 2005/059541,其涉及用于检测偷偷加入饮料中的药物的试剂盒。然而,该***仅保护拥有这种试剂盒的人。
因此,关键地和迫切地需要找到一种在暗中给予化学药物的情形下,不凭借检测装置或试剂盒就能够即时检测药物的非法滥用的方法。
发明内容
因此,本发明的主要目的是这样一种方法,其利用包含至少一种使得能够即时检测非法加入饮料中的药剂的化合物的药剂。本发明还涉及该药剂。
本发明的目的是提供一种用于防止暗中给予化学药物的新的方法。该目的通过用于防止暗中给予化学药物的方法来实现,所述方法包括:
-将包含活性物质和至少0.05mg,优选0.2-5mg,更优选0.3-2mg的至少一种口服可接受的水溶性着色剂的固体药剂溶解于饮料中,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿(quinzarin green)SS、橙II、酒石黄和日落黄FCF,以及
-通过饮料颜色的即时变化检测所述药剂。
本发明涉及至少0.05mg,优选0.2-5mg,更优选0.3-2mg的至少一种水溶性着色剂在用于防止暗中给予化学药物的固体药剂中的用途,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF。
本发明还涉及用于防止暗中给予化学药物的非薄膜包衣的固体药剂,其包含活性物质和至少0.05mg,优选0.2-5mg,更优选0.3-2mg的至少一种水溶性着色剂和药学可接受的赋形剂,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF。
在本发明中,“非薄膜包衣的固体药剂”应理解为是指在其意图用于与其溶解的介质或与黏膜接触的最外层表面不包括涂层的任何固体形式。因此,在片剂的情形中,后者将不包括外层包衣。但是,活性物质在该片剂内可存在于包衣颗粒中或以包衣颗粒的形式存在。
“暗中给予化学药物”应理解为是指出于犯罪目的或恶意地在受害人不知觉的情况下给予精神活性物质。
发明详述
构成本发明的各种元素的详细描述等同地适用于本发明的所有主题:方法、用途和组合物。
根据本发明的固体药剂包含活性物质和至少一种使得能够即时检测非法加入饮料中的所述固体药剂的水溶性着色剂。
整合到药剂中的着色剂使得能够对其中引入该药剂的饮料着色。由于该着色剂可使所有类型的饮料着色,不管饮料是透明的还是不透明的(除了非常深的饮料如咖啡或可口可乐以外),因此该着色剂特别有用。
水溶性着色剂
根据本发明的第一方面,可用于本发明的水溶性着色剂是可溶于至少部分包含水的任何液体中且药学可接受的着色剂。这种着色剂可选自如下:靛蓝胭脂红或E 132、赤藓红或E 127、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF。
着色剂以足够的量存在以使得色彩强度足以被裸眼察觉并且可以在将该药剂加入饮料中后的前几秒钟显现出来。因此,着色剂在药剂中以至少0.05mg,优选0.2-5mg,更优选0.3-2mg的比例存在。
当着色剂是靛蓝胭脂红时,立即从该药剂中释放蓝色,例如如果饮料为无色饮料如水或柠檬汽水,则使饮料着色为蓝色,或如果饮料为黄色饮料如橙汁,则使饮料着色为绿色。
赤藓红,另一种着色剂,使饮料着色为红色。
在本发明中,“即时”应理解为是指在将药剂加入饮料后少于一分钟,优选少于30秒,更优选少于15秒内发生的饮料感官特性的变化。例如在本发明的情况中,外观或颜色变化发生在少于30秒,优选少于15秒内。
根据本发明的另一方面,还可将术语“即时”定义为在将药剂加入饮料并搅拌后少于一分钟、优选少于30秒,更优选少于15秒内发生的饮料感官性质的变化。
“搅拌”应理解为是指液体处于运动中的情景,例如通过吸管、调羹或通过容器的移动。
根据本发明的不同的具体实施方式以及除了上述的使得能够对掺杂的饮料着色的着色剂以外,还可通过固体药剂中选自以下的至少一种化合物的存在来实现饮料中活性物质的检测:
-遮光剂,和/或
-荧光剂,和/或
-漂浮颗粒,和/或
-口中可感知的颗粒,和/或
-泡腾微颗粒。
在本发明的情况中,所述化合物可单独或组合地结合到固体药剂中。例如,可制备包含着色剂以及漂浮颗粒的药剂,或可提供实际上包含着色剂和上述化合物的混合物的固体药剂。
有利地,固体药剂包含至少一种着色剂和漂浮颗粒和/或口中可感知的颗粒和/或泡腾微颗粒。
遮光剂
遮光剂是可能使得饮料浑浊的无机化合物。这些化合物可以是硅酸盐(如硅酸镁、硅酸铝(特别是高岭土)、硅酸镁铝、硅酸钙)、二氧化钛及它们的混合物。这些化合物通常以至少15mg,优选15-100mg,更优选20-60mg,以及进一步优选25-40mg的量存在。在低于15mg时,不透明性可能更难以用裸眼检测。
遮光剂可能使得其中引入药剂的饮料浑浊。因此,饮料不仅变颜色,而且变浑浊,这进一步吸引想要该饮料的人的注意并因此有助于觉察到不希望的活性物质。
这些试剂对于使透明和清澈的饮料,如水、白葡萄酒、苹果汁,以及烈酒,如伏特加、白朗姆酒浑浊特别有用。
在将药剂引入到所述饮料中并优选搅拌后前几秒,饮料的不透明外观出现,同时伴随着颜色的变化。
荧光剂
固体药剂还可以包含至少0.1mg,优选至少1mg,更优选0.2-5mg,进一步优选0.3-2mg的量的荧光剂。该荧光剂可以是荧光素及其衍生物或靛青绿。
在紫外光存在下以及黑暗中,荧光剂在所有类型的饮料中都是可见的。这使得可能通过从掺杂的饮料中发射的荧光揭示包含荧光剂的药剂,这种荧光剂特别可用于当受害者处于易于将外物加入饮料中的黑暗空间中时警示受害者。
有利地,变为发荧光的掺杂饮料比包含具有着色剂但不含荧光剂的药剂的掺杂饮料更易于识别,从而使得可能立即警示受害者。
漂浮颗粒和口中可感知的颗粒
药剂可包含漂浮颗粒和/或口中可感知的颗粒。这些颗粒是包含不溶性的或通过不溶性聚合物涂覆或通过脂质材料涂覆变得在水或醇溶液中不溶的空白载体的微颗粒。
微颗粒
变得在水或醇溶液中不溶的微颗粒理解为是由覆盖有至少一层不溶于水或醇溶液的材料的溶于水或醇溶液中的材料构成的空白载体,且不溶于水或醇溶液的材料的作用是限制或实际上防止所述介质向载体的核心渗透。
不溶于水或醇溶液中的空白载体有利地包含至少一种选自以下的疏水性赋形剂:纤维素、纤维素衍生物(微晶纤维素)、磷酸盐衍生物(钙磷酸盐)、二氧化硅和硅酸盐衍生物(硅酸镁、硅酸铝及其混合物)和巴西棕榈蜡。
在本发明的情况中,还可使用可溶于水或醇溶液中的空白载体。可溶性空白载体可包含至少一种选自以下的赋形剂:淀粉、蔗糖、多元醇如甘露醇和乳糖以及它们的混合物。
重要的是通过用以下任一的涂层覆盖可溶性空白载体而使其变得在水或醇溶液中不可溶:
-包含至少一种疏水性聚合物和可能的惰性填充剂和/或增塑
剂和/或表面活性剂的聚合物性质的涂层,
-或包含至少一种脂质材料的脂质性质的涂层。
在本发明的情况中,不溶性空白载体也可由至少一种上述的涂层覆盖,条件是这不会不利地增加颗粒的密度。
涂层比表示构成涂层的干物质量相对于涂覆前微颗粒的总质量(作为干物质)的比。该涂层比为0.1%-50%m/m,优选为2%-30%m/m,以及更优选为5%-40%m/m。
该涂层比使得所得到的颗粒具有小于将引入所述颗粒的饮料的密度,优选地密度小于1,使得其保持在将引入其中的饮料的表面上。这样的颗粒被称为漂浮颗粒。
聚合物涂层:
用于确保微颗粒的不溶性的疏水性聚合物选自以下产品:非水溶性纤维素衍生物、(甲基)丙烯酸共聚物衍生物、聚醋酸乙烯酯衍生物和它们的混合物。更优选地,疏水性聚合物选自以下产品:乙基纤维素、醋酸丁酸纤维素、醋酸纤维素、以商品名Eudragit销售的A型和B型铵基甲基丙烯酸酯共聚物,特别是聚(丙烯酸乙酯、甲基丙烯酸甲酯、甲基丙烯酸三甲基铵基乙基酯)家族的EudragitRS 30D、EudragitNE 30D、EudragitRL 30D、EudragitRS PO和EudragitRL PO、聚醋酸乙烯酯以及它们的混合物。
疏水性聚合物的量为涂层干重的50-100%,优选为70-100%。
惰性填充剂可以疏水性涂层聚合物干重的0-50%m/m,优选0-20%m/m,更优选5-20%m/m的比例存在。
均匀分布于涂层中的惰性填充剂选自,特别是滑石、无水胶体二氧化硅、硬脂酸镁、单硬脂酸甘油酯和它们的混合物。
当通过水性途径形成涂层时,可将增塑剂以疏水性涂层聚合物干重的0%-50%m/m,优选2%-25%m/m的比例添加到涂层分散体中。
增塑剂特别选自以下产品:甘油及其酯(优选选自以下亚组:中链甘油三酯、乙酰化甘油酯、单硬脂酸甘油酯、三醋酸甘油酯、三丁酸甘油酯)、邻苯二甲酸酯(优选选自以下亚组:邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯和邻苯二甲酸二辛酯)、柠檬酸酯(优选选自以下亚组:柠檬酸乙酰基三丁酯、柠檬酸乙酰基三乙酯、柠檬酸三丁酯和柠檬酸三乙酯)、癸二酸酯(优选选自以下亚组:癸二酸二乙酯和癸二酸二丁酯)、己二酸酯、壬二酸酯、苯甲酸酯、氯丁醇、聚乙二醇、植物油、富马酸酯(优选富马酸二乙酯)、马来酸酯(优选马来酸二乙酯)、草酸酯(优选草酸二乙酯)、琥珀酸酯(优选琥珀酸二丁酯)、丁酸酯、鲸蜡醇的酯、丙二酸酯(优选丙二酸二乙酯)、蓖麻油(后者是特别优选的)以及它们的混合物。
表面活性剂任选以增塑剂干重的0-30%m/m,优选0-20%m/m,以及更优选5-15%m/m的比例存在于涂层中。表面活性剂优选选自以下产品:脂肪酸的碱金属或碱土金属盐(优选十二烷基硫酸钠和多库酯钠)、聚乙氧基化油(优选聚乙氧基化氢化蓖麻油)、聚氧乙烯-聚氧丙烯共聚物、聚乙氧基化脱水山梨糖醇酯、聚乙氧基化蓖麻油衍生物、硬脂酸盐(优选钙、镁、铝或锌的硬脂酸盐)、聚山梨酸酯、硬脂基富马酸盐(优选钠盐)、山嵛酸甘油酯、苯扎氯铵、乙酰基三甲基铵溴化物、鲸蜡醇以及它们的混合物。
脂质涂层:
也可通过用脂质材料涂覆来包被微颗粒。
根据本发明的脂质材料特别选自以下产品:棕榈酰硬脂酸甘油酯、蜡、聚氧化甘油酯(polyoxyl-glyceride)和山嵛酸甘油酯。
脂质材料的量是涂层干重的50-100%,优选80-100%。
选择脂质材料的量以使得所得到的颗粒的密度小于其将引入其中的饮料的密度,优选小于1的密度,从而颗粒保持在将引入其中的饮料的表面上。
漂浮颗粒的总直径(空白载体,必要时任选地涂覆)为50-500μm,优选为200-500μm,以便在口中不可感觉并确保对于患者的一定舒适性。另一方面,在口中可感觉的颗粒的总直径大于500μm,优选大于1mm,以便可由嘴唇感觉和尤其被味蕾感觉到。漂浮颗粒和在口中可感知的那些颗粒的直径由干式激光粒度测量(Malvern激光粒度计:Mastersizer 2000)测定。
总体有利地,可在口中感知的所述颗粒是漂浮颗粒。
包含在药剂中的漂浮颗粒和/或在口中可感知的颗粒的量至少为25mg,优选40mg。
优选地,漂浮的和/或在口中可感知的颗粒可通过至少一种如下着色剂着色:靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄、日落黄FCF,和/或可通过选自荧光素及其衍生物和靛青绿的荧光剂的方式被赋予荧光。
有利地,活性物质还可用至少一种上述的着色剂着色,以便防止活性物质与漂浮的和/或口中可感知的颗粒之间的可能的分选。
还有利地,漂浮的和/或口中可感知的颗粒适合用于所有类型的饮料。
从将药剂引入饮料中起,漂浮颗粒立即上升到饮料的表面并裸眼可见。这些颗粒保持在液体表面上至少5分钟且优选至少4小时,更优选至少12小时。
在口中可感知的颗粒还可以是漂浮颗粒。在受害者摄入第一口掺杂饮料时这些颗粒可被受害者立即察觉。
泡腾微颗粒
固体药剂还可包含泡腾微颗粒。泡腾微颗粒包含当存在苏打水或啤酒类型的酸性饮料时产生泡腾的碱性赋形剂。
根据第一方面,微颗粒包含涂覆有碱性试剂颗粒的空白载体(可溶的、不溶的或变得不溶的),所述碱性试剂选自碳酸氢钠、碳酸钙或它们的混合物。
碱性试剂的量至少大于5mg,优选大于10mg以及更优选大于20mg。
当将含有泡腾微颗粒的药剂加入酸性饮料中时,与存在的酸接触的碱性试剂的颗粒产生裸眼可见的泡腾。
根据本发明的具体实施方式,泡腾微颗粒可以是涂覆的。涂层具有充分的渗透性以在至少三十分钟到一小时内允许释放泡腾剂的颗粒。涂层包含纤维素衍生物、乙烯基衍生物或丙烯酸衍生物家族的至少一种不溶性聚合物。其可包含增塑剂和/或表面活性剂。可通过添加可溶的成孔剂如纤维素的可溶性衍生物、聚维酮或崩解剂来使其具有渗透性。
包含在药剂中的泡腾微颗粒的量至少为25mg,优选40mg。
优选地,泡腾微颗粒可通过选自以下的至少一种着色剂着色:靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF,和/或可通过选自荧光素及其衍生物和靛青绿的荧光剂的方式被赋予荧光。
因此,在引入包含所述微颗粒的药剂后,会在饮料的表面上出现泡腾。
活性物质
抗焦虑药是一类精神药物,优选选自阿普***、溴西泮、利眠宁、氯巴占、氯硝西泮、氯噻西泮、氯氮***、艾司***、氟硝西泮、劳拉西泮、氯甲西泮、咪达***、硝西泮、去甲西泮、奥沙西泮、普拉西泮、替马西泮、四氢西泮、***仑、氯氮平、奥氮平、哌仑西平、唑吡坦、佐匹克隆、扎来普隆、甲丙氨酯和依替福辛。
阿片样物质优选选自阿芬太尼、阿尼利定、布托啡诺、卡芬太尼、可待因、二乙酰***(***)、右丙氧芬、脑啡肽、内啡肽、芬太尼、氢可酮、氢***酮、***、***、纳布啡、羟考酮、羟***酮、戊唑辛、陪替丁(哌替啶)、丙氧酚、瑞芬太尼、舒芬太尼、曲马多和丁丙诺啡。
根据本发明的特定方面,存在于药剂中的活性物质是固体形式。
根据具体实施方式,活性物质还可通过至少一种着色剂着色,着色剂可以是上述之一,和/或可以通过添加荧光剂例如上述的荧光剂被赋予荧光。
根据另一实施方式,活性物质可被涂覆到漂浮和/或在口中可感知的颗粒上。
饮料
在本申请中,术语饮料用于指冷饮料和热饮料,例如水、苏打水、葡萄酒(红葡萄酒、白葡萄酒或淡红葡萄酒)、啤酒(棕色啤酒或淡啤酒)、利口酒、烈酒(如伏特加、朗姆酒、白兰地、龙舌兰酒、威士忌)、鸡尾酒、果汁(如橙汁或葡萄汁)、汽水(如可口可乐或柠檬水)、咖啡、茶或药茶。这些饮料是指示性的而决非限制性的。
在本发明中,包含药剂可引入其中的饮料的容器具有3厘升和1升之间的容量。
制备过程
根据活性物质的形式,其可以是微晶、微颗粒的形式或形成悬浮液中或涂覆到空白载体上。
当活性物质被涂覆到空白载体上时,活性物质是水性或有机溶剂中的溶液或悬浮液的形式。还可添加粘合剂、稀释剂和/或防静电剂。
空白载体可以是任何化学上和药学上惰性的赋形剂,特别是以晶体或无定形形式存在。作为例子,可举出糖的衍生物如乳糖或蔗糖、水解淀粉(麦芽糊精)或还可举出纤维素。混合物如蔗糖和淀粉或基于纤维素的混合物也可用于制备球形空白载体。
活性物质还可通过本身已知的方法制成微颗粒形式,例如是挤出-滚圆、在穿孔的涡轮式混合器中、在流化床中涂覆活性物质以及其他。
在“Remington’s pharmaceutical Sciences,第16版,1980年,Mack Publ.Co.of Easton,PA,USA”中给出的通过干或湿法造粒制备微颗粒的各种方法可用于本发明中。
活性物质可用基于希望的释放类型(即时、受控或延迟)或其掩味性质选择的聚合物涂覆。
接着活性物质与至少一种着色剂,可能地与可防止暗中给予化学药物的另一化合物,以及与至少一种药学上可接受的赋形剂组合。
本发明适合于任何药剂。根据有利的实施方式,本发明涉及用于防止暗中给予化学药物的固体非薄膜包衣的药剂,所述药剂包含活性物质和至少0.05mg,优选0.2-5mg,更优选0.3到2mg的至少一种水溶性着色剂,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF,所述着色剂使得能够立即改变所述固体非薄膜包衣药剂加入其中的饮料的颜色。
特别地,这种药剂可以是选自非包衣的片剂如常规片剂、含片、舌下片、咀嚼片、泡腾片、分散片、口腔分散片、用于扁囊或胶囊的粉末以及薄膜的口服剂型。
本发明更特别地可用于即时释放的药物组合物,因为罪犯想要尽可能快速地获得丧失警惕的效果。但是,它可适应于控制释放的形式。
本领域技术人员知道如何根据药剂和希望的释放类型来改变制剂。
用于本发明的固体非薄膜包衣药物组合物中的药学可接受的赋形剂是常规使用的赋形剂。
例如可列举如下:
-粘合剂:例如纤维素衍生物如HPMC(特别是Pharmacoat603和Pharmacoat606级)、或羟丙基纤维素或羟乙基纤维素、微晶纤维素、聚乙烯吡咯烷酮衍生物(特别是PVP K 30级)、聚乙二醇衍生物(特别是分子量为600-7000的聚乙二醇,特别是如PEG 4000和PEG 6000,以及它们的混合物)以及乙烯基衍生物(如聚乙烯醇);
-稀释剂:例如可溶性稀释剂(如乳糖或甘露醇)以及纤维素衍生物(如微晶纤维素);
-防腐剂:例如对羟基苯甲酸酯类,以及抗氧化剂(如抗坏血酸);
-增溶剂:例如泊洛沙姆和环糊精;
-崩解剂:例如交聚维酮和交联羧甲基纤维素钠;
-甜味剂:如阿司帕坦和乙酰舒泛钾;
-润滑剂:硬脂酸镁、硬脂基富马酸钠和棉籽油;
-调味剂:如薄荷、柠檬、黑樱桃香料等;
-表面活性剂:脂肪酸的碱金属或碱土金属盐、十二烷基硫酸钠和多库酯钠、聚乙氧基化油(优选聚乙氧基化氢化蓖麻油、聚氧乙烯-聚氧丙烯共聚物、聚乙氧基化脱水山梨糖醇酯、聚乙氧基化蓖麻油衍生物)、硬脂酸盐(优选硬脂酸的钙、镁、铝或锌盐)、聚山梨醇酯、硬脂基富马酸盐(优选钠盐)、山嵛酸甘油酯、苯扎氯铵、乙酰基三甲基溴化铵、鲸蜡醇以及它们的混合物;以及
-助流剂:例如二氧化硅、滑石以及它们的混合物。
在本发明的情况中,口腔分散片应理解为是指“与唾液接触不到40秒内在口中崩解的多颗粒片剂”。根据具体实施方式,本发明涉及基于赋形剂和具有固有压片特性的涂覆的活性物质颗粒的混合物的这样的片剂。赋形剂相对于涂覆的活性物质的混合比例为0.4到6重量份,优选1到4重量份。赋形剂的混合物包含:
-崩解试剂或崩解剂,
-具有粘合性质的可溶性稀释剂,
-润滑剂,
-可能地,渗透剂、甜味剂和香料,
-使得可以防止暗中给予化学药物的着色剂,
-以及可能地至少一种使得可能防止暗中给予化学药品的化合物,其选自遮光剂、荧光剂、漂浮颗粒、口中可感知的颗粒和/或泡腾微颗粒。
崩解剂和可溶试剂相对于片剂质量的比例,前者为1到15%重量,优选2到7%重量,后者为30-90%重量,优选40到70%重量。
具有粘合性质的可溶性稀释剂由少于13个碳原子的多元醇构成,其为颗粒平均直径为100-500微米的可直接压片的产物的形式,或为颗粒平均直径小于100微米的粉末的形式,这种多元醇优选选自:甘露醇、木糖醇、山梨醇和麦芽糖醇,山梨醇不可单独使用。
崩解剂选自特别包括以下的组:本领域中称为交联甲羧纤维素的交联羧甲基纤维素钠、交聚维酮及其混合物。通过这种崩解剂的选择和比例,当片剂保存于温度高至至少30℃的密封包装中时其保持对于正常片剂处理条件可接受的硬度。
优选用于这种赋形剂混合物中的润滑剂选自硬脂酸钠硬脂基富马酸钠、硬脂酸、微粉化聚乙二醇(微粉化Macrogol 6000)及它们的混合物。其可以以相对于片剂的总质量0.05-2%的比例使用。
作为渗透剂,使用特别地选自包括具有对水性溶剂的高亲和力的二氧化硅,例如以商标名Syloid更为人所知的沉淀二氧化硅、麦芽糊精、1-环糊精及其混合物的组的化合物。
渗透剂使得能够产生促进唾液渗透并因此有助于片剂的较好崩解的亲水性网络。
记载于FR 2785538、WO 0027357、FR 2679451、WO 93/01805、FR 2766089、WO 00/51568、FR 2790387、WO 03/039520和FR2831820中的用于口腔分散片剂的各种化合物和制备方法可用于本发明中。
以下,特别地通过仅用于说明的实施例详细说明本发明。
实施例
实施例1
制备含有5mg唑吡坦并具有如下组成的口腔分散片:
组分 | % | mg/单位 |
唑吡坦颗粒 | 32.8 | 41.05 |
微晶纤维素 | 10.0 | 12.50 |
甘露醇 | 43.7 | 54.57 |
交聚维酮 | 10.0 | 12.50 |
着色剂E132 | 0.4 | 0.50 |
阿司帕坦 | 1.0 | 1.25 |
香料 | 0.1 | 0.13 |
二氧化硅 | 1.0 | 1.25 |
硬脂酸镁 | 1.0 | 1.25 |
总计 | 100.0 | 125.0 |
如下制备口腔分散片。
首先制备具有如下百分比组成的唑吡坦颗粒:
NPTAB 190(180-220μm) | 56 |
酒石酸唑吡坦 | 13 |
羟丙甲纤维素603 | 7 |
1N HCl | 2 |
乙基纤维素水分散体ECD30 | 13 |
羟丙甲纤维素603 | 6 |
柠檬酸三乙酯 | 3 |
借助于HCl将酒石酸唑吡坦溶解于水中,然后通过添加羟丙甲纤维素603制备分散体。将NPTAB 190糖球和上述制备的分散体引入GPCG1流化床(Glatt)中。然后引入乙基纤维素水分散体ECD30、柠檬酸三乙酯和羟丙甲纤维素603的水性分散体以获得掩味涂层。
接着唑吡坦颗粒与压片赋形剂混合。然后将粉末状混合物在带有圆形凸形冲头的旋转压片机(SVIAC PR12)上以5kN的压力压片。
得到具有如下性质的7mm直径的125mg片剂:
硬度:24N
崩解(根据欧洲药典6.1专论2.9.1测量):15秒
脆性(根据欧洲药典6.1专论2.9.7测量):0.03%。
所述片剂显示令人愉快的口感。
将一药片加入含有250ml水的透明容器中。药片一崩解即出现强烈的蓝色。
将第二药片加入含有250ml橙汁的透明容器中。果汁的橙色立即变成强烈的绿色。
实施例2
制备含有10mg唑吡坦的常规速释片剂。
% | Mg/单位 | |
唑吡坦颗粒 | 32.8 | 82.0 |
微晶纤维素 | 10.0 | 25.0 |
乳糖 | 32.7 | 81.75 |
硅酸钙 | 20.0 | 50.0 |
聚维酮 | 3.0 | 7.5 |
二氧化硅 | 0.9 | 2.25 |
着色剂E132 | 0.1 | 0.25 |
硬脂酸镁 | 0.5 | 1.25 |
总计 | 100.0 | 250.0 |
首先制备吡唑坦颗粒。如实施例1制备吡唑坦颗粒。
然后将吡唑坦颗粒与上表中所述的赋形剂混合。然后将粉末状混合物压片。
然后将一药片溶解于一杯无果肉的橙汁中。在加入药剂并搅拌后立即以裸眼可见的方式显现绿色颜色和浑浊。
实施例3
制备各含有10mg吡唑坦并具有如下配方的两种类型口腔分散片:
组分 | % | mg/单位 |
唑吡坦颗粒 | 32.8 | 82.1 |
微晶纤维素 | 9.6 | 23.90 |
甘露醇 | 30.0 | 75.00 |
交聚维酮 | 5.0 | 12.50 |
漂浮颗粒 | 20.0 | 50.00 |
着色剂E132 | 1.0 | 2.50 |
香料 | 0.1 | 0.25 |
二氧化硅 | 1.0 | 2.50 |
硬脂酸镁 | 0.5 | 1.25 |
总计 | 100.0 | 250.0 |
采用上表中的组分,如实施例1制备这些片剂。
对于第一系列片剂(C1),如下制备漂浮颗粒:
用乙基纤维素、三醋精和滑石的水性分散体涂NPTAB 190(180-220μm)空白片。涂层因子是干质量的30%且滑石/聚合物比率是1∶2。
对于第二系列片剂(C2),漂浮颗粒是涂覆有棕榈酰硬脂酸甘油酯的磷酸二氢钙二水合物的磷酸盐颗粒。棕榈酰硬脂酸甘油酯/磷酸钙的比率为1∶4。
两个系列的片剂在不到30秒内崩解,并显示令人愉快的口感。
将各个类型的一个药片加入一杯水中。崩解立即发生且水转化为强烈的蓝色并在表面上裸眼可见颗粒的存在。这些漂浮颗粒在表面上可见超过3个小时。
实施例4
制备含有10mg唑吡坦、漂浮颗粒和着色剂并具有如下配方的口腔分散片。
mg/单位 | % | |
酒石酸吡唑坦涂覆颗粒* | 80.00 | 17.8 |
Avicel PH 200 | 45.00 | 10.0 |
甘露醇SD 200 | 65.05 | 14.5 |
漂浮颗粒 | 200.00 | 44.4 |
科利当CL | 45.00 | 10.0 |
黑樱桃香料 | 0.45 | 0.10 |
阿司帕坦 | 4.50 | 1.00 |
日落黄(E110) | 1.00 | 0.22 |
Syloid 244FP | 4.50 | 1.00 |
硬脂酸镁 | 4.50 | 1.00 |
总计 | 450.0 | 100.0 |
采用上表中的组分,如实施例1制备这些片剂。
如下制备漂浮颗粒:用乙基纤维素和myvacet 9-45的水性分散体涂覆NPTAB 190(180-220μm)空白片。涂层因子是干质量的30%以及增塑剂/聚合物的比率是24%。
将药剂加入一杯水中并搅拌后,药剂使水着色为中度橙黄并释放在表面上可见超过三个小时的漂浮颗粒。
实施例5
制备含有基于巴西棕榈蜡微颗粒的漂浮颗粒和着色剂的常规片剂。
mg/单位 | % | |
颗粒状盐酸羟考酮 | 10.89 | 4.36 |
Avicel PH 102 | 25.00 | 10.00 |
甘露醇SD 200 | 133.11 | 53.24 |
巴西棕榈蜡小球 | 50.00 | 20.0 |
淀粉1500 | 25.00 | 10.00 |
靛蓝胭脂红E132 | 1.00 | 0.40 |
Syloid 244FP | 2.50 | 1.00 |
硬脂酸镁 | 2.50 | 1.00 |
总计 | 250.0 | 100.0 |
在高剪切混合制粒机中用4.1%的HPMC 603将羟考酮颗粒化。然后将活性物质与上述配方的压片赋形剂混合。然后将混合物在装配有圆形凸形冲头的压片机(SVIAC PR12)上,以16kN的压力压片。
得到8.5mm直径的250mg片剂,其具有如下性质:
硬度:95N
崩解(根据欧洲药典6.1专论2.9.1测量):3分钟
脆性(根据欧洲药典6.1专论2.9.7测量):0.1%。
在将所得片剂加入饮料中后立即产生均匀的蓝颜色,并释放在表面上可见超过3个小时的漂浮颗粒。
实施例6
制备含有5mg无水盐酸羟考酮和着色剂的口腔分散片。
% | mg/单位 | |
盐酸羟考酮颗粒* | 22.0 | 29.65 |
Avicel PH 102 | 10.0 | 13.50 |
甘露醇SD 200 | 53.4 | 72.09 |
交聚维酮 | 10.0 | 13.50 |
靛蓝胭脂红E132 | 0.4 | 0.54 |
阿司帕坦 | 2.0 | 2.70 |
香料 | 0.50 | 0.675 |
Syloid 244FP | 0.50 | 0.675 |
硬脂酸镁 | 1.25 | 1.69 |
总计 | 100.0 | 135.00 |
如下制备口腔分散片。
首先制备具有如下百分比组成的羟考酮颗粒:
盐酸羟考酮颗粒 | % | mg/单元 |
NPTAB 250 | 54.0 | 16.01 |
盐酸羟考酮 | 18.3 | 5.43 |
羟丙甲纤维素603 | 7.6 | 2.25 |
Eudragit NE30D vs | 16.7 | 4.95 |
Syloid 244FP | 3.4 | 1.01 |
总计 | 100.0 | 29.65 |
将羟考酮溶解于水中,然后通过添加羟丙甲纤维素603制备分散体。将糖球NPTAB 250引入GPCG 1(Glatt)流化床中,以及将上述制备的分散体喷到这些糖球上。然后喷涂Eudragit NE30D和Syloid的水性分散体以获得掩味的涂层。
然后羟考酮颗粒与压片赋形剂混合。然后将粉末状混合物在装配有直径为7mm圆形的凸形冲头的旋转压片机(SVIAC PR12)上压片。得到135mg片剂。从将一药片加入一杯水中然后搅拌起,产生强烈和均匀的蓝色颜色。
实施例7
制备含有10mg盐酸羟考酮和着色剂的常规片剂。
mg/单位 | % | |
颗粒化盐酸羟考酮 | 10.89 | 5.45 |
Avicel PH 102 | 20.00 | 10.00 |
甘露醇SD 200 | 144.12 | 72.06 |
淀粉1500 | 20.00 | 10.00 |
靛蓝胭脂红E132 | 1.0 | 0.50 |
Syloid 244FP | 2.0 | 1.00 |
硬脂酸镁 | 2.0 | 1.00 |
总计 | 200.0 | 100.0 |
如实施例5制备颗粒化羟考酮。然后将其与压片赋形剂混合以在旋转压片机上得到8mm直径的200mg片剂。溶解于一杯苹果汁中的该片剂在不到一分钟内产生可见的绿色颜色。
实施例8
制备含有10mg吡唑坦、着色剂和遮光剂的常规片剂。
mg/单位 | % | |
酒石酸吡唑坦 | 10.00 | 4.0 |
Avicel PH 200 | 25.00 | 10.0 |
乳糖DCL 21 | 152.75 | 61.1 |
硅酸钙(FM 1000) | 50.00 | 20.0 |
PVP K30 | 7.50 | 3.0 |
着色剂E132 | 1.00 | 0.4 |
Syloid 244FP | 2.50 | 1.0 |
硬脂酸镁 | 1.25 | 0.5 |
总计 | 250.0 | 100.0 |
在该实施例中,活性物质以粉末状态直接与压片赋形剂混合。该混合物可在装配有直径为8.5mm的圆形冲头的旋转压片机上得到250mg片剂。将一药片加入一杯水并搅拌后,在不到一分钟内产生裸眼可见的蓝色颜色和浑浊。
实施例9
吡唑坦涂覆的颗粒
借助于盐酸将酒石酸吡唑坦溶解于水中,然后通过添加羟丙甲纤维素603制备分散体。
通过将分散体在流化床中喷射到NPTAB 190糖球上得到吡唑坦颗粒。
% | Mg/单位 | |
NPTAB 190(180-220μm) | 73.19 | 22.52 |
酒石酸吡唑坦 | 16.25 | 5.00 |
羟丙甲纤维素603 | 8.93 | 2.75 |
1N HCl | 1.64 | 0.50 |
总计 | 100.0 | 30.77 |
吡唑坦涂覆的颗粒的着色。
接着用HPMC、TEC(柠檬酸三乙酯)和着色剂制备乙基纤维素水分散体;将其喷到流化床中的活性物质涂覆的颗粒上。
漂浮颗粒的着色
这两个群体以如下比例混合:40.51mg吡唑坦着色颗粒和100mg着色漂浮颗粒。两个群体不可区分开。当打开胶囊并将其内容物加入一杯水中时,马上出现蓝色颜色和漂浮颗粒。
Claims (15)
1.一种用于防止暗中给予化学药物的方法,包括:
-将固体药剂溶解于饮料中,所述药剂含有活性物质和至少0.05mg,优选0.2-5mg,更优选0.3-2mg的至少一种水溶性着色剂,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF,以及
-检测以饮料颜色的即时变化为特征的所述药剂。
2.如权利要求1所述的用于防止暗中给予化学药物的方法,其特征在于,所述活性物质选自抗焦虑药、***、镇静药或止痛药。
3.如权利要求1或2所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂还包含遮光剂,所述遮光剂选自:硅酸盐如硅酸镁、硅酸铝、硅酸钙和硅酸镁铝、二氧化钛及它们的混合物。
4.如权利要求3所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂包含至少15mg,优选15-100mg,更优选20-60mg,以及进一步优选25-40mg的遮光剂。
5.如权利要求1-4任一所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂还包含荧光剂,所述荧光剂选自:荧光素或其衍生物、靛青绿以及它们的混合物。
6.如权利要求5所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂包含至少0.1mg,优选至少1mg,更优选0.2-5mg,进一步优选0.3-2mg的荧光剂。
7.如权利要求1-6任一所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂包含漂浮颗粒和/或口中可感知的颗粒。
8.如权利要求7所述的用于防止暗中给予化学药物的方法,其特征在于,所述漂浮颗粒和/或口中可感知的颗粒是微颗粒,所述微颗粒是不溶性的或者通过涂覆脂质材料或通过涂覆不溶性聚合物变成不溶性的。
9.如权利要求7或8所述的用于防止暗中给予化学药物的方法,其特征在于,所述颗粒的直径为50-500μm,优选200-500μm,和/或大于500μm。
10.如权利要求7-9任一所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂包含至少25mg,优选40mg的漂浮和/或口中可感知的颗粒。
11.如权利要求1-10任一所述的用于防止暗中给予化学药物的方法,其特征在于,所述药剂包含泡腾微颗粒。
12.至少0.05mg、优选0.2-5mg、更优选0.3-2mg的至少一种水溶性着色剂在药剂中用于防止暗中给予化学药物的用途,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF。
13.一种用于防止暗中给予化学药物的非薄膜包衣固体药剂,包含活性物质、至少0.05mg,优选0.2-5mg,更优选0.3-2mg的至少一种水溶性着色剂和至少一种药学可接受的赋形剂,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF。
14.如权利要求13所述的药剂,其特征在于,所述药剂是常规片剂、含片、舌下片、咀嚼片、泡腾片、分散片或口腔分散片、用于扁囊或胶囊的粉剂或薄膜的形式。
15.如权利要求14所述的药剂,其特征在于,所述药剂是含有至少一种包衣的活性物质、至少一种着色剂和赋形剂混合物的口腔分散片,所述着色剂选自靛蓝胭脂红、赤藓红、亮蓝FCF、α绿FG、固绿FCF、奎札因绿SS、橙II、酒石黄和日落黄FCF;所述赋形剂混合物包括:
-崩解剂,
-具有粘合性质的可溶性稀释剂,
-润滑剂,
-可能地,渗透剂、甜味剂和香料,
-以及可能地,至少一种使得能够防止暗中给予化学药物的化合物,所述化合物选自遮光剂、荧光剂、漂浮颗粒、口中可感知的颗粒、泡腾微颗粒以及它们的混合物。
Applications Claiming Priority (3)
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FR1055490A FR2962550B1 (fr) | 2010-07-06 | 2010-07-06 | Methode pour lutter contre la soumission chimique, utilisation d'agent colorant pour lutter contre la soumission chimique et composition pharmaceutique permettant la mise en oeuvre de la methode |
FR1055490 | 2010-07-06 | ||
PCT/FR2011/051600 WO2012010765A1 (fr) | 2010-07-06 | 2011-07-05 | Methode et agent pour la detection de drogues dans les boisson |
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CN103119435A true CN103119435A (zh) | 2013-05-22 |
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CN2011800334204A Pending CN103119435A (zh) | 2010-07-06 | 2011-07-05 | 用于检测饮料中的药物的方法和试剂 |
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US (1) | US20130098286A1 (zh) |
EP (1) | EP2591350B1 (zh) |
JP (1) | JP5916723B2 (zh) |
KR (2) | KR101957657B1 (zh) |
CN (1) | CN103119435A (zh) |
AU (1) | AU2011281482B2 (zh) |
CA (1) | CA2802402A1 (zh) |
ES (1) | ES2609831T3 (zh) |
FR (1) | FR2962550B1 (zh) |
IL (1) | IL223886B (zh) |
MX (1) | MX344783B (zh) |
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CN104237224A (zh) * | 2014-10-14 | 2014-12-24 | 厦门奥亚仪器有限公司 | 苯二氮卓的快速检测方法及其操作器皿组合 |
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WO2020225774A1 (en) * | 2019-05-07 | 2020-11-12 | Clexio Biosciences Ltd. | Dosage forms for preventing drug-facilitated assault |
US20220241238A1 (en) * | 2020-10-24 | 2022-08-04 | Michael Roth | Method for forming a beverage with a dissolvable thc tablet |
CN115112582A (zh) * | 2022-05-19 | 2022-09-27 | 西南科技大学 | 一种去甲芬太尼及芬太尼的检测试剂盒及其检测方法 |
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- 2011-07-05 EP EP11743099.1A patent/EP2591350B1/fr active Active
- 2011-07-05 KR KR1020187019307A patent/KR101957657B1/ko active IP Right Grant
- 2011-07-05 US US13/808,807 patent/US20130098286A1/en not_active Abandoned
- 2011-07-05 MX MX2012015103A patent/MX344783B/es active IP Right Grant
- 2011-07-05 JP JP2013517480A patent/JP5916723B2/ja active Active
- 2011-07-05 ES ES11743099.1T patent/ES2609831T3/es active Active
- 2011-07-05 AU AU2011281482A patent/AU2011281482B2/en active Active
- 2011-07-05 KR KR1020137003073A patent/KR20130091321A/ko active Application Filing
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JP5916723B2 (ja) | 2016-05-11 |
ZA201300099B (en) | 2014-03-26 |
EP2591350A1 (fr) | 2013-05-15 |
KR20130091321A (ko) | 2013-08-16 |
KR101957657B1 (ko) | 2019-03-12 |
KR20180080374A (ko) | 2018-07-11 |
MX344783B (es) | 2017-01-06 |
CA2802402A1 (fr) | 2012-01-26 |
JP2013530206A (ja) | 2013-07-25 |
IL223886B (en) | 2018-03-29 |
US20130098286A1 (en) | 2013-04-25 |
WO2012010765A1 (fr) | 2012-01-26 |
MX2012015103A (es) | 2013-05-28 |
AU2011281482A1 (en) | 2013-01-17 |
AU2011281482B2 (en) | 2015-10-01 |
EP2591350B1 (fr) | 2016-10-26 |
FR2962550B1 (fr) | 2013-06-14 |
FR2962550A1 (fr) | 2012-01-13 |
ES2609831T3 (es) | 2017-04-24 |
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