CN101455649A - 防止所含活性剂被误用的经皮给药器的处置系统 - Google Patents
防止所含活性剂被误用的经皮给药器的处置系统 Download PDFInfo
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- CN101455649A CN101455649A CNA2008101707103A CN200810170710A CN101455649A CN 101455649 A CN101455649 A CN 101455649A CN A2008101707103 A CNA2008101707103 A CN A2008101707103A CN 200810170710 A CN200810170710 A CN 200810170710A CN 101455649 A CN101455649 A CN 101455649A
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Abstract
本发明涉及一种经皮给药器处置系统,用于处置含有至少一种制药活性组分的经皮给药器。该处置系统含有至少一个其上涂有胶粘剂的片材或基材;以及一种或多种下列组分:(a)单体,以及任选地共聚单体,用于聚合;(b)引发剂,以及任选地共引发剂,用于引发聚合反应;(c)至少一种交联剂,用以交联(共)聚合物;以及(d)至少一种去活剂,用以从化学上改变、降解和/或去活经皮给药器中所含活性组分,例如类阿片拮抗药或类阿片激动剂去活剂,从而使经皮给药器中所含活性组分的欣快作用在活体中至少暂时地被抑制、减少或终止,其中至少一个胶粘剂涂布的片材或基材粘贴、固定或隔离以及防止、抑制或减少对至少一个经皮给药器中所含的活性组分的误用或滥用。
Description
本发明申请是PCT专利申请PCT/US03/18256,申请日为2003年6月10日发明名称为“防止所含活性剂被误用的经皮给药器的处置系统”的发明专利申请的分案申请,母案进入中国的申请号为CN03813555.8。
技术领域
本发明涉及一种防止、抑制和/或减少故意和/或不经意误用或滥用含活性药剂如类阿片的经皮给药器(“TDD”)用的处置系统。本发明还涉及处置TDD和/或防止TDD或TDD的任何成分被误用或滥用的方法。
背景技术
经皮剂量形式是许多不同的活性治疗有效剂(包括但不限于镇痛剂,例如类阿片镇痛剂)给药的方便剂量形式。典型的类阿片镇痛剂包括但不限于芬太尼、叔丁啡、依托啡以及其它高效麻醉剂。其它可利用经皮给药系统给药的治疗有效药剂包括但不限于止吐药(东莨菪碱)、心血管药剂(硝酸盐和可乐定)、激素(雌激素和睾酮)、尼古丁、维生素、营养补充剂等。
最常见的经皮剂量形式是采用流体储液或胶粘剂基质包药型系统的扩散驱动式经皮系统(经皮贴剂)。其它经皮剂量形式包括但不限于局部凝胶、洗液、软膏、经粘膜系统和器具,以及电离子透入疗程(电扩散)给药系统。
经皮剂量形式对于活性剂的定时和持续释放特别有用。然而,许多剂量形式,特别是用于活性剂定时和持续释放的那些,含有大量活性剂,经常是实际吸收剂量的许多倍。经常,这些剂量形式含有过量活性剂,或者送达给治疗对象的活性剂少于其活性剂的总量。这导致大多数活性剂使用后仍残留在剂量形式中。不论未使用的剂量形式还是使用后残留在剂量形式中的那部分活性剂都存在可能被非法滥用的危险,尤其是如果该活性剂是麻醉剂或管制物质的话。例如,含有过量或未用类阿片的使用过的剂量形式就可能被药物滥用者通过咀嚼或提取而产生不当后果。即便小心处置用过的剂量形式,也可能无法完全有效地防止滥用,特别是在不彻底或部分遵守的情况下。
Cubbage等人的美国专利5,804,215涉及一种用于含药剂如尼古丁的经皮贴剂的处置系统,其包含涂胶粘剂的柔性抗撕裂基材。将用过的经皮贴剂粘贴在基材上以便包封和防止接触该经皮贴剂。橡胶基胶粘剂是Cubbage优选的。
Granger等人的美国专利5,149,538和Lee等人的5,236,714各自涉及用于类阿片经皮给药的防误用剂量形式。在这些专利中,经皮贴剂各自均提供以类阿片拮抗药,旨在一旦贴剂被咀嚼或受到提取处理时就从贴剂中提取出来。类阿片拮抗药旨在阻断通过滥用该剂量形式所追求的欣快效果。
经皮给药器的不经意和/或故意误用和/或滥用依旧是一个重大健康问题。因此,目前需要一种比现有技术已知的更不容易遭到滥用的经皮给药处置系统。
发明内容
本发明的一种实施方案涉及一种TDD处置系统,它包含至少第一基材,其一面上具有胶粘剂涂层;以及至少存在于该胶粘剂涂层之中或之上或者第一基材之中或之上或其任意组合的下列组分之一或多种:
(a)单体,以及任选地至少一种共聚单体;
(b)引发剂,以及任选地至少一种共引发剂;
(c)至少一种交联剂;以及
(d)至少一种活性剂去活剂,例如,用于包含类阿片激动剂的TDD使用的类阿片拮抗药。
本发明另一种实施方案涉及一种TDD处置系统,它还包含至少存在于该胶粘剂涂层之中或之上或者第二基材之中或之上或其任意组合的下列组分之一或多种:
(a)单体,以及任选地至少一种共聚单体;
(b)引发剂,以及任选地至少一种共引发剂;
(c)至少一种交联剂;以及
(d)至少一种活性剂去活剂。
本发明另一种实施方案涉及一种试剂盒(kit),它包含含有至少一种活性剂的经皮给药器;以及TDD处置系统,其中TDD处置系统包含:
(i)至少第一基材,其一面上具有胶粘剂涂层;以及
(ii)至少存在于该胶粘剂涂层之中或之上或者第一基材之中或之上或其任意组合的下列组分之一或多种:
(a)单体,以及任选地至少一种共聚单体;
(b)引发剂,以及任选地至少一种共引发剂;
(c)至少一种交联剂;以及
(d)至少一种活性剂去活剂。
在一种实施方案中,TDD处置系统包含被至少包括在胶粘剂涂层之中或之上或者第一和/或第二基材之中或之上或其任意组合上的至少一种非-μ-类阿片去活剂。
本发明另一种实施方案涉及一种试剂盒,它包含经皮给药器,该器具含有至少一种活性剂;以及TDD处置系统,其包含至少第一刚性、非平面基材,其至少一个面上具有胶粘剂涂层。
本发明再一种实施方案涉及一种试剂盒,它包含经皮给药器,该器具含有叔丁啡或叔丁啡的任何药学可接受形式或衍生物;以及TDD处置系统,其包含至少第一基材,其一个面上具有胶粘剂涂层。
本发明另外一种实施方案涉及一种试剂盒,它包含经皮给药器,其含有芬太尼或芬太尼的任何药学可接受形式或衍生物;以及TDD处置系统,其包含至少第一基材,其一个面上具有胶粘剂涂层。
本发明另外一种实施方案涉及一种试剂盒,它包含经皮给药器,其含有羟可待酮或羟可待酮的任何药学可接受形式或衍生物;以及TDD处置系统,其包含至少第一基材,其一个面上具有胶粘剂涂层。
本发明另一种实施方案涉及一种TDD处置系统,它包含至少第一基材,其一个面上具有胶粘剂涂层,其中胶粘剂是硅酮基胶粘剂。
本发明另一种实施方案涉及一种TDD处置系统,它包含至少第一基材,其一个面上具有胶粘剂涂层,其中胶粘剂是丙烯酸酯基胶粘剂。
本发明又一种实施方案涉及一种TDD处置系统和/或一种包含它的试剂盒,其中TDD处置系统的第一基材显示出一项或多项下列性质:
(a)基本不透溶剂;
(b)基本不被溶剂溶胀;
(c)基本抗撕裂;以及
(d)基本抗切割。
附图说明
图1A~1D每一幅显示一种本发明的TDD处置系统,具有用于固定和隔离单个TDD如贴剂,或多个TDD的区域。
图2A~2C分别显示储液型、聚合物基质型和胶粘剂包药型TDD。
图3显示一种TDD处置系统,它在同一区域内包含单体、引发剂和任选交联剂的混合物,并且还含有去活剂,任选与降解剂成混合物。
图4显示一种TDD处置系统,在第一区域具有去活剂,任选地与降解剂成混合物,并在第二区域具有单体、引发剂和任选交联剂的混合物。
图5~10每一幅分别显示通过蒸馏水、乙酸乙酯、乙醇、乙醚、丙酮和甲醇的提取作用可从图2B的TDD中提取因而可供滥用的叔丁啡(BUP)的量,以及当TDD被固定和隔离在图1B的叔丁啡TDD处置系统中时的量。
图11显示一种本发明封闭型TDD处置系统,它以一页或多页的形式结合成一本书,每一页具有用于固定和隔离单个TDD如贴剂或多个TDD的区域。
图12A~D显示一种本发明封闭型TDD处置系统,以多个双折页的形式结合成一本书,每一页具有用于固定和隔离单个TDD如贴剂或多个TDD的区域。
图13显示本发明的一种试剂盒,它包括盒子,其包含一个或多个经皮给药器,以及结合在盒子外表面的小册子形式的TDD处置系统。
图14显示一种包含2个刚性非平面基材的本发明TDD处置系统。
定义
术语“经皮给药器”或“TDD”在这里用来指任何一种器具,当接触患者皮肤时,它能通过皮肤而经皮传送治疗有效量的任何生物活性剂如药剂化合物例如类阿片到体循环中。
术语“类阿片”当在本文中隔离下使用时,指的是具有μ-类阿片受体激动剂活性的化合物。
本文所用的术语“非-μ类阿片”和“非μ类阿片激动剂”是指一种活性剂,它(任选立体特异地)结合到任何κ-类阿片受体、δ-类阿片受体和/或ORL-1类阿片受体上,但明显不结合到任何μ-类阿片受体上,并产生激动剂活性。
本文所使用的术语“去活剂”与术语“降解剂”为同义语,并涵盖“钝化剂”。
本文所使用的术语“非-μ类阿片去活剂”指的是使非-μ类阿片激动剂去活或降解但不使本文所定义的类阿片激动剂去活或降解的药剂。
当然,应当理解,除非另行指出,在本公开全文中每当指任何一种药物化合物时它都不仅包括该药物化合物,即,该化合物的所谓游离形式,而且包括该化合物的药学可接受衍生物,例如,该化合物的药学可接受盐形式、该化合物的碱形式及其混合物,还包括其游离形式与任何或所有其衍生物和立体异构体的混合物。
本文所用术语“药学可接受盐”,例如对于类阿片而言,指的是由酸和类阿片的碱性氮基团生成的盐。优选的盐包括但不限于,硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、glucaronate、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和pamoate(即,1,1′-亚甲基-双-(2-羟基-3-萘甲酸盐))。
本文所用术语“碱形式”,例如对于类阿片而言,指的是由具有酸性官能团如羧酸或磺酸官能团的类阿片与药学可接受无机或有机碱制备的盐。合适的碱包括但不限于,碱金属如钠、钾和锂的氢氧化物;碱土金属如钙和镁的氢氧化物;其它金属如铝和锌的氢氧化物;氨,以及有机胺如未取代或羟基取代的一、二或三烷基胺;二环己基胺;三丁基胺;吡啶;N-甲基,N-乙基胺;二乙胺;三乙胺;一、二或三(2-羟基低级烷基胺),例如一、二或三(2-羟基乙基)胺、2-羟基-叔丁基胺,或三(羟甲基)甲胺,N,N-二低级烷基-N-(羟基低级烷基)胺,例如N,N-二甲基-N-(2-羟基乙基)胺,或三(2-羟基乙基)胺;N-甲基-D-葡糖胺;以及氨基酸如精氨酸、赖氨酸等。
本文所用术语“基本上”,当修饰紧跟其后的形容词或形容词短语时,应理解为相对于该形容词或形容词短语所修饰的名词或代词,该形容词或形容词短语至少在约95%程度上,优选在至少约98%程度上,更优选至少99%程度上,例如在至少约99.9%程度上适用。或者,术语“基本上”可与术语“完全”互换使用。
本文所用短语“基本上不”或“基本上没有”,当修饰紧跟其后的形容词或形容词短语时,应理解为相对于该形容词或形容词短语所修饰的名词或代词,该形容词或形容词短语在不超过约5%的程度上,优选不超过约2%的程度上,更优选不超过约1%的程度上,例如不超过约0.1%的程度上适用。或者,短语“基本上不”和“基本上没有”分别可与短语“完全不”和“完全没有”互换地使用。
术语“约”,在本发明中当用来修饰数值或范围时,应理解为该数值或范围加或减10%。
本文使用的术语“共聚物”包括含有至少两种不同单体亚单元的聚合物。于是,由3种不同单体构成的聚合物链(也称作三元共聚物)也被涵盖在术语“共聚物”中,同样,含有超过3种的不同单体单元的聚合物链也是。
本文所使用的术语“低聚物”包括含有重复单体单元的化合物,类似聚合物或共聚物,但是其分子量很低,以致该化合物不能算作聚合物。
具体实施方式
本申请要求2002-06-10提交的美国临时申请号60/387,800优先权,在此将其全文收作参考。
本发明处置系统可用于处置任何类型的TDD,不论该给药器的构造或形式,也不论给药器中包含的活性剂是什么。一般可由TDD给药的活性剂包括但不限于,类阿片、非-μ-类阿片、止吐药(东莨菪碱)、心血管药剂(硝酸盐和可乐定)、激素(雌激素和睾酮)、尼古丁、维生素、营养补充剂。为了便于说明,在这里将主要就含类阿片镇痛剂作为药学活性剂的TDD的情况来说明。
1、经皮给药器
典型TDD包括药物化合物,例如至少一种类阿片,以及任选至少一种类阿片拮抗药,其量足以在该类阿片和类阿片拮抗药被例如经口、静脉内、经颊、经鼻、胃肠外、经直肠和/或经阴道向哺乳类,通常是人给药后,抑制该类阿片的欣快作用。当接触患者皮肤时,此种典型TDD允许类阿片实现经皮给药,但是(a)对于类阿片拮抗药则只允许其以不足以抑制类阿片镇痛作用的少量经皮给药,或(b)不允许类阿片拮抗药的经皮给药。然而,如果此种TDD被用于通过经皮以外的其它途径输送类阿片,例如静脉内、经颊、经鼻、经口服、胃肠外、经直肠和/或经阴道途径,则类阿片拮抗药将钝化或抑制类阿片的欣快作用。优选的是,倘若非经皮给药的话,此种TDD抑制类阿片的欣快作用,而不论该器具此前是否曾恰当地用于治疗或防止疼痛。
虽不需要,但可以这样来构造TDD,以便阻遏滥用者,防止其(a)从类阿片中分离类阿片拮抗药或者(b)从TDD中离析出类阿片,随后通过其它途径自行给药,例如但不限于经口、胃肠外、经鼻、静脉内,经颊、或吸入蒸汽,即,通过能产生滥用者青睐的快速欣快高潮(亦称作“burst”)的给药途径。例如,倘若滥用者试图通过将TDD放入到溶剂中提取出类阿片,则类阿片拮抗药也将一起被提取,结果提供一种类阿片与类阿片拮抗药的混合物。如果该类阿片和类阿片拮抗药的混合物被经过有意的经皮途径以外的其它途径服用,则类阿片拮抗药将发挥其拮抗作用以抑制类阿片的欣快作用。
本领域技术人员已知的任何用于经皮输送治疗药剂给患者的器具都可成为TDD。例如,TDD可以是储液型TDD、聚合物基质型TDD或胶粘剂包药型TDD(例如参见,H.S.Tan和W.R.Pfister,《经皮给药系统用压敏胶粘剂》,PSTT,卷2,第二期,1999-02,第60~69页,在此将其公开内容收作参考)。TDD应设计成,当接触患者皮肤时,镇痛有效量的类阿片将经皮输送给患者。但类阿片拮抗药则或者留在TDD中不输送给患者,或者给患者的量不足以抑制类阿片的镇痛作用。
储液型TDD一般包含储液,通常是一种液体,位于不透性背衬膜与速率控制膜之间,后者覆盖以压敏胶粘剂皮肤接触层。该储液,可以是溶液或分散体,含有类阿片和类阿片拮抗药。TDD由不透性背衬膜支承,胶粘剂表面则由剥离衬保护着。要输送类阿片时,揭去剥离衬从而露出压敏胶粘剂,并让压敏胶粘剂接触皮肤。类阿片可透过速率控制膜,于是渗透穿过它和胶粘剂,接触到皮肤,从而渗透皮肤。类阿片的给药速率通常取决于类阿片透过速率控制膜的速率。优选的是,压敏胶粘剂对类阿片的给药速率不产生不利影响,也不与之发生化学反应。给药速率达到使镇痛有效量的类阿片输送给患者。然而,与类阿片不同,类阿片拮抗药,可存在于储液的任何地方,优选地不透过速率控制膜,或者即便透过,其量应不足以抑制类阿片的镇痛作用。
图2A示出一种储液型TDD的实施方案。TDD 10包含储液11,通常采用溶液或分散体12的形式,其中分散着类阿片13和类阿片拮抗药14。储液11配置在不透性背衬膜15、速率控制膜16和压敏胶粘剂17之间。剥离衬18施用在压敏胶粘剂层17上,并在使用前揭去。优选的是,类阿片和类阿片拮抗药分散在整个储液内,尽管不一定要分散均匀。
一种储液型TDD的变形方案是聚合物基质形式。在聚合物基质形式中,类阿片和类阿片拮抗药分散在控制类阿片给药速率的聚合物基质中。类似于液体储液形式,聚合物基质储液支持在不可透背衬层上。然而,替代设置连续的胶粘剂层,聚合物基质形式一般包括位于贴剂边缘的胶粘剂周边环。剥离衬保护着胶粘剂表面和聚合物基质的表面。为输送类阿片,揭去剥离衬以露出聚合物基质和压敏胶粘剂环,于是器具与皮肤接触。胶粘剂的环保持器具在皮肤上,以便使聚合物基质直接接触皮肤。当聚合物基质接触皮肤时,类阿片扩散出聚合物基质从而接触患者皮肤,并渗透皮肤。类阿片激动剂的给药速率一般取决于类阿片扩散出聚合物基质的速率。该给药速率应使镇痛有效数量类阿片输送给患者。另一方面,类阿片拮抗药,可存在于聚合物基质中的任何地方,应或者不扩散出聚合物基质,或者即便扩散出来,但其数量不足以抑制类阿片的镇痛作用。
图2B示出一种本发明典型聚合物基质型TDD的实施方案。TDD 20包含聚合物基质22形式的储液21,其中分散着类阿片23和类阿片拮抗药24。优选的是,类阿片和类阿片拮抗药在整个聚合物基质内分散,尽管不一定要均匀分布。聚合物基质21由不透性背衬层25支承并具有沿着贴剂边缘设置的胶粘剂周边环26。剥离衬28施用在胶粘剂周边环26和聚合物基质22上并在使用前揭去。
胶粘剂包药型TDD包含直接分散在压敏胶粘剂基质中的类阿片激动剂和类阿片拮抗药。胶粘剂基质通常在其顶面支持以不透性背衬膜,且在其面朝皮肤的一侧支持以不透性剥离衬。为输送类阿片,揭去剥离衬以露出胶粘剂基质,并让器具接触皮肤。胶粘剂基质起将器具粘附在皮肤上以及,典型地,控制类阿片的给药速率的作用。类似于聚合物基质样式,胶粘剂包药式样式允许类阿片扩散出胶粘剂基质,接触患者皮肤,并透过皮肤。类阿片的给药速率一般取决于类阿片扩散出胶粘剂基质的速率。给药速率应达到,使镇痛有效量的类阿片输送给患者。另一方面,类阿片拮抗药,可存在于胶粘剂基质中的任何地方,不扩散出胶粘剂基质或者扩散出的量不足以抑制类阿片的镇痛作用。
图2C示出一种本发明典型的胶粘剂包药型TDD实施方案。TDD 30包含胶粘剂基质31,其中整体分散着类阿片32和类阿片拮抗药33。优选的是,类阿片和类阿片拮抗药分散在整个胶粘剂基质当中,尽管不一定要均匀分散。胶粘剂基质31支撑在不透性背衬层34上并在其面朝皮肤的一侧具有使用前将除去的不透性剥离衬35。
储液型、聚合物基质型和胶粘剂包药型TDD乃是本领域技术人员熟知的(例如参见,H.Tan和W.Pfister,《经皮给药系统用压敏胶粘剂》PSTT,卷2,1999-02,在此将其内容收作参考)。在一种优选的实施方案中,本发明TDD处置系统有利地固定并隔离聚合物基质型TDD和/或胶粘剂包药型TDD以防止、控制或抑制对包含在TDD中的活性剂的误用和/或滥用。
任何本领域技术人员已知的速率控制膜都可用于本发明的TDD中。优选的是,选择那些不允许任何,或者任何可察觉数量的类阿片拮抗药经其透过的膜,特别是在类阿片拮抗药能渗透患者皮肤的情况下。适合作速率控制膜的材料包括但不限于,聚乙烯;聚丙烯;乙烯/丙烯共聚物;乙烯/丙烯酸乙酯共聚物;乙烯/醋酸乙烯酯共聚物;聚丙烯酸酯;聚甲基丙烯酸酯;硅酮弹性体;药物级聚二甲基硅氧烷;氯丁橡胶;聚异丁烯;氯化聚乙烯;聚氯乙烯;氯乙烯-醋酸乙烯酯共聚物;聚甲基丙烯酸酯聚合物(水凝胶);聚偏二氯乙烯;聚对苯二甲酸乙二醇酯;丁基橡胶;表氯醇橡胶;乙烯-乙烯醇共聚物;乙烯-乙烯基氧乙醇共聚物;硅酮共聚物,例如聚硅氧烷-聚碳酸酯共聚物、聚硅氧烷-聚氧乙烯共聚物、聚硅氧烷-聚甲基丙烯酸酯共聚物、聚硅氧烷-链烯共聚物(例如聚硅氧烷-乙烯共聚物)、聚硅氧烷-链烯硅烷共聚物(例如聚(硅氧烷-共聚-乙烯硅烷)等;纤维素聚合物,例如甲基或乙基纤维素、羟丙基甲基纤维素和纤维素酯;聚碳酸酯;聚四氟乙烯;淀粉;明胶;天然和合成树胶;任何其它天然或合成聚合物或纤维;及其组合。
背衬层可以是任何合适的材料,只要对储液腔、聚合物基质或胶粘剂基质内的物质不可透。合适的背衬膜材料乃是本领域技术人员熟知的,包括但不限于,封闭性聚合物,例如聚氨酯、聚酯如聚对苯二甲酸乙二醇酯、聚醚酰胺、共聚酯、聚异丁烯、聚酯,高和低密度聚乙烯、聚丙烯、聚氯乙烯、金属箔和适当聚合物薄膜的金属箔层压材料。
适合作聚合物基质的材料乃是本领域技术人员熟知的,包括但不限于,聚乙烯;聚丙烯;乙烯/丙烯共聚物;乙烯/丙烯酸乙酯共聚物;乙烯/醋酸乙烯共聚物;硅酮弹性体,尤其是药物级聚二甲基硅氧烷;氯丁橡胶;聚异丁烯;氯化聚乙烯;聚氯乙烯;氯乙烯-醋酸乙烯共聚物;聚甲基丙烯酸酯聚合物(水凝胶);聚偏二氯乙烯;聚对苯二甲酸乙二醇酯;丁基橡胶;表氯醇橡胶;乙烯-乙烯醇共聚物;乙烯-乙烯基氧乙醇共聚物;硅酮共聚物,例如聚硅氧烷-聚碳酸酯共聚物、聚硅氧烷-聚氧乙烯共聚物、聚硅氧烷-聚甲基丙烯酸酯共聚物、聚硅氧烷-链烯共聚物(例如聚硅氧烷-乙烯共聚物)、聚硅氧烷-链烯硅烷共聚物(例如,聚(硅氧烷-共聚-乙烯硅烷)等;纤维素聚合物,例如甲基或乙基纤维素、羟丙基甲基纤维素和纤维素酯;聚碳酸酯;聚四氟乙烯;及其组合。优选的是,聚合物基质的玻璃化转变温度低于室温。该聚合物可以(但不一定要求)具有在室温的非零结晶度。交联单体单元或部位可结合到聚合物中。例如,交联单体可结合到聚丙烯酸酯聚合物中。该交联单体用于在类阿片和类阿片拮抗药细微分散到聚合物中以后提供使聚合物基质交联的部位。用于聚丙烯酸酯聚合物的已知交联单体包括但不限于,多元醇的聚甲基丙烯酸酯,例如丁二醇的二丙烯酸酯和二甲基丙烯酸酯、三羟甲基丙烷的三甲基丙烯酸酯等。其它提供交联部位的单体包括烯丙基丙烯酸酯、烯丙基甲基丙烯酸酯、二烯丙基马来酸酯等。优选的是,选择那些不允许任何,或任何可察觉数量类阿片拮抗药经其扩散出的聚合物基质,尤其是在类阿片拮抗剂可渗透患者皮肤的情况下。
适合用于压敏胶粘剂基质的材料乃是本领域技术人员熟知的,包括但不限于,聚异丁烯、聚硅氧烷和聚丙烯酸酯共聚物(聚丙烯酸酯)、天然橡胶/刺梧桐树胶基胶粘剂、水凝胶、亲水聚合物以及聚氨酯,例如描述在H.Tan和W.Pfister,《经皮给药系统用压敏胶粘剂》PSTT,卷2,1999-02中,在此将其内容收作参考。胶粘剂还可包含改性单体、增粘剂、增塑剂、填料、蜡、油和其它赋予要求的胶粘剂性质的添加剂。优选的是,选择不允许任何,或者任何可察觉数量类阿片拮抗药经其扩散出的压敏胶粘剂基质,特别是在类阿片拮抗药能渗透患者皮肤的情况下。
优选的是,器具的尺寸可从约1cm2直至大于200cm2,典型值介于约5~50cm2。制造TDD的方法乃是本领域技术人员熟知的。
用于经皮给药器的器具例子包括但不限于,描述在美国专利4,806,341;5,069,909;5,236,714;5,240,711;5,718,914;5,902,603;5,968,547;6,162,456;和6,344,212中的那些,在此将其公开内容收作参考。
TDD可任选地包括一种或多种增加类阿片透过患者皮肤的速度的渗透促进剂。优选的是,渗透促进剂不加速类阿片拮抗药透过皮肤的渗透。渗透促进剂应透过速率控制膜或扩散出聚合物基质或胶粘剂基质,以便使它能接触到患者的皮肤并改进类阿片透过患者皮肤的渗透。适合用于本发明方法和TDD中的渗透促进剂包括但不限于,C2~C4醇如乙醇和异丙醇,聚乙二醇单月桂酸酯、聚乙二醇-3-月桂酰胺、二甲基月桂酰胺、脱水山梨醇三油酸酯、脂肪酸、约10~约20个碳原子的脂肪酸的酯;脂肪酸甘油单酯或单酯总含量至少是51%的脂肪酸甘油单酯的混合物,其中单酯是具有10~20个碳原子的那些;以及脂肪酸甘油单酯、二酯和三酯的混合物。合适的脂肪酸包括但不限于,月桂酸、肉豆蔻酸、硬脂酸、油酸、亚油酸、和棕榈酸。甘油单酯渗透促进剂包括,例如甘油单油酸酯、甘油单月桂酸酯和甘油单亚油酸酯。可用于本发明方法的渗透促进剂的例子包括但不限于,描述在下列美国专利中的那些:3,472,931;3,527,864;3,896,238;3,903,256;3,952,099;3,989,816;4,046,886;4,130,643;4,130,667;4,299,826;4,335,115;4,343,798;4,379,454;4,405,616;4,746,515;4,316,893;4,405,616;4,060,084,4,379,454;4,560,5534,863,952;4,863,970;4,879,275;4,940,586;4,960,771;4,973,968;5,066,648;5,164,406;5,227,169;5,229,130;5,238,933;5,308,625;4,326,566;5,378,730;5,420,106;5,641,5045,716,638;5,750,137;5,785,991;5,837,289;5,834,468;5,882,676;5,912,009;5,952,000;6,004,578;和Idson,PercutaneousAbsorption,J.Pharm.Sci.
卷64,第b6期,1975-06,第901~924页,在此将其公开内容收作参考。
TDD还可包含医疗产品中惯用的其它添加剂。例如,TDD还可包括一种或多种防腐剂或抑菌剂,例如羟基苯甲酸甲酯、羟基苯甲酸丙酯、氯甲酚、苯扎氯铵等;或者其它活性成分如抗菌剂,特别是抗生素;麻醉剂;其它镇痛剂;以及止痒剂。
技术上已知的任何类阿片或非-μ-类阿片、其药学可接受盐、其碱形式或者此类类阿片和/或其衍生物的任意组合的混合物,都可包括在TDD中。据信具有至少某些μ-类阿片受体激动剂活性(和任选地在一种或多种κ-类阿片受体、δ-类阿片受体和ORL-1受体上也具有至少某些激动剂活性)的类阿片包括但不限于,阿芬他尼、烯丙罗定、阿法罗定、阿尼利定、苄基吗啡、苯腈米特、叔丁啡、布托啡诺、氯尼他秦、可待因、去氧吗啡、右吗拉胺、地佐辛、地恩丙胺、diamorphone、二氢可待因、双氢吗啡、dihydromorphone、dihydroisomorphine、地美沙多、美沙醇、甲嗯丁胺、吗苯丁酯、地匹帕酮、依他佐辛、伊索庚嗪、甲乙噻丁、乙基吗啡、依托尼唑、依托啡、二氢依托啡、芬太尼、海洛因、氢可酮、氢吗啡酮、hydromorphodone、羟哌替啶、异美沙酮、凯托米酮、羟甲左吗喃、levophenacylmorphan、罗芬太尼、度冷丁、美普他酚、美他佐辛、美沙酮、美托酮、吗啡、麦罗啡、narceine、尼可吗啡、羟啡烷、去甲美沙痛、烯丙吗啡、纳布啡、去甲吗啡、诺匹帕酮、阿片、羟可待酮、羟吗啡酮、阿片全碱、阿片金碱、复方樟脑酊、喷他佐辛、苯吗庚酮、苯双甲吗啉、phendimetrazone、羟苯乙吗喃、非那佐辛、苯吡丁酮、匹米诺定、氰苯双哌酰胺、propheptazine、盐酸二甲哌替啶、丙哌利定、丙氧酚、丙己君、舒芬太尼、替利定、曲马朵及其混合物。非-μ-类阿片包括但不限于,ORL-1-特异类阿片激动剂,例如,nociceptin、deltorphin等,及其混合物。在优选的实施方案中,类阿片包括叔丁啡、其药学可接受盐、其碱形式,芬太尼、其药学可接受盐、其碱形式,羟可待酮、其药学可接受盐、其碱形式,以及此类类阿片和/或其衍生物的任意组合。
在某些优选的实施方案中,类阿片激动剂包括氢可酮、吗啡、羟吗啡酮、羟可待酮、可待因、左啡诺、度冷丁、美沙酮、羟吗啡酮、叔丁啡、芬太尼、地匹帕酮、海洛因、tramadol、依托啡、二氢依托啡、布托啡诺、羟甲左吗喃、其药学可接受盐、其碱形式,及其任意和所有混合物。更优选的是,类阿片激动剂包括羟可待酮、氢可酮、芬太尼、叔丁啡、其药学可接受盐、其碱形式,及其任意和所有混合物。最优选的是,类阿片激动剂包括叔丁啡、其药学可接受盐、其碱形式,芬太尼,其药学可接受盐,其碱形式以及此类类阿片和/或其衍生物的任意组合。
优选的是,尤其是对于被动贴剂来说,类阿片是游离类阿片,即,不是该类阿片的药学可接受盐形式。然而,对于采用电离子透入疗法来加速类阿片对皮肤的渗透的贴剂来说,则优选使用类阿片的药学可接受盐形式。
可选地、替代地或者除类阿片激动剂之外,TDD可含有能诱导要求的生理或药理效应的药理活性剂,这些效应包括但不限于,(1)影响生命过程;(2)对患者具有预防效果并防止不良效应,例如防止感染;(3)减轻疾病所引起的状况或疾病症状,例如减轻疼痛或炎症;和/或(4)减轻、减少或完全消除患者的疾病、状况或症状。活性剂的作用可以是局部的,例如用于提供麻醉作用,或者它可以是全身的或其组合。活性剂的大类,在一种实施方案中,可包括但不限于:ACE抑制剂;腺垂体激素;肾上腺素能神经元阻滞剂;肾上腺皮质类固醇;肾上腺皮质类固醇生物合成的抑制剂;α-肾上腺素能激动剂;α-肾上腺素能拮抗药;选择性α-2-肾上腺素能激动剂;雄激素;抗上瘾剂;抗雄激素药;抗感染剂,例如抗生素、抗菌素和抗病毒剂;镇痛剂和镇痛剂组合;厌食剂;驱虫药(antihelmintics);抗关节炎药;止喘药;抗惊厥药;抗抑郁药;抗糖尿病剂;止泻剂;止吐药和促运动药;抗癫痫药;抗雌激素药;抗真菌剂;抗组织胺药;消炎药;抗偏头痛制剂;抗毒蕈碱剂;止恶心药;抗瘤药;抗寄生物药;抗帕金森综合征药;抗血小板药;抗孕素;止痒药;抗精神病药;退热药;镇痉药;抗胆碱能药;抗甲状腺剂;镇咳药;氮杂螺癸烷二酮类;拟交感神经药;黄嘌呤衍生物;心血管制剂,包括钾和钙通道阻滞剂、α受体阻滞剂、β受体阻滞剂和抗心律不齐药;抗高血压药;利尿剂和抗利尿剂;血管舒张剂,包括总冠状动脉、末梢血管和脑血管;中枢神经系统兴奋剂;血管收缩剂;咳嗽和感冒制剂,包括减充血剂;激素,例如雌二醇和其它类固醇,包括皮质激素;安眠药;免疫抑制剂;肌肉弛缓剂;抗副交感神经药;精神兴奋剂;镇静剂;安定剂;尼古丁及其酸加合盐;苯并二氮类;巴比妥类(barbituates);benzothiadiazides;β-肾上腺素能激动剂;β-肾上腺素能拮抗药;选择性β-1-肾上腺素能拮抗药;选择性β-2-肾上腺素能拮抗药;胆汁盐;影响体液容量和组成的药剂;丁酰苯类;影响钙化的药剂;儿茶酚胺;胆碱能激动剂;胆碱酯酶激活剂;皮肤病药剂;二苯基丁基哌啶类;麦角生物碱;神经节阻滞剂;乙内酰脲类;用于控制胃酸度和治疗消化性溃疡的药剂;生血药;组胺;5-羟基色胺拮抗药;用于治疗高脂蛋白血症的药剂;缓泻药;甲基黄嘌呤;moncamine氧化酶抑制剂;神经肌肉阻滞剂;有机硝酸盐;胰酶;吩噻嗪;前列腺素类;类维生素A;用于痉挛状态和急性肌肉痉挛的药剂;琥珀酰亚胺;thioxanthines;溶血栓药;甲状腺药;有机化合物管运输抑制剂;影响子宫活动性的药剂;维生素;以及诸如此类;或者它们的组合。
可选地、替代地或者除类阿片激动剂之外,TDD可含有包括但不限于下列的活性组分:氟孕酮酯、羟孕酮、醋酸羟孕酮、己酸羟孕酮、醋酸甲羟孕酮、炔诺酮、乙酸炔诺酮、妇康、异炔诺酮、炔雌醇、3-酮基炔雌酮、gestadene、左旋甲炔诺酮、雌二醇、雌二醇苯甲酸酯、雌二醇戊酸酯、雌二醇cyprionate、雌二醇癸酸酯、雌二醇乙酸酯、炔雌醇、雌三醇、雌酮、炔雌醇甲醚、倍他米松、乙酸倍他米松、可的松、氢化可的松、醋酸氢化可的松、皮质酮、醋酸氟轻松、泼尼松龙、泼尼松、去炎松、醛固酮、安状基林、睾酮、甲基睾酮或者它们的组合。
可选地、替代地或者除类阿片激动剂之外,TDD可含有包括但不限于下列的活性组分:a)皮质激素,例如皮质素、质皮醇、泼尼松龙、丙酸倍氯松、地塞米松、倍他米松、氟米松、去炎松、去炎舒松、氟轻松、醋酸氟轻松、醋酸氟西奈德、特美肤等,或者其组合;b)镇痛消炎剂,例如醋氨酚、甲芬那酸、氟芬那酸、消炎痛、扶他林、双氯芬酸钠、马耳芬、布芬酸、羟保松、保泰松、布洛芬、氟比洛芬、优洛芬、水杨酸、水杨酸甲酯、乙酰水杨酸、1-薄荷醇、樟脑、slindac、托麦汀钠、naproxen、fenbufen等,或其组合;c)安眠药,例如鲁米那、异戊巴比妥、环巴比妥、劳拉西泮、氟哌啶醇等,或其组合;d)安定剂,例如氟奋乃静、硫利哒嗪、地西泮、氟西泮、氯丙嗪等或其组合;e)抗高血压药,例如可乐定、盐酸可乐定、波吲洛尔、噻马洛尔、吲哚洛尔、普萘洛尔、盐酸普萘洛尔、布拉洛尔、茚旦醇、香豆心安、硝苯地平、布尼洛尔等或其组合;f)降压利尿剂,例如苄氟噻嗪、泊利噻嗪、methylchlorthiazide、trichlormethiazide、环戊氯噻嗪、benzylhydrochlorothiazide、hydrochlorothiazide、布美他尼等或其组合;g)抗生素,例如青霉素、四环素、土霉素、美他环素、多西环素、米诺环素、硫酸新霉素、红霉素、氯霉素等,或其组合;h)麻醉剂,例如利多卡因、苯佐卡因、乙基氨基苯甲酸酯等或其组合;i)抗菌剂,例如苯扎氯铵、呋喃西林、制霉素、磺胺醋酰、clotriamazole等或其组合;j)抗真菌剂,例如戊霉素、两性霉素B、吡咯菌素、克霉唑等或其组合;k)维生素,例如,维生素A、维生素D2、维生素D3、octotriamine、维生素B2丁酸酯等或其组合;1)抗癫痫药,例如硝西泮、甲丙氨酯、氯硝西泮等或其组合;m)抗组胺药例如盐酸苯海拉明、氯苯那敏、双苯咪唑等或其组合;n)镇咳药,例如美沙芬、特布他林、麻黄碱、盐酸麻黄碱等或其组合;o)性激素,例如孕酮、雌二醇、雌三醇、雌酮等或其组合;p)抗抑郁药,例如多塞平;q)血管舒张剂,例如硝酸甘油、硝酸异山梨酯、nitroglycol、四硝酸季戊四醇酯、双嘧啶醇胺等或其组合;r)其它药物,例如5-氟脲嘧啶、双氢麦角胺、去氨加压素、地高辛、灭吐灵、多潘立酮、东莨菪碱、盐酸东莨菪碱等或其组合;等等;或者以上的组合。
在TDD中存在的活性剂的有效数量将取决于具体活性剂、器具的类型、用于制造器具的材料,以及活性剂输送给患者所持续的时间。但当活性剂是类阿片时,TDD中存在的类阿片的镇痛有效量通常介于约0.1~约500mg,优选约1~约100mg,更优选约1~约50mg。在本领域技术人员能力范围内,他们能轻易地确定特定指征所需要的类阿片或非-μ-类阿片的镇痛有效量。
2、TDD处置系统
本发明TDD处置系统优选包含至少一个其上涂有胶粘剂的基材。至少有一个是柔性(即,能轻易地对折而基本上不丧失其机械完整性)或者是刚性(即,机械上或物理上抗对折,或不基本上丧失机械完整性就无法对折,不论是用手或是用机械)的。柔性基材可代表为例如图1B(单个TDD处置系统)和1D(多TDD处置系统)。刚性基材可代表为例如图1A(单个TDD处置系统)和1C(多TDD处置系统)。至少一个本发明基材的柔性和刚性度不仅受基材材料的化学性质的影响,而且,特别是受基材材料的尺寸(厚度、长度和/或宽度)的影响。
如图1A所示,本发明TDD处置系统包括外层(1)和内层(4),二者由覆盖内层第一部分的胶粘剂(3)连结。内层和外层的组合,在内层的朝外层一侧与外层的朝内层一侧之间构成封闭的固定和/或密封区域(2)。又如图1B所示,内层和外层优选被连结而在两层之间形成可密封的开口。如图1B所示,该开口优选地通过折片(6)来密封,该折片的至少一部分上覆盖着胶粘剂(3)用以密封该开口。图1C和1D分别表示图1A和1B所示单个基材TDD处置系统的多基材小册子处置系统。
如果仅有一个涂布了胶粘剂的基材,则它优选是柔性的,以便能对折从而将放在其中的TDD固定和隔离。或者,如果仅有一个涂布了胶粘剂的基材,还可存在一个补充基材,该第二基材优选应能不可逆地粘附在至少一个涂胶粘剂的基材上。在此种替代的实施方案中,涂胶粘剂的基材和第二补充基材,根据要求,可以是柔性的或是刚性的。
在某些实施方案中,一个或多个基材可以足够刚性,以使该基材不破坏或碎裂就不能对折。按照此类实施方案,处置系统可包含一个或多个刚性基材,它们既可以是平面的也可以是非平面的。如图14A和14B所示,非平面基材优选具有的构造和尺寸能在一面中提供接收TDD用的凹穴50。视基材厚度和凹穴深度而定,与凹穴相反一面的基材面可以是平面或非平面的。如在图14A中所示实施方案表示的,该基材可在其一面上具有凹穴并在相反一面具有相应的凸出表面。优选的是,胶粘剂涂层和任何任选存在的组分被配置在该凹穴内至少基材之内或之上,以及基材该面的另一部分上。另外,可提供2个各自具有凹穴的基材。在使用中,TDD可基本上放在第一基材的凹穴内,第二基材可与第一基材对准并与之接触而放置,使第二基材的凹穴基本上从上方对准TDD,而该TDD、第一基材和第二基材则不可逆地粘合在一起。凹穴50的深度可小于、等于或大于TDD的厚度。优选地,如果有一个基材,则凹穴的深度大致等于或大于TDD的厚度。如果有两个基材,则其中一个或两个可备有凹穴。在此种实施方案中,一个或多个凹穴的总深度可小于、等于或大于TDD的厚度,优选大致等于TDD的厚度。
在某些实施方案中,基材可另外含有一个或多个凸起构件,它们足够刚性和/或尖锐,以致能刺入放在其中的TDD内。此类实施方案对于旨在刺破储液型TDD的储器以便让活性剂更容易地逃出储器并与基材、胶粘剂以及存在的任何其它任选组分相互作用而言是特别适宜的。
图3示出本发明的一种替代实施方案。该制品是一种TDD处置系统,具有配置在TDD处置系统的固定和/或密封区域中的引发剂(以及任选共引发剂)、单体(以及任选共聚单体)、交联剂和去活剂(针对TDD活性组分)的之一或多种。具体地说,本发明该TDD处置系统包括胶粘剂层(任选地含有一种或多种附加组分)(41),后者具有转移(transfer)侧和背侧。该制品还包括外层(43),具有朝胶粘剂层的一侧和背侧,其中胶粘剂层与外层结合,从而在胶粘剂层背侧与外层的朝胶粘剂层一侧之间形成固定和/或密封区域(44)。优选的是,本发明TDD处置系统的每一层都是抗撕裂的。
图4表示本发明另一种TDD处置系统的实施方案,具有转移侧和背侧,以及任选地,配置在转移侧周边的胶粘剂(61)。转移侧包含第一(62)和第二(63)区域,其可任选地由膜或不透性阻挡层(64)彼此分开。第一区域或第二区域之一或者二者具有配置在其中的上述组分至少之一。优选的是,如果第一和第二区域都包含至少一种上述组分,则存在的该组分在每个区域中不完全一样。该TDD处置系统还任选地包括覆盖该胶粘剂的剥离层,并且该剥离层是任选可剥离的。
本发明TDD处置系统中包括的基材可优选地包括但不限于,韧性、抗撕裂(共)聚合物和/或(共)聚合物复合材料。该基材(共)聚合物可以是无定形的,或者有利地可以某种方式取向,包括但不限于,单轴地、双轴地、多轴地、平面方式或者折叠链晶状、伸长链晶状、伸长链非晶状、液晶状、纤丝状、片状、球晶状等,或者其任意组合。本发明TDD处置系统用的基材的例子包括但不限于:聚酯,例如聚对苯二甲酸乙二醇酯、聚对苯二甲酸丁二醇酯、聚(酯-醚)共聚物、聚(酯-酰胺)共聚物等;聚碳酸酯;聚氨酯,例如聚(酯-氨酯)、聚(醚-氨酯)、聚(醚-氨酯-脲)、聚(酯-氨酯-脲)、聚(醚-脲)、聚(酯-脲)、聚(硅氧烷-氨酯)、聚(碳酸酯-氨酯)等;聚(甲基)丙烯酸酯,例如聚甲基丙烯酸甲酯、乙烯-(甲基)丙烯酸酯共聚物,金属盐部分中和的聚(甲基)丙烯酸,部分脂族烃皂化的聚(甲基)丙烯酸等;聚(甲基)丙烯酸类;聚醋酸乙烯类,例如乙烯-醋酸乙烯共聚物;聚酰胺,例如尼龙、芳族聚酰胺纤维,例如聚(酯-酰胺)共聚物、聚(醚-酰胺)共聚物等;聚醚,例如聚(醚-醚-酮)、聚(醚-酮-酮)、聚(醚-酯)共聚物、聚(醚-酰胺)共聚物等;聚酰亚胺;碳纤维复合材料;聚合物-陶瓷复合材料;聚合物-金属(合金)复合材料;美国专利4,588,580、5,573,778或5,750,134中描述的那些聚合物,在此将每一篇的公开内容收作参考;或诸如此类;等等;或其组合。
特别是就那些包含一种或多种刚性基材的实施方案而言,基材可包括任何聚合物或聚合物复合材料,其具有足够的厚度和刚度以防止基材折叠时不发生破坏或碎裂。除了上述聚合物和上面列举的聚合物复合材料之外,此类刚性基材还可包括任何玻璃纤维、金属和/或陶瓷和/或包含一种或多种此类组分与任何聚合物的复合材料。例如,此种刚性基材可包括金属如铝、钛、钢、不锈钢以及含此类金属的金属/陶瓷复合材料。
虽然对基材的厚度不做特定限制,但柔性基材优选比刚性基材薄。另外,基材的要求厚度特别是取决于其为防止、抑制或减少误用或滥用比如类阿片激动剂的相对阻挡性能(即,基材材料对例如潜在的提取溶剂的阻挡性能越好,所要求的厚度就越小)。例如,柔性基材可有利地具有约0.0005英寸(13μm)~约0.01英寸(250μm),优选约0.001英寸(25μm)~约0.005英寸(130μm)的厚度,而刚性基材则优选比约0.005英寸(130μm)更厚,优选具有约0.01英寸(250μm)~约1英寸(25mm)的厚度。
虽然基材的长度和宽度不受特定限制,但本发明小册子型、多基材型TDD处置系统优选这样的基材(且特别是涂以胶粘剂的基材部分,若不是整个基材都涂布的话),在其面上具有近似于待处置的TDD的面积,尽管一般地只需要让该基材(且特别是涂以胶粘剂的基材部分,如果不是整个基材都涂布的话)具有足以覆盖或容纳TDD或其中的活性组分以防止误用或滥用的横截面面积。就是说,所要求的基材长度和宽度(且特别是涂以胶粘剂的基材部分,如果不是整个基材都涂布的话)特别是取决于其对TDD的粘附力的相对不可逆性,和/或隔离或密封该TDD或其中的活性组分以防止、抑制或减少误用或滥用例如类阿片激动剂的能力(即,胶粘剂涂布的基材对TDD的粘附力越好和/或粘附的基材-TDD组合所提供的防止例如溶剂提取的阻挡作用越好,则需要的基材(或特别是涂以胶粘剂的基材部分,如果不是整个基材都涂布的话)长度和/或宽度越小)。在一种实施方案中,基材该面的横断面面积(且特别是涂以胶粘剂的基材部分,如果不是整个基材都涂涂布的话)比它所粘附的TDD大不超过10%,或者比TDD大不超过约5%,例如与TDD大致相等。
基材可备有适当标签,告诉使用者恰当用法。还有,基材可以是彩色的,例如红色,以便与典型TDD的颜色形成反差。
本发明TDD处置系统中基材上的胶粘剂涂层可有利地与前面关于TDD应用所列举的那些相似或相同。附加或可选地,基材上的胶粘剂涂层可包括但不限于,环氧化物、聚酰亚胺、聚酰胺、硅酮、丙烯酸类、所包括的重复单元带取代或未取代酚部分的聚合物等,或者其共聚物或组合。可用于基材上涂层的特别优选的胶粘剂包括但不限于,环氧基胶粘剂,例如可由Durapower供应的那些,以及压敏胶粘剂,例如丙烯酸基胶粘剂387-2051和387-3054,由National Starch供应,以及硅酮基胶粘剂7-4102、7-4202、7-4302、7-4402、7-4502和7-4602,由DowSilicones供应。不拟囿于理论,但据信,至少在非刚性基材上,硅酮基胶粘剂在隔离粘附在其上的TDD的活性组分并从而防止、抑制或减少其误用或滥用方面,至少比其它橡胶基胶粘剂,例如美国专利5,804,215中列举的那些有优势。另外,据信丙烯酸基胶粘剂也具有优势。
虽然胶粘剂涂层的厚度不受特定限制,但优选的是,厚度足以将其上置有胶粘剂涂层的基材基本上粘附在TDD上并粘附在其自身、至少一个基材的非胶粘剂涂布部分或者第二基材(若存在的话)上。例如,胶粘剂涂层可有利地具有约0.0005英寸(13μm)~约0.1英寸(2.5mm),优选约0.001英寸(25μm)~约0.01英寸(250μm),更优选约0.002英寸(50μm)~约0.004英寸(100μm)的厚度。在优选的实施方案中,胶粘剂涂层的厚度足以基本上将TDD密封在其固定和隔离区域内,并将胶粘剂涂布的基材基本上不可逆地粘贴在其自身、至少一个基材的非胶粘剂涂布部分或者第二基材(若存在的话)上。
任选但优选地,本发明TDD处置系统可有利地包含胶粘剂背衬材料,例如剥离背衬层或通过承载可剥离地配置在基材上的胶粘剂涂层上的剥离涂层而被制成剥离背衬层的层,以便该背衬能轻易地从胶粘剂涂层上除去,例如剥去,当要求将胶粘剂层基本上粘附在TDD、其本身、至少一个基材的非胶粘剂涂布部分和/或第二基材(若存在的话)上时。
在一种优选实施方案中,本发明TDD处置系统可有利地包含多个基材,每一个具有胶粘剂涂层,在其上优选可剥离地配置胶粘剂背衬材料或剥离涂层,使它可轻易地从胶粘剂涂层上除掉,例如剥去,当要求将胶粘剂层基本上粘附到TDD、其自身、至少一个基材的非胶粘剂涂布部分和/或第二基材(若有的话)上时。该多个基材可有利地各自粘贴、固定、隔离和/或防止、抑制或减少对一种或多种TDD的误用或滥用。
在另一种优选的实施方案中,本发明TDD处置系统包含多个基材,每个上面涂布胶粘剂,并且还任选地含有多个胶粘剂背衬材料,每个可剥离地配置在多个基材上的胶粘剂涂层之一上,且其中多个基材结合在一起成为小册子型形式。此种实施方案表示在图11中。单个页,例如(72)和(74),各包含TDD处置系统,结合成小册子(70)的形式。正如上面详细讨论的,每个单个的页都由至少一个涂有胶粘剂的基材构成,例如(76),该页任选地包含下列组分:单体,以及任选至少一种共聚单体;引发剂,以及任选至少一种共引发剂;至少一种交联剂;至少一种类阿片激动剂去活剂,例如类阿片拮抗药;及其混合物。在图11中示出的实施方案中,保护性胶粘剂背衬材料,例如图中所示的剥离背衬层(78),在使用某页以处置至少一个TDD之前被从该页上除去并处置掉。小册子,在此具有封皮(80)和(82),当用完后,例如每页已被使用而处置TDD,可以适当方式处置。要求的话,可在该处置系统例如基材剥离层上备有适当文字,说明TDD的处置方法。
在另一种优选的实施方案中,本发明TDD处置系统包含多个双折基材,每个上面涂有胶粘剂,并且任选地还包含多个胶粘剂背衬材料,每个可剥离地配置在多个基材上的胶粘剂涂层之一上,且其中多个基材结合在一起成为小册子型形式。此种实施方案表示在图12A中。单个双折页,为方便仅示出其中的一个(92),每个包含TDD处置系统,结合成小册子(90)的形式。正如上面详细讨论的,每个单个双折页由至少一个涂有胶粘剂的基材构成,该页任选地包含下列组分:单体,以及任选至少一种共聚单体;引发剂,以及任选至少一种共引发剂;至少一种交联剂;至少一种类阿片激动剂去活剂;及其混合物。
多个双折页TDD处置系统小册子被用来按如下所述处置TDD。图12B示出,将保护性胶粘剂背衬材料的一部分例如图中所示的剥离背衬层(94)从页上除去,由此至少一个TDD,例如从患者身上取下的用完的TDD,可粘贴到该页的外露胶粘剂涂层(96)上。优选地,TDD的胶粘剂涂布表面与该页的胶粘剂涂层相接触。除掉的剥离背衬层在除去以后可适当地处置。图12C示出,将TDD(98)放置于该页的胶粘剂上,并将另一部分保护性胶粘剂背衬材料,例如图中所示的剥离背衬层(100)从该页除去。除掉的剥离背衬层在除去后做适当处置。图12D示出,将双折页的具有外露胶粘剂(102)的部分折叠到TDD上面,以便基本上隔离该TDD。小册子在用完,例如每一页已被用于处置TDD之后,以适当方式处置。处置系统的此种样式可容易地被因地制宜地结合到优选的包装样式中,与此同时满足减少滥用风险的需要。要求的话,在处置系统,例如基材或剥离层上可备有关于TDD处置适当说明的文字。
如图13所示,在某些实施方案中,本发明包含一种试剂盒,它包括盒子52,其用于包封一个或多个贴剂,和包含多个基材56的小册子54形式的TDD处置系统。
在另一种优选的实施方案中,本发明TDD处置系统是下列当中的一种或多种:基本上不透溶剂;基本上溶剂不可溶胀;基本上抗撕裂;基本上耐切割;就其中所装TDD的固定和隔离区域而言,一旦TDD被装入其中,便基本上被密封;一旦胶粘剂涂布的基材基本上粘贴在其自身、至少一个基材的非胶粘剂涂布部分(例如通过折叠),或者第二基材(若存在的话)上,就基本上不可逆地粘附;基本上阻挡对活性剂(例如含在TDD中的类阿片激动剂)的提取;等等;或其任意组合。
任选但优选地,本发明TDD处置系统包括下列组分当中的一种或多种(可选地两种或多种):待聚合单体(和任选共聚单体);引发剂(和任选共引发剂)以引发聚合反应,优选通过能量如紫外线、UV-VIS或可见光和/或热能(或红外辐射)的活化;至少一种交联剂,以交联该(共)聚合物;至少一种类阿片激动剂的去活剂,例如类阿片拮抗药,以对抗、抑制、减少或终止TDD中所含类阿片激动剂的欣快作用,以防试图误用或滥用TDD中所含类阿片激动剂,或通过去活、生物无法利用、物理无法利用、令活性剂丧失对滥用者的诱惑力等或其组合,使类阿片激动剂无法使用;至少一种类阿片激动剂去活剂,以便从化学上改变、降解和/或去活TDD中所含类阿片激动剂,以便一旦误用或滥用,TDD中所含类阿片激动剂的欣快作用至少暂时(并优选永久地处于其经改变、降解和/或去活的形式)在活体内被抑制、减少或终止;等等;或其组合。在一种实施方案中,本发明TDD处置系统可包括非-μ-类阿片去活剂。
存在的话,此类任选组分可有利地被包括在本发明TDD处置系统的任何部分之内和/或之上,以便一旦该TDD被装入到本发明TDD处置系统内,这些任选组分就可以接触该TDD。在一种优选的实施方案中,这些任选组分溶解或分散在至少一个基材上的胶粘剂涂层中。附加或可选地,这些任选组分可存在于第二基材(若存在的话)之中和/或之上。
在一种实施方案中,至少一种任选组分存在于至少一个基材和/或第二基材(若存在的话)上的胶粘剂涂层的第一区域中,而至少一种其它任选组分存在于至少一个基材和/或第二基材(若存在的话)上的胶粘剂涂层的第二区域中。在另一种实施方案中,所有存在的任选组分全都存在于至少一个基材和/或第二基材(若存在的话)上的胶粘剂涂层的同一区域中。
可包括在本发明TDD处置系统中的单体和/或共聚单体(若存在的话)可有利地包括任何可用来制造例如TDD处置系统和/或TDD的胶粘剂(涂层)层、TDD的速率控制膜材料、至少一个基材的材料等或其共混物或共聚物的单体和/或共聚单体。范例单体/共聚单体包括但不限于,二异氰酸酯、二醇、二酸(优选羧酸)、二酯、二胺、环氧化物、二环氧化物、氰基丙烯酸酯、(甲基)丙烯酸、一价(甲基)丙烯酸金属盐、有机(甲基)丙烯酸酯、醋酸乙烯、聚乙烯醇前体、纤维素单体/低聚物(例如,乙酸纤维素、丙酸纤维素、丁酸纤维素、乙酸丙酸纤维素、乙酸丁酸纤维素、丙酸丁酸纤维素、硝酸纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素、羧乙基纤维素、纤维素盐及其组合或共聚物,它们可任选地以某种方式改性,例如部分或完全酯化、部分或完全硝化、部分或完全再生、部分或完全醚化、部分或完全酸化、部分或完全酸中和等,或其组合)、室温稳定的α-烯烃、含硅单体(例如有机硅烷、硅氧烷等,或其组合)、磷腈,等等,或者其任意组合。
本发明TDD处置系统可包括的引发剂和/或共引发剂(若存在的话)可有利地包括任何技术上已知能引发本发明TDD处置系统中存在的单体(和/或共聚单体)(共)聚合反应的引发剂/共引发剂,并优选具体选择以用于该特定的单体/共聚单体。如果需要的话,本领域技术人员将能通过有限常规实验做出此种特定选择。引发剂/共引发剂的例子包括但不限于,一元胺(例如,用于引发环氧化物)、自由基生成化合物(例如过氧化物、双偶氮化合物等,例如用于引发α-烯烃;(甲基)丙烯酸或其金属盐;有机(甲基)丙烯酸酯等),特别是可紫外、光或热活化的那些化合物,等等,或其任意组合。
许多类型自由基引发剂适合用于引发交联,例如偶氮和重氮化合物,例如偶氮二异丁腈(“AIBN”)、有机过氧化物、氢过氧化物、过硫酸盐和过硫酸氢盐,例如过氧化苯甲酰、无机过氧化物和过硫酸盐,例如过氧化物-还原体系,碳-碳引发剂,例如六取代的乙烷,和光引发剂;许多例子在技术上是已知的。(参见Sanchez等人,“引发剂(自由基型)”,载于《Kirk-Othmer化学工艺大全》,第四版,John Wiley & Sons,纽约,1995,卷14,第431-460页,在此将其公开内容收作参考)。适合引发交联的阴离子引发剂在技术上是已知的,包括芳族基团阴离子,例如萘基钠;烷基锂化合物,例如叔丁基锂;芴基碳负离子;1,1-二苯基甲基碳负离子;枯基钾;以及描述在Quirk等人,“引发剂(阴离子型)”中的那些,载于《Kirk-Othmer化学工艺大全》,第四版,John Wiley & Sons,纽约,1995,卷14,第461~476页,在此将其公开内容收作参考。适合用于引发交联的阳离子引发剂在技术上也是已知的,包括质子酸、阳离子给体(引发剂)/Friedel-Carfts酸(共引发剂)体系、稳定的阳离子盐,以及描述在Faust,“引发剂(阳离子型)”中的那些,载于《Kirk-Othmer化学工艺大全》,第四版,John Wiley & Sons,纽约,1995,卷14,第476~482页,在此将其公开内容收作参考。
当需要引发聚合和/或交联时,自由基、阴离子或阳离子型引发剂可采用任何已知措施实现分解,例如借助热或光。特别是光引发剂,例如在McGinniss的“辐射固化”,《Kirk-Othmer化学工艺大全》,第四版,John Wiley & Sons,纽约,1996,卷20,第848~850页中描述的那些,在此将其公开内容收作参考,在技术上已知被用于引发交联。
例如,自由基生成化合物可包括但不限于,过氧化二枯基(例如作为PEROXIMON DC 由Elf AtochemN.A.,和作为ESPERAL 由Witco市售供应);1,1-二(叔丁基过氧)-3,3,5-三甲基环己烷(例如作为VAROX 由R.T.Vanderbilt,和作为LUPERCO 由ElfAtochemN.A.供应);α,α′-双(叔丁基过氧)-二异丙基苯(例如,作为RETILOX 由Elf Atochem N.A.市售供应);2,5-二甲基-2,5-二(叔丁基过氧)己烷(例如,作为VAROX 由R.T.Vanderbilt,和作为LUPERCO 由Elf Atochem N.A.市售供应);二(叔丁基)过氧化物(例如,由Witco市售供应);2,5-二甲基-2,5-二(叔丁基过氧)-3-己炔;叔丁基枯基过氧化物;正丁基-(4,4-二叔丁基过氧)-戊酸酯;过氧化苯甲酸叔戊基酯;4,4-偶氮二(4-氰基戊酸);1,1’-偶氮二(环己腈);2,2′-偶氮二异丁腈;过氧化苯甲酰;2,2-双(叔丁基过氧)-丁烷;1,1-双(叔丁基过氧)-环己烷;2,5-双(叔丁基过氧)-2,5-二甲基己烷;双[1-(叔丁基过氧)-1-甲基乙基]-苯;叔丁基氢过氧化物;过乙酸叔丁酯;叔丁基过氧异丙基碳酸酯;过氧化叔丁基;过氧化苯甲酸叔丁酯;氢过氧化枯烯;氢过氧化环己酮;氢过氧化月桂酰;氢过氧化硬脂酰;2,4-戊二酮过氧化物;过乙酸等;或其组合。
当然,聚合和/或交联也可利用高能电离辐射源来实施。例如,交联可通过让聚合物和单体(特别是平均官能度大于2的单体)的组合暴露于电子束、紫外辐射(通常在光引发剂的存在下),以及高能电离辐射源(例如,由60Co或137Cs源发出的γ-射线、α-粒子、β-粒子、快中子和X-射线)来实现。这些技术中的每一种可导致自由基和/或离子的发生,它们继而引发聚合和/或交联。(参见Sanchez等人,“引发剂(自由基型)”,第454~457页;Sheppard等人,“引发剂”,载于《Kirk-Othmer化学工艺大全》,第3版,John Wiley & Sons,纽约,1981,卷13,第367~370页,在此将其公开内容收作参考)。
至少以下3种辐射交联或接枝方法在技术上是熟知的:(1)“预辐照”方法,其中聚合物先接受辐照然后再与单体相互作用,(2)“相互辐照”方法,其中聚合物和单体在辐照下彼此接触,以及(3)“过氧化物”方法,其中聚合物在空气或氧存在下接受辐照,然后再与单体相互作用。(参见Stannett等人,“高能辐射聚合”,《综合聚合物科学》,Pergamon出版社,牛津,1989,卷4,Eastmond等人主编,第327~334页,在此将其公开内容收作参考)。
于是,可借助热和/或光解离起作用的用于交联和/或聚合的自由基引发剂手段可以是选自下列的引发剂:偶氮化合物、重氮化合物、有机过氧化物、有机氢过氧化物、有机过硫酸盐、有机过硫酸氢盐、无机过氧化物、无机过硫酸盐、过氧化物-还原体系、碳-碳引发剂、光引发剂及其混合物。
本发明TDD处置系统中可包括的交联剂(如果存在)可有利地包括任何技术上已知能化学或物理地交联在本发明TDD处置系统中存在的单体(和/或共聚单体)或随后由其生成的低聚物和/或(共)聚合物的交联剂,并优选地针对具体使用的(共聚)单体/低聚物/(共)聚合物来选择。若需要的话,本领域技术人员将能通过有限常规实验做出此种选择。
交联剂优选具有(a)能与已生成的低聚物或(共)聚合物上或侧挂的多个官能团起反应的官能团,或者(b)能与多个链增长的低聚物或(共)聚合物的链端起反应,从而在低聚物或(共)聚合物内形成链间交联的可聚合基团。交联剂的例子包括但不限于,平均具有一个或多个以下的化合物:多于2个的异氰酸酯官能团,多于2个的羟基官能团,多于2个的酯官能团(例如,用于酯交换反应)、多于2个的(优选羧酸)酸官能团、多于2个的胺官能团(即,每个具有至少一个活性部位)、一个或多个环氧官能团、多于1个的可聚合不饱和基团、多于2个的一价羧酸金属盐基团等,或多于2个的上面列举的官能团的组合。
交联剂也可与已生成的低聚物或(共)聚合物上之前非活性的部位起反应以便使之活化。随后,该活性部位本身便可与另一个已生成的低聚物或(共)聚合物链上的活性或之前非活性的部位起反应。或者,该活性部位可与本发明TDD处置系统中存在的其它化合物,例如上面提到的单体/共聚单体起反应,最终与另一个已生成的低聚物或(共)聚合物链上的活性或之前非活性的部位起反应。
在本发明TDD处置系统中可包括至少一种活性剂去活剂。例如,任何技术上已知能化学地改变、降解和/或去活TDD中包含的类阿片激动剂,以便在误用或滥用的情况下,使TDD中所含类阿片激动剂的欣快作用在活体内至少暂时(且优选永久地处于其经改变、降解和/或去活的形式)被抑制、减少或终止的类阿片激动剂去活剂皆可包括在内。类阿片激动剂去活剂,若存在的话,优选地具体针对TDD中所含特定类阿片激动剂来选择,尽管某些类阿片激动剂去活剂能引起许多普通类阿片激动剂的化学改变、降解和/或去活。需要的话,本领域技术人员将能通过有限常规实验做出此种具体选择。
活性剂去活剂的其它例子包括但不限于,强氧化性化合物和强反应性自由基生成化合物,例如上面作为引发剂(和/或共引发剂)列出的那些过氧化物、过酸、过(金属氧化物)、过(非金属氧化物)和偶氮化合物,或其组合。附加或可选地,去活剂可包括但不限于,过氧化氢;过(非金属氧化物)酸,例如高碘酸;等等;或其组合。
可包括在内的活性剂去活剂的另一个例子是活性剂,去活剂如类阿片拮抗药。可包括在本发明TDD处置系统中的至少一种类阿片激动剂去活剂优选地包括任何技术上已知的类阿片激动剂去活剂,例如任何类阿片拮抗药,以便在试图误用或滥用TDD中所含类阿片激动剂的情况下,能对抗、抑制、减少或终止TDD中所含类阿片激动剂在活体内的欣快作用。类阿片激动剂去活剂若存在的话,优选具体地针对TDD中所含特定类阿片激动剂来选择,尽管某些类阿片拮抗药拮抗许多普通类阿片激动剂的欣快作用。如果需要的活,本领域技术人员将能通过有限常规实验做出此种具体选择。
类阿片激动剂去活剂可有利地通过令活性剂失活而使之无法利用,失活作用例如是化学失活或改变类阿片激动剂的受体结合部位;机械失活或改变类阿片激动剂的受体结合部位;生物无法利用;物理无法利用;丧失类阿片激动剂对滥用者的诱惑力,例如,产生不可容忍坏味道或不可容忍反应的去活剂,例如极端恶心等,或者与此类似的效果;或者其任何组合。
例如,就有待通过放在本发明TDD处置体系中来处置的经皮贴剂或其它给药器中的类阿片激动剂来说,去活剂可以是能改变该剂量形式中残留的类阿片分子并使之失活的化学或变性剂。去活剂可选地或附加地是能把残留的类阿片结合到不溶性配体-受体配合物中的类阿片受体。去活剂可选地或附加地是类阿片受体拮抗药,优选对受体的特异性和/或亲和力比对类阿片更大,其将在误用/滥用时随同残留的类阿片一起被隔离或给药,从而与残留的类阿片竞争类阿片受体,借此挫败误用/滥用该类阿片的目的。这将使残留类阿片在活体中变得无用。去活剂可选地或附加地物理螯合残留类阿片激动剂,例如将其螯合在不可透微球中或者永久结合的基质中。类似地,去活剂可选地或附加地是具有一旦被吸收将令人痛苦或烦躁不安性质的非类阿片,从而使得不再想误用/滥用。
去活剂的例子包括但不限于,大鼠或人类μ-类阿片受体;类阿片中和抗体;类阿片/麻醉剂拮抗剂,例如纳洛酮、纳曲酮、纳美芬、cyclazacine、赛拉佐辛、烯丙吗啡、纳布啡、左洛啡烷、布托啡诺、喷他佐辛等或其组合;焦躁或刺激剂,例如东莨菪碱、氯胺酮、阿托品、芥子油等或其组合;等等;或其任意组合。
在一种实施方案中,TDD处置系统可包括非-μ-类阿片去活剂,包括但不限于,大鼠或人类κ-类阿片受体;大鼠或人类δ-类阿片受体;naltrindole;norbinaltorphimine;J-113397(即,在Ozaki等人(2000),Eur.J.Pharmacol.,402:45中公开的);JTC-801(即,如Yamada等人(2002),Br.J.Pharmacol.,135:323中公开的);[Nphel,Arg14,Lys15]nociceptin-NH2(如Calo等人(2002)Br.J.Pharmacol.,136:303公开);以及其组合。其它合适的非-μ-类阿片去活剂应是本领域技术人员知道的。
要指出的是,某些组分可有利地被选择用来在本发明经皮给药处置系统中发挥多重作用。例如,将过氧化物结合到该系统中,该过氧化物可起到TDD中药物化合物例如类阿片激动剂的去活剂作用,同时也起引发剂和/或共引发剂(若存在的话)的作用来引发TDD处置系统中存在的单体(和/或共聚单体)的(共)聚合。
当在本发明TDD处置系统中存在时,存在的单体(包括任何共聚单体)的总量可介于约0.01%~约15%,优选约0.1%~约10%,可选地约0.1%~约5%,均重量计,基于单体所居于其内和/或其上的层的总重量。当在本发明TDD处置系统中存在时,存在的引发剂(包括任何共引发剂)的总量可介于约0.001%~约5%,优选约0.01%~约3%,可选地约0.1%~约2%,均重量计,基于引发剂所居于其内和/或其上的层的总重量。
当在本发明TDD处置系统中存在时,存在的交联剂的总量可介于约0.1%~约20%,优选约0.5%~约10%,可选地约1%~约5%,均重量计,基于交联剂所居于其内和/或其上的层的总重量。
当在本发明TDD处置系统中存在时,存在的去活剂的总量可介于约0.001%~约25%,优选约0.01%~约15%,可选地约0.1%~约5%,均重量计,基于去活剂所居于其内和/或其上的层的总重量。
当在本发明TDD处置系统中存在时,存在的去活剂的总量可介于约0.001%~约15%,优选约0.01%~约10%,可选地约0.1%~约5%,均重量计,基于去活剂所居于其内和/或其上的层的总重量。
附加或可选地,本发明TDD处置系统或其任何组分的某些方面描述在共同未决PCT专利申请PCT/US02/12920(指定美国,2002-04-23提交)中,以及在美国临时专利申请60/285,862和60/292,601中,分别于2001-04-23和2001-05-22提交,并且本PCT申请要求这两篇的优先权。因此,在此将以上刚提到的PCT和临时申请的公开内容全文收作参考。
本发明另一个方面涉及用于处置TDD和/或防止TDD的组分(例如,类阿片激动剂)误用或滥用的方法。该方法包括提供一种本发明TDD处置系统,它包含至少一个基材,其上涂有胶粘剂层。如果仅有一个其上涂有胶粘剂的基材,它优选是柔性的,以便能自身对折从而固定和隔离放在其上的TDD。或者,如果仅有一个其上涂有胶粘剂的基材,则还可存在第二补充基材,该第二基材优选能不可逆地粘贴到至少一个胶粘剂涂布的基材上。在此种替代的实施方案中,胶粘剂涂布的基材和第二补充基材可以是柔性或者是刚性的,根据要求而定。有利的是,该基材和胶粘剂可包括上面所描述的那些。
任选但优选也提供可剥离地配置在基材的胶粘剂涂层上的胶粘剂背衬材料或剥离涂层,以便当要求胶粘剂层基本上粘贴在其自身、该至少一个基材的非胶粘剂涂布部分、或者第二基材(若存在的话)上时,它能被轻易地从胶粘剂涂层上除掉,例如剥掉。
该方法还包括将TDD放在胶粘剂涂层区域上,并将TDD基本上覆盖或包含在至少该区域内,以在其中固定和隔离TDD,这可通过折叠基材,以便使胶粘剂涂层基本上粘贴到其自身或者粘附到至少一个基材的非胶粘剂涂布的部分上,或者使该基材上的胶粘剂涂层接触第二基材,以便使该胶粘剂涂层基本上粘贴在第二基材上来实现。附加或可选地,该方法还可包括将TDD基本上不可逆地粘贴到该胶粘剂涂层或至少一个基材的至少一个区域,以便在其上固定和隔离TDD,随后形成可将TDD包含在其中的固定和隔离区域。
任选但优选地,该方法还可包括在本发明TDD处置系统中提供一种或多种下列组分:单体(和任选共聚单体),用于聚合成(共)聚合物;引发剂(和任选共引发剂),用于引发(共聚)单体的聚合,优选通过以能量例如紫外线、UV-VIS或可见光和/或热能(或红外射线)的活化;至少一种交联剂,用以交联(共)聚合物;至少一种类阿片激动剂去活剂,用以在试图误用或滥用该TDD中所含类阿片激动剂时,对抗、抑制、减少或终止TDD中所含类阿片激动剂的欣快作用,或者通过令活性剂失活、生物无法利用、物理无法利用、失去对滥用者的诱惑力而使类阿片激动剂无法利用等等,或其组合;至少一种类阿片激动剂减活剂,用以化学地改变、降解和/或去活TDD中所含类阿片激动剂,以便在误用或滥用情况下使TDD中所含类阿片激动剂的欣快作用在活体内至少暂时(且优选永久处于其经改变、降解和/或失活的形式)被抑制、减少或终止;等等;或者其组合。
存在的话,这些任选组分可有利地配置在本发明TDD处置系统的任何部分之中和/或之上,从而使该TDD一旦被装入本发明TDD处置系统中,这些任选组分便可与TDD接触。在一种优选的实施方案中,这些任选组分被溶解或分散在至少一个基材上的胶粘剂涂层中。在另一种优选的实施方案中,这些任选组分溶解或分散在至少一个基材中。附加或可选地,这些任选组分可配置在第二基材(若存在的话)之中和/或之上。
在一种优选的实施方案中,该方法包括提供多个基材,每个具有胶粘剂涂层,在涂层上优选可剥离地配置胶粘剂背衬材料或剥离涂层,以便当要求胶粘剂层基本上粘贴在TDD、其自身、至少一个基材的非胶粘剂涂布部分和/或第二基材(如果存在的话)上时,它能轻易地从胶粘剂涂层上除掉,例如剥掉。这些多个基材每个可有利地粘贴、固定、隔离和/或防止、抑制或减少对一个或多个TDD的误用或滥用。
在另一种优选实施方案中,该方法包括提供包含多个基材的TDD处置系统,每个基材上涂有胶粘剂,并任选地还包含多个胶粘剂背衬材料,每个可剥离地配置在多个基材上的胶粘剂涂层之一上,且其中多个基材结合在一起成为小册子型形式。该小册子的多个基材每个可方便和有利地粘贴、固定、隔离和/或防止、抑制或减少对一个或多个TDD的误用或滥用。
实施例
下面的实施例用于说明,而不是限定本发明的范围。
实施例1
在实施例1中,如图2B所示经皮给药器被负载以叔丁啡(BUP)。实施例1所使用的具体BUP TDD在组成上类似于瑞士的Gruenenthal按商品名TRANSTEC在欧洲销售的那些,但它总共仅含有20mg BUP剂量(因此,其表面积不同于市售品TDD)。该BUP TDD随后用如图1B所示TDD处置系统固定和隔离。然后,通过利用下列溶剂的提取来确定某些情况下从TDD处置系统包含的TDD中可提取的BUP(由此可能被供以滥用的)的量:蒸馏水、自来水、0.026M小苏打水溶液、5%醋、丙酮、甲醇、乙醇、乙酸乙酯或乙醚。提取是在以下提取条件下进行的:在约25℃的室温下在提取溶剂中5min、60min和120min之后。就每种提取溶剂而言,TDD存在于下列被隔离状态:(1)不折叠TDD基材(“开敞面”),(2)基材自体对折并自体粘贴(“折叠”),(3)基材自身对折并自体粘贴,随后切割成约10~约50块(“折叠并切割”),以及(4)不折叠,而是将TDD基材粘贴到TDD处置系统的胶粘剂上(粘贴器具的胶粘剂一侧朝下)(“被胶粘剂膜被覆”)。
所采用的TDD处置系统全部由约46μm厚聚对苯二甲酸乙二醇酯/聚(乙烯-共聚-醋酸乙烯)薄膜构成,由3M公司供应(#9733),涂以由DowSilicones获得的硅酮压敏胶粘剂(#7-4302)约220μm厚。为保护胶粘剂,在其上施加约74μm厚的涂剥离剂的聚对苯二甲酸乙二醇酯膜,由3M公司提供(#1022)。该剥离剂涂布膜在临要将TDD处置系统粘贴到该BUP TDD之前被除去。
图5~10每一幅显示可分别用蒸馏水、乙酸乙酯、乙醇、乙醚、丙酮和甲醇从存在于每种上述隔离状态下的TDD中提取的BUP百分率。下表1是绘制图5~10时所依据的,显示每个提取实施例的数据。
表1
经以下时间后的叔丁啡溶剂提取百分数%
溶剂 5分钟 1小时 2小时
开敞面折叠面 折叠并 被胶粘 开敞面 折叠面 折叠并 被胶粘 开敞面 折叠面折叠并 被胶粘
切割 剂被覆 切割 剂被覆 切割 剂被覆
蒸馏水 8.1 0 0 0 19.3 0 0.8 0 27.7 0 2.0 0
(6.6pH)
自来水 7.3 0 0 0 20.9 0 0 0 30.5 0 3.9 0
(7.4pH)
0.026M小苏打 1.1 0 0 0 0.9 0 0 0 0.9 0 0 0
溶液
(8.2pH)
5%醋 5.9 0 0.2 0 18.5 0 1.8 0 27.1 0 2.2 0
(2.4pH)
丙酮 83.4 0.4 1.6 0.3 88.5 5.9 21.7 1.1 91.5 8.6 34.4 4.9
甲醇 41.9 6.2 4.9 0 83.4 1.5 21.5 0.8 84.9 2.0 23.4 3.1
乙醇 64.9 0.2 3.4 0 78.3 2.7 16.7 1.9 79.7 4.9 16.8 1.5
乙酸乙酯 89.6 0.4 3.0 0.2 96.3 3.5 12.9 1.6 96.2 6.8 16.8 2.6
乙醚 64.9 1.9 7.2 0.2 100 7.8 29.1 - 98.5 4.1 46.7 9.3
预演实施例2
就预演实施例2来说,如图2B所示经皮给药器被负载以BUP,如同实施例1。该BUP TDD随后用如图1C所示TDD处置系统固定和隔离。然后,通过利用下列溶剂的提取来确定某些情况下从包含在TDD处置系统中的TDD中可提取的BUP(由此可能被供以滥用)的量:蒸馏水、自来水、0.026M小苏打水溶液、5%醋、丙酮、甲醇、乙醇、乙酸乙酯和/或乙醚。提取是在以下提取条件下进行的:在约25℃室温,和在回流(即,在大约提取溶剂的沸腾温度)下在提取溶剂中5min、60min和120min之后。就每种提取溶剂而言,TDD存在于下列被隔离状态:(1)不将第一基材(即,已粘贴到TDD上的)粘贴到第二基材上(粘贴器具的胶粘剂一侧朝上)(“开敞面”),(2)将TDD粘贴在第一和第二基材之间(“夹芯”),(3)将TDD粘贴在第一和第二基材之间,随后切割或碎裂成约10~约50块(“折叠并切割”),以及(4)不将第一基材(即,已粘贴到TDD上的)粘贴到第二基材上(粘贴器具胶粘剂一侧朝下)(“被胶粘剂膜被覆”)。
用于该实施例的TDD处置系统由约46μm厚聚对苯二甲酸乙二醇酯/聚(乙烯-共聚-醋酸乙烯)薄膜构成,由3M公司供应(#9733),其涂以胶粘剂混合物。该胶粘剂混合物包含约95wt%丙烯酸基胶粘剂,由Solutia获得(#2464),以及约5%过氧化苯甲酰(以胶粘剂混合物固体含量为基准计)。胶粘剂混合物涂层为约150~350μm厚。为保护该胶粘剂混合物,在其上施加约50~100μm厚的涂布剥离剂的聚对苯二甲酸乙二醇酯膜,由3M公司提供(#1022)。该剥离剂涂布膜在TDD处置系统被粘贴到含活性剂的TDD上之前除去。
本发明的范围不限于这里所描述的具体实施方案。实际上,各种各样本发明变形方案,除了这里已经描述过的那些之外,在本领域技术人员研读了上面的描述和附图之后将是显而易见的。此类变形方案都应落在所附权利要求的范围内。
所援引的全部专利、申请、出版物、试验方法、文献和其它材料在此一律收作参考。
Claims (4)
1.一种试剂盒,它包含:
经皮给药器,包含至少一种活性剂;以及
至少第一刚性、非平面基材,其至少一个面上具有胶粘剂涂层。
2.权利要求1的试剂盒,还包含第二刚性非平面基材,其至少一个面上具有胶粘剂涂层。
3.权利要求1的试剂盒,其中第一基材和第二基材各规定了其构造和尺寸用于在其中接受经皮给药器的凹穴,且其中第一和第二基材上的胶粘剂涂层至少配置在第一和第二基材的规定了该凹穴的部分上。
4.权利要求1的试剂盒,还包含至少存在于第一基材、第二基材、第一基材至少一个面上的胶粘剂涂层、第二基材至少一个面上的胶粘剂涂层之中或之上或其任意组合的一种或多种下列组分:
(a)单体,以及任选地至少一种共聚单体;
(b)引发剂,以及任选地至少一种共引发剂;
(c)至少一种交联剂;以及
(d)至少一种活性剂去活剂。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108601747A (zh) * | 2015-11-19 | 2018-09-28 | 欧洲凯尔特公司 | 用于治疗疼痛的防滥用的透皮递送装置和包含类阿片激动剂和不透皮递送的类阿片拮抗剂的n-氧化物衍生物的组合物 |
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