CN102048713A - 透皮治疗系统 - Google Patents
透皮治疗系统 Download PDFInfo
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- CN102048713A CN102048713A CN2011100034841A CN201110003484A CN102048713A CN 102048713 A CN102048713 A CN 102048713A CN 2011100034841 A CN2011100034841 A CN 2011100034841A CN 201110003484 A CN201110003484 A CN 201110003484A CN 102048713 A CN102048713 A CN 102048713A
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Abstract
本发明涉及透皮治疗系统，特别是含有硅氧烷粘附层的透皮治疗系统、提供特定血浆浓度的透皮治疗系统、它们的制备和用途。
Description
本申请为2006年10月10日提交的、发明名称为“透皮治疗系统”的PCT申请PCT/US2006/039557的分案申请，所述PCT申请进入中国国家阶段的日期为2008年5月21日，申请号为200680043422.0。
技术领域
本发明涉及包含背衬层、储药层和粘附层的透皮治疗系统、具有特定释放性质的透皮治疗系统、它们的制备和用途。
背景技术
一般来讲，透皮治疗系统(TTS)和它们的制备是本领域众所周知的。EP 1047409公开了包含利凡斯的明(rivastigmine)和抗氧化剂的TTS。GB2203040公开了包含利凡斯的明和亲水聚合物的TTS。
这些TTS具有有价值的性质。然而，仍需要有性能改进的TTS。具体来讲，需要提供改进依从性、粘附性、耐受性和/或安全性的TTS。
发明内容
因此，本发明的一个目的是提供具有改进的依从性、粘附性、耐受性和/或安全性的TTS。
本发明的另一个目的是提供TTS，该TTS含有相对大量的活性成分并具有保证在整个用药期间安全使用的粘附力。
本发明的另一个目的是提供TTS，该TTS含有相对大量的活性成分，同时体积不会过大。
本发明的另一个目的是提供TTS，该TTS呈现出改进的粘附性能，但没有改变活性成分的释放性质。
本发明的另一个目的是提供显著提高利凡斯的明的效力和耐受性的治疗方法和控释制剂。
本发明的另一个目的是提供显著减少利凡斯的明达到治疗效果所需要的时间和资源的治疗方法和控释制剂。
本发明的另一个目的是提供显著提高利凡斯的明治疗的依从性的治疗方法和控释制剂。
本发明的另一个目的是提供治疗方法和控释制剂，就产生治疗效果所需的利凡斯的明的血浆浓度而言，其呈现显著更小的个体间差异，并没有不可接受的副作用。
权利要求1和从属权利要求所定义的TTS可以实现上面所述。
附图说明
图1显示了一幅柱状图，其图示说明了含有额外的硅氧烷粘附层的TTS(TTS #2)和不含额外的硅氧烷粘附层的TTS(TTS #1)的不同粘附力。
图2显示了一幅图，其图示说明了通过含有额外的硅氧烷粘附层的TTS(TTS #2)和没有额外的硅氧烷粘附层的TTS(TTS #1)给药，利凡斯的明通过人全层皮肤的不同透过率。
图3显示了一幅图，其图示说明了通过含有额外的硅氧烷粘附层的TTS(TTS #2)和没有额外的硅氧烷粘附层的TTS(TTS #1)给药，利凡斯的明通过EVA膜的不同透过率。
图4显示了一幅图，其图示说明了通过胶囊(上面的)和TTS #2(下面的)给药后的血浆PK性质。
使用治疗阿尔茨海默病的活性成分的测试已惊人地显示：一层硅氧烷可应用至粘附力弱的储药基质中，这样能显著提高制剂的粘附性质，而不影响TTS的热力学性质，即不会减少活性成分从基质中的释放和它的穿过皮肤的渗透。
由申请人完成的、自治疗阿尔茨海默病的活性成分的透皮应用的测试中得到的发现，当然可以适用于其它类活性成分。应当说明的是，一般来讲，对于许多活性成分而言，如果所述活性成分在室温下是固体，在TTS的粘着的聚合物基质中的活性成分的比例增加将显著降低TTS的粘附性能。通常，如果活性成分在室温是液体状态的，为了实现聚合物的机械加工性，必须加入大量的所谓“增稠聚合物”(例如纤维素或聚丙烯酸酯衍生物)，其也可导致粘附性能降低。
本发明提供了包含背衬层、含有至少一种活性成分和聚合物的储药层以及含有硅氧烷聚合物和增粘剂的粘附层的TTS。
本发明的TTS显示了改进的粘附性能。另外，非常令人惊奇地是，当与标准的TTS相比时，这样得到的TTS基本具有相同的释放性质。
本发明还涉及显著改进利凡斯的明的效力和耐受性的方法，该方法包括应用大小为2-50cm2的TTS，所述制剂在施用后平均约2-16小时提供约1-30ng/mL的平均最大血浆浓度，并在重复“QD”(即每天一次)给药后提供大约25-450ng·h/mL的AUC24h值。
与暴露于相同水平(AUC24h)的
胶囊相比，本发明的TTS相当令人吃惊地显示出提高的耐受性，特别是胃肠的不良反应例如恶心和呕吐。
除非另外说明，本发明中所用的术语有以下含义：
术语“透皮治疗系统”是指能透过皮肤释放药物活性成分的任何装置。这特别包括自身具有粘性的装置，例如贴剂。
术语“背衬层”是指远离皮肤的层。该层优选为活性成分不能渗透的。可用任何适当的材料或材料组合。例如可以应用聚对苯二甲酸乙二酯(PET)、聚乙烯、聚丙烯、聚氨基甲酸酯等。
术语“储药层”是指包含一种或多种活性成分以及一种或多种聚合物的层。在一个优选实施方案中，储药层包含在聚合物基质形式中的活性成分。
术语“粘附层”是指面向皮肤的一层。该层包含硅氧烷聚合物和增稠剂。
术语“可分离的保护层”是指在其施用至皮肤前，从贴剂中除去的一层。该层优选为活性成分不能渗透的。可以应用任何合适的材料或材料组合。例如硅化处理的PET、硅化处理的聚丙烯、硅化处理的聚乙烯、氟聚合物包被的(coated)PET、氟聚合物包被的聚丙烯、氟聚合物包被的聚乙烯等。
术语“活性成分”是指适合透皮给药的任何活性成分。活性成分包括水溶和水不溶的药学活性成分，其可以是无机物质或有机物质。优选有机物质。根据它们的适应征，活性成分可用做镇痛剂、退热剂、抗风湿剂、镇静剂、安眠药、抗癫痫药、抑制药和兴奋剂、麻醉剂、神经安定镇痛药、抗组胺药、抗高血压药、抗凝血药、抗血栓药、精神病药物、精神抑制药、化疗药物(例如抗生素、磺胺类药物、抗结核药(结核菌抑制剂)或抗热带感染的化疗药物)、利尿剂、解痉药、心血管药物例如拟交感神经药、抗高血压药、心脏兴奋剂例如强心苷类和洋地黄类(digitaloids)、胃肠外糖治疗(parenteral sugar therapeutics)、作用于中枢神经系统的兴奋剂、老年病药物、tonolytics(横纹肌的)、抗帕金森病药物、细胞生长抑制剂、免疫抑制剂、滋补剂和维生素，如B.Helwig(Moderne Arzneimittel)，1980所述。
优选的活性成分选自α-肾上腺素受体激动剂、β-肾上腺素受体激动剂、α-肾上腺素受体阻断剂、麻醉镇痛剂、非麻醉镇痛剂、雄激素、麻醉剂、抗过敏药物、抗雄激素物质、抗心绞痛药物、抗心律失常药物、青霉素类、抗糖尿病药物、抗组胺药、抗偏头痛药物、水合麦角生物碱类、Ca++拮抗剂、血清素拮抗剂、血小板聚集抑制剂、抗抑郁药、broncholytics、雌激素类、孕激素类、血管扩张剂、激素类、抗痴呆药物(包括胆碱酯酶抑制剂)。
优选的抗生素包括青霉素、四环素、金霉素、杆菌肽、制霉菌素、链霉素、新霉素、多粘霉素(polymicin)、短杆菌肽、土霉素、氯霉素、红霉素、利福平、头孢唑啉、头孢西丁、头孢磺啶、头孢替安和美福仙。优选的化疗药物包括磺胺二甲嘧啶、磺胺甲嘧啶、磺胺甲二唑和磺胺异
唑。优选的镇静剂和安眠药包括水合氯醛、戊巴比妥、苯巴比妥、司可巴比妥、可待因和卡溴脲(carbroma)。优选的强心苷和洋地黄类包括洋地黄毒苷和地高辛。优选的拟交感神经药物包括肾上腺素。
具体地讲，根据本发明，退热剂、镇痛剂和抗风湿药剂可以以水溶的形式或水不溶的形式用做说明书中的活性成分，例如异丙安替比林、氨基比林、阿司匹林(ASA)、安替比林、甲基尼芬那宗(methyl nifenazine)、甲磺比林(melaminsulfone)、sulfenazone、非那西汀、喷他佐辛、乳酰对乙氧苯胺、扑热息痛、奎宁、氯芬那酸、甲芬那酸、托芬那酸、甲氯芬那酸、尼氟酸、氯尼辛或clonixidin、氟尼辛、布洛芬、舒洛芬、酮洛芬、非诺洛芬、吡洛芬、双氯芬酸、异丁芬酸、procticic acid、萘普生、环洛芬、托美丁、氯吡酸、噻洛芬酸、奥沙普秦、芬克洛酸、芬替酸、环氯茚酸、芬氯酸(fenclonac)、非诺洛芬、氟比洛芬、卡洛芬、舒林酸、桂美辛、芬布芬(fenbuten)、依托度酸、butifufen。
优选的精神病药物包括精神安定药、抗抑郁药(antidepressants)、抗抑郁剂(thymoleptics)、thymerethical药、安神剂，如硫利哒嗪、丙咪嗪、去甲丙咪嗪、氯米帕明、剀替帕明、奥匹哌醇、阿米替林、去甲替林、利血平、aromazine、氯丙嗪、氟丙嗪、美索丙嗪、阿利马嗪、二乙嗪、异丙嗪、氨丙嗪、甲哌啶嗪、匹哌马嗪、马普替林和美金刚。
优选的抗高血压药包括氧烯洛尔和美托洛尔。
活性成分优选选自抗痴呆药物，例如利凡斯的明、多萘哌齐、加兰他敏、司来吉兰、美金刚(memanitine)以及这些活性成分的药理学上可接受的盐。
优选的胆碱酯酶抑制剂包括他克林、利凡斯的明、多萘哌齐、毒扁豆碱、石杉碱甲和它们的药理学上可接受的盐。
优选用利凡斯的明和美金刚的组合做为活性成分。
最优选的活性成分选自利凡斯的明和重酒石酸利凡斯的明。利凡斯的明
可用于治疗轻度到中度的阿尔茨海默型痴呆(也称为阿尔茨海默病)和与帕金森氏病和创伤性脑损伤症状相关的痴呆。
术语“聚合物”，当其与活性成分储药层一起使用时，是指聚合物，其选自分别与树脂混合的聚二甲基硅氧烷、聚丙烯酸酯、聚异丁烯、聚丁烯和苯乙烯-异戊二烯-苯乙烯嵌段共聚物或它们的混合物。
优选的用于储药层的聚合物选自聚丙烯酸酯，例如来自国民淀粉(National Starch)的Durotak 2353。
术语“硅氧烷聚合物”是指基于聚二甲基硅氧烷的聚合物，例如选自道康宁(Dow Corning)的amincompatible Bio-PSA Q7-4302。
术语“增粘剂”是指可增加透皮制剂的粘附性的物质。优选的增粘剂选自硅氧烷油、氢化树脂酸甘油酯、氢化枞醇(hydroabietyl alcohol)、树脂酯类、氢化木松香甲酯、部分氢化的木松香酯、松香酯等和它们的组合。正如技术人员所知，TTS是由具有独特性能的数层组成的。这些层可根据各自的组成和各层的厚度而变化。
在本发明的优选实施方案中，所用的活性成分在硅氧烷粘附剂中的饱和溶解度低。活性成分在硅氧烷粘附剂中的饱和溶解度例如低于15％重量百分比，优选低于10％重量百分比，最优选为2-8％重量百分比。
硅氧烷粘附层优选使活性成分从储药层透过皮肤的渗透减少不超过40％，尤其优选不超过20％，更尤其优选不超过10％。
硅氧烷粘附层单位面积的重量例如是5-60g/m2，优选10-30g/m2。
根据本发明的组合物可以用于给药许多活性物质。合适的活性物质为如上所述的那些。
在一个优选实施方案中，储药层还可包含辅助剂例如填充剂、抗氧化剂、着色剂、皮肤穿透促进剂和/或防腐剂。这些辅助剂是专家公知的，并可从标准教科书中选择，特别参见Fiedler的“Lexicon der Hilfstoffe”，第四版，ECV Aulendorf 1996以及Wade和Weller编辑的“药物赋形剂手册(Handbook of Pharmaceutical Excipients)”(1994)，将其内容引入文中作为参考。
在一个特别优选的实施方案中，储药层包含抗氧化剂，例如α-生育酚、维生素C棕榈酸酯或丁化羟基甲苯(BHT)。
在一个优选实施方案中，储药层包含皮肤穿透促进剂，例如二乙二醇乙醚(Transcutol)、甘油、甘油酯、脂肪酸、脂肪酸盐、月桂氮卓酮、二乙基甲苯酰胺(Diethyl-toluolamide)、丙二醇(Propylengylcol)、丙二醇酯类、丁二醇、异丙酯类、尿素等。
在一个优选实施方案中，储药层和粘附层的厚度比是5∶1至1∶2，优选2∶1至1∶1。
在一个优选实施方案中，TTS的粘附力＞5N/10cm2，优选＞10N/10cm2。在一个优选实施方案中，TTS的粘附力＜100N/10cm2，优选＜50N/10cm2。粘附力可根据例如在实施例中所述的标准方法测定。
在一个优选实施方案中，TTS的大小是2-50cm2，特别优选5-20cm2。
在一个优选实施方案中，在施用后平均2-16h，TTS提供1-30ng/mL的利凡斯的明的平均最大血浆浓度，并提供为25-450ng·h/mL的AUC24h。更优选，在施用后平均4-12h，TTS提供2.5-20ng/mL的利凡斯的明的平均最大血浆浓度，并提供45-340ng·h/mL的AUC24h。
在另一个实施例中，不但聚合物基质包含活性成分，而且硅氧烷粘附层也包含活性成分。
在另一方面，本发明提供引入作为活性成分的游离形式或药学上可接受的盐形式的胆碱酯酶抑制剂的TTS，其用于预防、治疗痴呆或延迟痴呆的恶化。
在另一方面，本发明提供了在需要此类治疗的个体中预防、治疗与帕金森氏病有关的痴呆或延迟其恶化的方法，该方法包括对所述个体施用治疗有效剂量的TTS，该TTS引入了作为活性成分的游离或药学上可接受的盐形式的胆碱酯酶抑制剂。
在另一方面，本发明提供了在需要此类治疗的个体中预防、治疗阿尔茨海默病或延迟其恶化的方法，该方法包括对所述个体施用治疗有效剂量的TTS，该TTS引入了作为活性成分的游离或药学上可接受的盐形式的胆碱酯酶抑制剂。
根据本发明，TTS的制备可用本领域技术人员公知的任何方法完成。
在另一方面，本发明提供了制备TTS的优选方法。这种方法包括下列步骤：
a.)制备在粘合液(adhesive solution)中的活性成分
b.)将在粘合液中的活性成分涂覆(coating)
c.)干燥在粘合液中的活性成分
d.)制备硅氧烷粘合液
e.)将硅氧烷粘合液涂覆
f.)将硅氧烷层压到含药物的粘附层上
g.)冲切和装袋
在另一方面，本发明提供了：包含作为活性成分的游离或药学上可接受的盐形式的利凡斯的明并且提供特定血浆浓度的TTS。
关于利凡斯的明在人体中的生物药剂学性质几乎没有详细报告。它能被迅速并完全地吸收。我们发现它主要通过酯酶(例如乙酰胆碱酯酶和丁酰胆碱酯酶)水解代谢，血浆半衰期为1h。它通过系统前和系统代谢。我们现已发现可以制备包含利凡斯的明的具有有利性质(例如更好的耐受性)的TTS。
因此，本发明提供了包含作为活性成分的游离或药学上可接受的盐形式的利凡斯的明的TTS，其施用后平均约2-16h的平均最大血浆浓度为约1-30ng/ml。
另外，本发明提供了包含作为活性成分的游离或药学上可接受的盐形式的利凡斯的明的TTS，其施用后平均约2-16h的平均最大血浆浓度为约1-30ng/ml，重复“QD”(即每天一次)给药后，24h的AUC值为约25-450ng＊h/mL。
本领域技术人员熟悉如何生产具有如上所定义的血浆性质的TTS。本领域技术人员将理解可通过以下改变获得这类血浆性质，例如
●第一种和/或第二种成分的组成，例如赋形剂和/或活性成分的性质和量
●粘附层的类型
●贴剂的尺寸
可以制备TTS，这需要考虑以下方面：
●在活性成分释放之前的时间(延滞时间或延迟时间)
●活性成分释放的速度(快或慢)
●活性成分释放的持续时间(长或短)
●减少首过代谢
●提高病人的依从性
●缩短施用间隔
这些方面可在标准体外溶出实验中观察到，所述溶出实验例如在水里或如果需要的话在体液中，如人工胃液中进行。
几乎没有可靠的时间-控释制剂(其可在预定时间释放单一或重复剂量的活性成分)的已经被发表。商业上可接受的这类制剂是为所需的。
大量试验后，现在我们已发现可以制备能在特定时间(即具有延迟时间或延滞时间)释放药物活性成分或活性成分混合物的TTS，所述释放例如基本上不依赖存在于胃肠环境中的离子浓度和类型，例如氢离子和氢氧离子，即不依赖pH、磷酸根离子，也不依赖存在于周围体液中的酶。
根据本发明，利凡斯的明可以以游离碱或其药学上可接受的盐的形式应用。优选使用游离碱。
将要给药的TTS的准确量和活性成分剂量的准确量取决于多种因素，例如治疗的条件、治疗所希望的持续时期和活性成分释放的速率。
例如，所需的活性成分的量和其释放速率可根据已知的体外或体内技术确定，以确定在血浆中的具体活性成分浓度在可接受的疗效水平保持多长时间。
例如对于利凡斯的明而言，对于70-75kg的哺乳动物如人和在标准动物模型中每天可以使用1-12mg剂量的活性成分。
本发明的TTS可以例如为患者(其必须每天，例如在特定时间，使用多于一次剂量的活性成分)制备每天一次的药物剂型，这样简化了他们的治疗。借助这类组合物，利凡斯的明的耐受性可以得到提高，并且这也允许使用更高的起始剂量，从而减少剂量调整的步数。
由这些组合物提供的利凡斯的明的耐受性的提高可通过标准动物实验和临床实验进行观察。
具体实施方式
下面的非限制性实施例举例说明本发明：
实施例
I.TTS的制备
用以其游离碱形式存在的胆碱酯酶抑制剂利凡斯的明进行下面的示例性实验。为了这些实验，制备了以下两种TTS：
TTS #1：制备具有下列组成的单位面积重量为60g/m2的底物部分(Substrate portions)：
利凡斯的明(游离碱) 30.0％重量百分比
维生素E 0.1％重量百分比
TTS#2：制备双层形式的底物部分，所述双层中的一层对应于TTS#1。该层引入了单位面积重量为30g/m2的硅氧烷粘附层，所述硅氧烷粘附层组成如下：
Bio-
Q7-4302(硅氧烷粘附剂) 98.9％重量百分比
硅氧烷油 1.0％重量百分比
维生素E 0.1％重量百分比
游离碱形式的利凡斯的明在硅氧烷粘合剂中的饱和溶解度大约是5％重量百分比。
II.粘附力的测定
两种TTS的粘附力是用本领域技术人员公知的方法测定的，并考虑进下列细节：
-底物部分的大小：10cm2
-测试板：钢
-剥离(peeling)角度：90°
-剥离速度：300mm/min
对两种TTS而言，获得了如图1所示的粘附力。图1的柱状图清楚地表明用硅氧烷粘附层涂覆丙烯酸酯粘附基质显著增加了它的粘附力。
游离碱形式的利凡斯的明在室温下是液体。因此，当引入30％重量百分比的活性成分时，必须加入“增稠聚合物”(
B)。因此得到低粘附力的底物。当使用额外的硅氧烷粘附层时，粘附力大约是没有使用额外的硅氧烷粘附层的可比较的TTS的粘附力的五倍。
III.渗透性质
为了测定额外的硅氧烷粘附层的使用是否影响活性成分的释放，就两种TTS而言，对利凡斯的明穿透全层人皮肤和EVA膜的渗透进行了测试。该渗透测试所用条件如下：
将全层人皮肤和EVA膜分别置于改进的Franz扩散池中。扩散表面积是1.51cm2。含有0.1％叠氮化钠的磷酸盐缓冲液用做受主介质(acceptor medium)。受主介质的体积为9ml。测试温度用水浴调到32℃，对应于体内实验人皮肤的表面温度。
为了确保整个测试期间保持理想的漏槽状态(sink condition)，在8、24、32、48、56和72小时后，将整个受主介质用新鲜的受主介质替换。
利凡斯的明在受主介质中的含量可用HPLC测定。
渗透实验结果在图2和3中以绘图表示。
上述结果说明，就以游离碱形式存在的利凡斯的明通过人皮肤的透过率而言，在两种TTS之间没有观察到实质上的差异(图2)。微小的差异可能是由所用的生物材料如皮肤引起的，并可由例如微小损伤和毛囊的局部皮肤变化来解释。
为了消除由所用的生物材料引起的变化，用人工膜(EVA膜)重复该渗透实验。图3所示的结果证实了用全层人皮肤获得的发现，即就它们的渗透性质而言，两种TTS没有差异。
令人吃惊地是，额外的硅氧烷粘附层的应用对活性成分透过皮肤没有影响。
根据本发明，可以制备具有显著更高的粘附力同时保持其原始大小的TTS。
IV.药代动力学特征
在患有轻度到中度阿尔茨海默病的患者中在稳态评价25cm2、10cm2、15cm2、20cm2的TTS#2和1.5mg、3mg、4.5mg、6mg每天两次的
胶囊的标签公开、组平行、四阶段、剂量成比例增加的研究。
将诊断为患有轻度到中度阿尔茨海默病的患者随机地用TTS#2或胶囊治疗。选择患者的标准是：男性和女性(无怀小孩能力的)患者、50-85岁、符合阿尔茨海默型痴呆标准(DSM-IV)。患者应根据NINCDS-ADRDA标准诊断为很可能患有AD，MMSE得分为10-26(两者都包括在内)，并没有能影响研究结果的其它医疗条件。
根据以前临床实验的经验，14天的剂量调整步骤(titration step)用于这次研究。
在分析期间，以下数量的患者完成了所有的四个阶段的研究，可包括在药代动力学评估中：
在两种治疗后的每个剂量调整期(titration period)的最后一天研究利凡斯的明的药代动力学，除了最高剂量外，其在治疗后第三天进行研究(为了不错过血浆取样，所述和血浆取样可能由于耐受性较差的早期退出而错过)。对于利凡斯的明而言，将血浆样品用LC-MS/MS分析，定量下限(LLOQ)是0.2ng/mL。标准的无房室药代动力学参数用WinNonlin Pro由个别的血浆浓度-时间图衍化得到。
利凡斯的明的药代动力学参数总结在表1(胶囊治疗)和表2(TTS#2治疗)中。平均值(±SD)血浆浓度-时间图显示在图4中。
在TTS#2使用期间，对于所有大小的TTS，都在8h的中值t最大达到利凡斯的明稳态血药浓度。如表3所示，随着剂量的增加，暴露量也呈超比例的增加，但是其程度小于使用胶囊的程度，尤其是对AUC24h而言更是如此。
对于利凡斯的明的暴露量参数(C最大和AUC24h)而言，与口服施用(CVs为39-68％)相比，用变异系数(CVs)评价的个体间的变异性在施用贴剂(CVs为33-48％)后通常更低。
V.药理学性质
正如标准动物实验和临床研究所显示，与胶囊制剂相比，TTS#2显示了改进的药理学性质。
表2.在施用TTS #2后，利凡斯的明的药代动力学的描述性统计
na＝无法得到
表3.随剂量增加，利凡斯的明的暴露量增加的程度
Claims (25)
1.透皮治疗系统(TTS)，其包含
a)背衬层，
b)储药层，其包含作为药学活性成分的游离碱或药学上可接受的盐形式的利凡斯的明和一种或多种聚合物，
c)硅粘附层，其包含硅氧烷聚合物和增粘剂，其中所述增粘剂是硅氧烷油，
其中活性成分在施用后平均约2-16小时具有约1-30ng/ml的最大血浆浓度。
2.根据权利要求1的TTS，其在施用后平均约4-12小时提供约2.5-20ng/ml的最大血浆浓度。
3.根据权利要求1或2的TTS，其在重复每天一次给药后具有约25-450ng＊h/mL的AUC24h。
4.根据权利要求3的TTS，其在重复每天一次给药后具有约45-340ng＊h/mL的AUC24h。
5.根据权利要求1-4中任意一项的TTS，其中该TTS具有＞5N/10cm2、特别是＞10N/10cm2、特别是＜50N/10cm2、特别是＜100N/10cm2的粘附力。
6.根据权利要求5的TTS，其中储药层包含在聚合物基质形式中的药学活性成分。
7.根据权利要求1-6中任意一项的TTS，其为贴剂。
8.根据权利要求7的TTS，其中贴剂的尺寸为2-50cm2，特别是5-20cm2。
9.根据权利要求7或8的TTS，其中贴剂具有5cm2的尺寸和9mg的利凡斯的明负载剂量。
10.根据权利要求7或8的TTS，其中贴剂具有10cm2的尺寸和18mg的利凡斯的明负载剂量。
11.根据权利要求7或8的TTS，其中贴剂具有15cm2的尺寸和27mg的利凡斯的明负载剂量。
12.根据权利要求7或8的TTS，其中贴剂具有20cm2的尺寸和36mg的利凡斯的明负载剂量。
13.根据权利要求1-12中任意一项的TTS，其中背衬层为活性成分不能渗透的。
14.根据权利要求1-13中任意一项的TTS，其包含另外的可分离的保护层。
15.根据权利要求1-14中任意一项的TTS，其特征在于所述硅氧烷粘附层使活性成分从储药层透过皮肤的渗透减少不超过40％。
16.根据权利要求1-15中任意一项的TTS，其特征在于所述硅氧烷粘附层的单位面积重量是5-60g/m2。
17.根据权利要求1-16中任意一项的TTS，其特征在于所述活性成分是重酒石酸利凡斯的明。
18.根据权利要求1-16中任意一项的TTS，其特征在于所述活性成分是利凡斯的明。
19.根据前述权利要求之一的TTS，其特征在于所述储药层包含分别与树脂混合的选自聚二甲基硅氧烷、丙烯酸酯、甲基丙烯酸酯、聚异丁烯、聚丁烯和苯乙烯-异戊二烯-苯乙烯嵌段共聚物的聚合物或它们的混合物。
20.根据前述权利要求之一的TTS，其特征在于所述增粘剂选自硅氧烷油、氢化树脂酸甘油酯、氢化枞醇、树脂酯类、氢化木松香甲酯、部分氢化的木松香酯·松香酯等和它们的组合。
21.根据前述权利要求之一的TTS，其特征在于所述活性成分也包含在硅氧烷粘附层中。
22.根据任何前述权利要求的TTS，该TTS包含作为活性成分的利凡斯的明和美金刚。
23.制备根据前述权利要求中的任意一项的TTS的方法，该方法包括下列步骤：
a)制备在粘合液中的活性成分
b)将在粘合液中的活性成分涂覆
c)干燥在粘合液中的活性成分
d)制备硅氧烷粘合液
e)将硅氧烷粘合液涂覆
f)将硅氧烷粘附层压到含药物的粘附层上
g)冲切和装袋。
24.根据权利要求1-22中任意一项的TTS在制备预防、治疗阿尔茨海默病、与帕金森氏病有关的痴呆、创伤性脑损伤症状或延迟其恶化的药物中的用途。
25.根据前述权利要求中任意一项的TTS，所述TTS用于预防、治疗阿尔茨海默病、与帕金森氏病有关的痴呆、创伤性脑损伤症状或延迟其恶化。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523656A (zh) * | 2014-11-20 | 2015-04-22 | 美吉斯制药（厦门）有限公司 | 一种卡巴拉汀缓释透皮贴剂及其制备方法 |
| CN114007595A (zh) * | 2019-07-09 | 2022-02-01 | 罗曼治疗系统股份公司 | 包括包含丙烯酸类聚合物的含活性剂层和包含硅酮凝胶粘合剂的皮肤接触层的透皮治疗系统 |
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