CN101522146A - 具有高活性成分利用率和定量给药精确度的透皮治疗系统 - Google Patents
具有高活性成分利用率和定量给药精确度的透皮治疗系统 Download PDFInfo
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- CN101522146A CN101522146A CNA2007800372464A CN200780037246A CN101522146A CN 101522146 A CN101522146 A CN 101522146A CN A2007800372464 A CNA2007800372464 A CN A2007800372464A CN 200780037246 A CN200780037246 A CN 200780037246A CN 101522146 A CN101522146 A CN 101522146A
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Classifications
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Abstract
透皮治疗系统,用于以最高30mg的日剂量给予至少一种在室温下非挥发性的药物活性成分,所述透皮治疗系统包含背对皮肤的、不透过活性成分的背衬层,邻接的远离皮肤的聚合物层,其基于聚异丁烯且具有至少80g/m2涂布量,紧贴所述远离皮肤的聚合物层的粘附性皮肤接触层,其基于丙烯酸酯共聚物且具有至多50g/m2的涂布量,以及可以自所述皮肤接触层剥离的、不透过活性成分的保护层。
Description
透皮治疗系统(TTS)引入治疗中已多年。对于特别是在疼痛治疗领域中的应用的参考参见文献(B.Asmussen,TransdermaleTherapeutische System-Eigenschaften und Anwendungen;In:Likar,Rudolf:Praxis der transdermalen Schmerztherapie,第1版-Bremen 2002)。
近年来一系列活性成分被引入透皮疗法中,特别是日剂量低于30mg、甚至还低于5mg的高活性的活性成分:尼古丁、芬太尼、丁丙诺啡、硝酸甘油、雌二醇、罗替高汀,仅列数例。对全部这些物质都使用了平面系统,所述系统使用有机硅聚合物、聚异丁烯粘合材料或聚丙烯酸酯粘合材料的聚合物类中的至少一种。因为通过相应的衍生化对活性成分的需要做出应对的便利可能性,还因为通常不需其它添加剂便足以粘附在皮肤上,特别优选使用丙烯酸酯聚合物用于透皮治疗系统。对此的实例特别是新近引入的Durogesic ,以及大量普通芬太尼-TTS,其由Ratiopharm公司和Hexal公司在德国于2005年和2006年上市。然而也优选用丙烯酸共聚物的聚合原理使其它活性成分可用于人的皮肤上。例如具有尼古丁()、丁丙诺啡,Grünenthal)和雌二醇(Estraderm ,Novartis)的透皮治疗系统成功上市。
这种透皮治疗系统的系统构造包含一个或多个层,其中特别是在早些年尤其考虑通过系统自身来控制给药方面。因此,较早期的典型构造在粘附层、膜层和储库层间设置有分隔层(Trennung),其中活性成分的主要份额包含在储库层中。
所有这些系统共同的是,常常只能透皮给予可利用的活性成分的很小部分,因此所谓的系统利用率也相对低。这在包含昂贵活性成分特别是新的合成活性成分如罗替高汀、芬太尼、丁丙诺啡或舒芬太尼的透皮治疗系统的情况下尤其重要。
达到高活性成分利用率的需求,与粘附力和可制备性所需的粘附层和储库层的大层厚(涂布量)相矛盾,还与大多数粘合剂材料在达到透皮使用必需的高热力学活性(接近饱和溶解度)前就溶解高份额活性成分的特性相矛盾。
对大层厚和活性成分在聚合物中的高饱和溶解度的共同需求导致大多数透皮治疗系统中遗憾地不希望的高活性成分用量。对于具有受限制的活性成分利用的透皮系统领域中的现有技术以举例方式例如提及US 5,240,711,其中描述了添加了其它成分的具有0.1-20%丁丙诺啡-碱的聚丙烯酸酯基质。US 6,090,405描述了丁丙诺啡的透皮治疗系统,其包含丙烯酸酯共聚物和在其中包含的交联的丙烯酸聚合物颗粒。WO 03/018075描述了具有作为活性成分的芬太尼或相关物质的透皮治疗系统,其包含基于聚丙烯酸酯的基质层。出于更高活性成分利用率的原因在此选择不含丙烯酸基团的共聚物,因为否则芬太尼和类似活性成分的通过离子对效应促进的溶解度将被羧基基团过度提高。
WO 03/097020描述了双层系统,其中皮肤侧的层相对远离皮肤的层具有较小的活性成分亲合性并同时具有较大的层厚。
根据该公开的技术教导的目的是在较长时期内达到恒定的释放速率。由此只能继续容忍因在溶解更佳的远离皮肤的层中残留的活性成分引起的低利用率。
EP 1 137 406 B1描述了用于挥发性活性成分,特别是尼古丁的透皮施用的贴片。所述贴片是两层的,其中远离皮肤的层由含活性成分的有机硅粘合材料构成,皮肤接触层由丙烯酸粘合剂构成,且这两个层具有大致相同的厚度。在此指出,在层合并达到平衡后,所述丙烯酸粘合剂层同样包含一部分活性成分即大约2.5到3.0重量%。
除了前述的经济因素,审批机构对透皮治疗系统的定量给药精确度日益严格的要求也发挥了重要的作用。因此通过经济可行的计量添加方法可以达到约+/-5g/m2标准偏差的涂层-精确度。现有技术中常规的单位面积重量是约50-100g/m2,由此涂层-精确度的偏差和之后经切割的(gestanzten)TTS的活性成分含量的偏差在5到10%的范围内。这种精确度完全满足迄今为止的药品审批程序。然而,按照2005年修订的欧洲药典中的专题论述,如果所达到层重的中位数偏离所要求的值达10%,则要求小于3%标准偏差的精确度。该要求因此使得经济上不再可能用例如按照WO 03/018075教导的约50g/m2的层厚来涂覆具有5%活性成分含量的整块聚丙烯酸酯系统,因为考虑到定量给药精确度可以预见所描述的系统无法获得官方的药用许可。
另一方面,本领域人员优选良好溶解和良好粘附的聚合物用于皮肤粘附,以改善这种系统的可接受性和生物利用度。近年来聚丙烯酸酯作为皮肤粘附性聚合物表明是理想的,然而作为缺点其具有对通常适于透皮疗法的药物活性成分的高溶解能力。
因此,本发明的目的是提供透皮治疗系统,其具有丙烯酸酯共聚物皮肤接触层,相比现有技术改善的活性成分利用率和相比现有技术提高的定量给药精确度。
根据本发明通过提供透皮治疗系统(TTS)实现上述目的,所述透皮治疗系统包含基本上不透过活性成分的背衬层,基于聚异丁烯的远离皮肤的层,基于丙烯酸酯共聚物的粘附性皮肤接触层,其相比所述远离皮肤的层更薄并且在制备所述TTS后包含绝大部分活性成分,以及可剥离且基本上不透过活性成分的保护层。所述远离皮肤的层按照本发明具有至少80g/m2,优选100-200g/m2的涂布量;所述皮肤接触层按照本发明具有至多50g/m2,优选20-30g/m2的涂布量。
在一个优选实施方式中,远离皮肤的层的涂布量与皮肤接触层的涂布量的比例为至少2:1,特别优选3:1到5:1。尽管作为远离皮肤的层的基质结合的聚异丁烯相比根据现有技术使用的聚硅氧烷具有更低的扩散性,但是令人惊讶的显示,本发明的透皮治疗系统在活性成分利用率和定量给药精确度方面优于现有技术中已知的系统。
前文所描述的TTS可以如下制备:
将活性成分或活性成分混合物在适宜的挥发性溶剂或这样的溶剂的混合物中溶解,将所得溶液与旨在用于远离皮肤的层的基于聚异丁烯的聚合物材料混合,将所得混合物以至少200μm(相当于200g/m2)的层厚均匀地施涂于适宜的底材上,例如经硅化的塑料层上。干燥并蒸发溶剂部分后,将含活性成分的聚合物层用另一层膜覆盖,所述另一层膜是之后的本发明的TTS的背衬层。在除去用作底材的塑料膜后,在所产生的叠层上以这样的方式层合不含活性成分的、基于丙烯酸酯共聚物的粘附性皮肤接触层以及可剥离的保护膜:含活性成分的远离皮肤的层和粘附性的皮肤接触层相互重叠。立即开始的扩散平衡后,大部分活性成分从远离皮肤的层迁移至皮肤接触层。
前文所描述的发明使得可能通过将活性成分引入由聚异丁烯构成的聚合物材料从而非常精确和有效地定量给予活性成分,所述聚合物材料一方面以相对更大的层厚施涂而另一方面对本发明所使用的活性成分具有非常低的溶解能力,以及由于相对高的层厚在用活性成分-/聚合物混合物来涂覆膜时具有非常高的精确度。由如下事实还产生其它优点,基于丙烯酸酯共聚物的粘附性皮肤接触层不是必须用活性成分涂覆,从而所述层的厚度减少至现有技术中常规的并且是精确定量给药所必需的大于50g/m2的涂布量以下,优选甚至限制为20-30g/m2的典型涂布量。
用作基本不透过活性成分的背衬层的是任选地用聚异丁烯、聚丙烯酸酯或聚硅氧烷涂层的聚对苯二甲酸乙二酯膜。
与皮肤接触的基质层(皮肤接触层)由丙烯酸酯共聚物构成。这是指由单体的丙烯酸、甲基丙烯酸和/或适宜的衍生物和可选地单体的乙烯化合物形成的共聚物。示例性地提及以下单体:丙烯酸,甲基丙烯酸、丙烯酸酯和甲基丙烯酸酯,例如特别是丙烯酸正丁酯、甲基丙烯酸正丁酯、丙烯酸乙酯、丙烯酸2-乙基己酯、甲基丙烯酸乙酯、丙烯酸甲酯、甲基丙烯酸甲酯、丙烯酸叔丁酯、丙烯酸仲丁酯、甲基丙烯酸叔丁酯、甲基丙烯酸环己酯、甲基丙烯酸2-乙基己酯、甲基丙烯酸异冰片酯、甲基丙烯酸异丁酯、丙烯酸异丙酯、甲基丙烯酸异丙酯以及这些单体的混合物。这些单体涉及丙烯酸或甲基丙烯酸的酯,所述酸具有直链、支化或环状脂族C1-C12-取代基。这些取代基可以就其而言被如羟基基团取代。作为酯示例性地提及甲基丙烯酸2-羟基乙酯、丙烯酸3-羟基丙酯和甲基丙烯酸3-羟基丙酯。作为适宜的乙烯化合物提及乙酸乙烯酯。
适用于本发明目的的活性成分特别是具有高活性的那些。本领域技术人员通常将其理解为这样的活性成分,其日剂量为毫克范围如1-500mg。然而根据本发明优选日剂量最高为30mg的活性成分。
用于本发明TTS中的适宜活性成分例如是止痛剂、支气管扩张药、抗糖尿病药、血管舒张药、戒瘾药和帕金森药。
然而本发明的TTS特别适用于疼痛治疗,优选用选自阿片样物质类别的活性成分。属于该药物活性成分类别的尤其是吗啡、海洛因和其它吗啡衍生物;双氢吗啡衍生物如氢吗啡酮(双氢可待因)、羟考酮;吗啡衍生物如左啡诺、丁丙诺啡;哌替啶类别的止痛剂如哌替啶、凯托米酮、洛哌丁胺、地芬诺酯;美沙酮和衍生物如左美沙酮、右吗拉胺、右丙氧芬;芬太尼及其衍生物(例如阿芬太尼、舒芬太尼、瑞芬太尼),苯并吗啡烷衍生物如喷他佐辛和苯基氨基环己炔基衍生物如替利定、曲马多。为治疗突破性疼痛(Durchbruchschmerzen)特别优选快速、短期有效的阿片类物质如吗啡、曲马多、替利定、羟考酮、氢吗啡酮、丁丙诺啡、芬太尼和左美沙酮。
此外,选自止痛剂类别的考虑如下成分:安乃近,安替比林,异丙安替比林,氟吡汀,奈福泮,选自抗癫痫类别的卡马西平,加巴喷丁,氯硝西泮,还有抗抑郁药如阿米替林。
本发明还涉及由两种或更多种药物组成的活性成分组合的用途,特别是前文提及的止痛剂的组合的用途。
聚合物层,优选本发明TTS的皮肤接触层,此外还可以包含不同的助剂和添加剂,例如选自增溶剂、溶剂、增塑剂、增粘剂、渗透促进剂、pH-调节剂、抗氧化剂和防腐剂类别的那些。
本发明借助实施例解释如下:
实施例1:
将丙烯酸-丙烯酸2-乙基己酯-乙酸乙烯酯共聚物的30%(g/g)乙酸乙酯溶液以约65-70μm的层厚涂覆于经硅化的聚对苯二甲酸乙二酯膜(100μm厚)上,在25℃下晾置干燥2小时,形成20g/m2的粘附层。在另一个操作中,将2g芬太尼-碱、70g聚异丁烯-100、28g聚异丁烯-10、100g甲基-乙基酮和200g正庚烷制成粘性溶液,并再搅拌2小时。将该相以约500μm的层厚涂覆于15μm厚的聚对苯二甲酸乙二酯膜上,从而制得100g/m2的含活性成分的干燥粘附层。将该层以粘附侧与先前制得的丙烯酸酯共聚物层(粘附层紧挨粘附层)这样地层合,使之产生邻接的、两层的基质。剥去保护膜后产生能粘附的系统,其可以用聚丙烯酸酯侧粘附于皮肤上。所述系统可以通过适宜的切割设备来切割为所需的尺寸。
实施例2:
将丙烯酸2-乙基己酯-乙酸乙烯酯-丙烯酸2-羟基乙酯-甲基丙烯酸2,3-环氧丙酯共聚物的30%(g/g)乙酸乙酯溶液以约65-70μm的层厚涂覆于经硅化的聚对苯二甲酸乙二酯膜(100μm厚)上,在25℃下晾置干燥2小时,从而形成20g/m2的粘附层。在另一个操作中,将1.5g芬太尼-碱、70g聚异丁烯-100、28g聚异丁烯-10、100g甲基-乙基酮和200g正庚烷制成粘性溶液,并再搅拌2小时。将该相以约500μm的层厚涂覆于15μm厚的聚对苯二甲酸乙二酯膜上,从而形成100g/m2的含活性成分的干燥粘附层。
将该层以粘附侧与先前制得的丙烯酸酯共聚物层(粘附层对粘附层)这样来层合,使之产生邻接的、两层的基质。剥去保护膜后产生能粘附的系统,其可以用聚丙烯酸酯侧粘附于皮肤上。所述系统可以通过适宜的切割设备来切割为所需的尺寸。
Claims (20)
1.透皮治疗系统,用于以最高30mg的日剂量给予至少一种在室温下非挥发性的药物活性成分,所述透皮治疗系统包含背对皮肤的、不透过活性成分的背衬层,邻接的远离皮肤的基于聚异丁烯的聚合物层,紧贴所述远离皮肤的聚合物层的基于丙烯酸酯共聚物的粘附性皮肤接触层,以及可以从所述皮肤接触层剥离的、不透过活性成分的保护层,其特征在于,所述远离皮肤的层具有至少80g/m2的涂布量并且所述皮肤接触层具有至多50g/m2的涂布量。
2.权利要求1的透皮治疗系统,其特征在于,所述远离皮肤的层具有100-200g/m2的涂布量。
3.权利要求1的透皮治疗系统,其特征在于,所述皮肤接触层具有20-30g/m2的涂布量。
4.权利要求1到3的透皮治疗系统,其特征在于,所述远离皮肤的层的涂布量与所述皮肤接触层的涂布量的比例至少为2∶1。
5.权利要求4的透皮治疗系统,其特征在于,所述比例为3∶1到5:1。
6.前述权利要求中至少一项的透皮治疗系统,其特征在于,在制备所述系统并达到扩散平衡后,所述活性成分大部分从所述远离皮肤的层迁移至所述皮肤接触层。
7.权利要求1的透皮治疗系统,其特征在于,所述皮肤接触层的聚合物基质由选自丙烯酸、甲基丙烯酸、丙烯酸酯、甲基丙烯酸酯和乙烯化合物的组的单体的共聚物组成。
8.权利要求5的透皮治疗系统,其特征在于,所述乙烯化合物是乙酸乙烯酯。
9.前述权利要求中至少一项的透皮治疗系统,其特征在于,所述活性成分选自止痛剂、支气管扩张药、抗糖尿病药、血管舒张药、戒瘾药和帕金森药的组。
10.权利要求9的透皮治疗系统,其特征在于,所述活性成分是止痛剂。
11.权利要求10的透皮治疗系统,其特征在于,所述活性成分中至少一种是阿片样物质。
12.权利要求11的透皮治疗系统,其特征在于,所述阿片样物质是芬太尼和/或其衍生物之一。
13.权利要求12的透皮治疗系统,其特征在于,所述芬太尼衍生物是阿芬太尼、舒芬太尼或瑞芬太尼。
14.制备权利要求1的透皮治疗系统的方法,其特征在于,将溶于适宜的挥发性溶剂或溶剂混合物中的活性成分与旨在用于远离皮肤的层的基于聚异丁烯的聚合物材料混合,将所得混合物以至少200μm的层厚均匀地涂覆于经硅化的塑料膜上,干燥并蒸发溶剂后,将所获叠层用所述背衬层覆盖,并在除去经硅化的塑料膜后,在所述远离皮肤的层上以这样的方式层合所述粘附性皮肤接触层以及所述可剥离的保护层,即将含活性成分的远离皮肤的层与粘附性的皮肤接触层相互重叠。
15.权利要求14的方法,其特征在于,这样地将远离皮肤的层和皮肤接触层重叠层合,使得活性成分能够从前者迁移至后者中。
16.权利要求14和15的方法,其特征在于,所述远离皮肤的层具有100-200g/m2的涂布量并且所述皮肤接触层具有20-30g/m2的涂布量。
17.权利要求16的方法,其特征在于,所述远离皮肤的层的涂布量与所述皮肤接触层的涂布量的比例为至少2:1。
18.权利要求17的方法,其特征在于,所述比例为3:1到5:1。
19.权利要求14-17的方法,其特征在于,所述活性成分是芬太尼或芬太尼衍生物。
20.权利要求19的方法,其特征在于,所述芬太尼衍生物是阿芬太尼、舒芬太尼或瑞芬太尼。
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CN111372575A (zh) * | 2017-11-21 | 2020-07-03 | Lts勒曼治疗系统股份公司 | 基于粘合性增塑剂聚合物基质的tts |
CN111372575B (zh) * | 2017-11-21 | 2023-12-01 | Lts勒曼治疗系统股份公司 | 基于粘合性增塑剂聚合物基质的tts |
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US9056026B2 (en) | 2015-06-16 |
CN101522146B (zh) | 2013-06-19 |
BRPI0719006B8 (pt) | 2021-05-25 |
JP5881935B2 (ja) | 2016-03-09 |
DE102006054733A1 (de) | 2008-05-29 |
JP2016033148A (ja) | 2016-03-10 |
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US20160324799A1 (en) | 2016-11-10 |
ZA200902579B (en) | 2009-12-30 |
KR101471216B1 (ko) | 2014-12-09 |
JP2010510260A (ja) | 2010-04-02 |
CA2662510A1 (en) | 2008-05-29 |
AU2007323401B2 (en) | 2013-02-07 |
WO2008061639A1 (de) | 2008-05-29 |
RU2009123370A (ru) | 2010-12-27 |
EP2094213B1 (de) | 2015-09-02 |
KR20090082411A (ko) | 2009-07-30 |
AU2007323401C1 (en) | 2013-07-25 |
EP2094213A1 (de) | 2009-09-02 |
MX2009005343A (es) | 2009-06-01 |
IL198714A0 (en) | 2010-02-17 |
BRPI0719006A2 (pt) | 2013-12-17 |
AU2007323401A1 (en) | 2008-05-29 |
US20150238437A1 (en) | 2015-08-27 |
BRPI0719006B1 (pt) | 2020-12-01 |
ES2549692T3 (es) | 2015-10-30 |
US20110020407A1 (en) | 2011-01-27 |
NZ575043A (en) | 2012-01-12 |
JP6109280B2 (ja) | 2017-04-05 |
RU2454994C2 (ru) | 2012-07-10 |
CA2662510C (en) | 2014-07-29 |
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