CN107595818A - 具有可调节封闭性的贴剂 - Google Patents

具有可调节封闭性的贴剂 Download PDF

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CN107595818A
CN107595818A CN201710819641.3A CN201710819641A CN107595818A CN 107595818 A CN107595818 A CN 107595818A CN 201710819641 A CN201710819641 A CN 201710819641A CN 107595818 A CN107595818 A CN 107595818A
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percutaneous
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polymer
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W·穆勒
P·摩尔
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LTS Lohmann Therapie Systeme AG
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Abstract

本发明涉及经皮或外用的含有效成分的贴剂，所述贴剂具有非封闭背衬层，由一个或多个聚合物层形成并且在一个或多个层中具有至少一种药学有效成分的基质，其中一个或多个层的形成结构的基础聚合物不封闭或者仅少量封闭，并且在至少一个聚合物层中分散有第二聚合物，所述第二聚合物不与基础聚合物混溶或者仅与基础聚合物极少量混溶并且具有低水蒸汽渗透性。

Description

具有可调节封闭性的贴剂
本申请是原始中国专利申请号201280046758.8，申请日2012年9月25日，发明名称“具有可调节封闭性的贴剂”的分案申请。
在有效成分的经皮或外用给药中，角质层是限制有效成分吸收的亲脂性屏障。一种最有效的并且事实上在任何作用于全身的经皮系统中所使用的用于降低角质层的屏障功能的物理方法是封闭。通过使用几乎无水蒸汽渗透性的材料用于经皮系统的背衬层和/或使用相邻层或一个或多个含有效成分的层的无水蒸汽渗透性的配制剂从而实现封闭。这种贴剂的示意图示于图1。对于背衬层在大多数情况下使用聚酯薄膜。然而原则上不排除其他具有低水蒸汽渗透性的薄膜，例如聚乙烯或聚丙烯的薄膜。作为具有低水蒸汽渗透性的聚合物或压敏粘合剂，例如使用聚异丁烯或苯乙烯和丁二烯或苯乙烯和异戊二烯的嵌段聚合物。
特别地，具有例如非类固醇抗炎药的外用系统具有对应于待治疗区域的面积的尺寸，并且因此具有要求贴剂系统的一定的伸展性从而提高佩戴舒适性的尺寸。由于上述用于背衬层的封闭材料在对于该目合适的厚度下不具有足够的伸展性或弹性，对于这种贴剂通常使用纺织材料。然而这种纺织背衬层的缺点在于，其由于其开孔性而具有极高的水蒸汽渗透性并且因此无法实现封闭条件。因此，在具有纺织背衬层的贴剂的情况下，必须通过其他无水蒸汽渗透性或者至少低水蒸汽渗透性的另外的层实现封闭。当然，为此不能使用不可伸展和无弹性的材料。最简单的是，通过使用低水蒸汽渗透性的压敏粘合剂，例如基于聚异丁烯或苯乙烯和丁二烯或异戊二烯的嵌段聚合物的压敏粘合剂，从而实现封闭。然而其缺点在于，这种压敏粘合剂在由于封闭而湿润的皮肤上的粘合性极差，并且特别在关节区域中容易部分或完全脱落。
WO 01/91718 A2中描述了两相基质，其中含有效成分的聚丙烯酸酯相分散在基于聚异丁烯或苯乙烯-丁二烯-苯乙烯-嵌段聚合物的外部自粘合配制剂中。其缺点在于，封闭效果在实际层厚度下总是最大，并且如上所述的外部相在湿润皮肤上的粘合性极差。这种基质的唯一的优点在于，有效成分存在于具有更高饱和溶解度的聚合物中。
聚丙烯酸酯粘合剂或有机硅粘合剂在这种情况下表现明显更好，但是由于其高水蒸汽渗透性可能自身无法实现封闭条件。因此，根据现有技术，聚丙烯酸酯粘合剂或有机硅粘合剂的使用使得具有不同组成的层的多层基质成为必须，因此制备方法复杂并且升高了对于这种产品系列来说重要的制备成本。
因此需要这样的封闭贴剂，所述封闭贴剂具有可伸展的纺织背衬层和在湿润皮肤上良好粘附的基于聚丙烯酸酯或有机硅粘合剂的压敏粘合剂，具有尽可能简单的构造并且可以简单制备。
根据本发明出人意料地发现，所述问题的解决方案在于，将低水蒸汽渗透性的聚合物，例如聚异丁烯或苯乙烯和丁二烯或异戊二烯的嵌段聚合物，分散在一个或多个由水蒸汽渗透性压敏粘合剂构成的基质层中。由于其物理化学性质，有效成分最大量地包含在这种基质的聚丙烯酸酯相中。通过无水蒸汽渗透性的聚合物的量和基质的厚度使得封闭效果可以在大范围内变化。因此，在最简单的情况下，根据本发明的贴剂由纺织背衬层、含有效成分的基于聚丙烯酸酯粘合剂或有机硅粘合剂并且其中分散有水蒸汽渗透性聚合物的基质层，和在使用之前待除去的保护层组成。这种贴剂的构造示于图2。
本发明因此涉及经皮或外用的含有效成分的贴剂，所述贴剂具有非封闭背衬层，由一个或多个聚合物层形成并且在一个或多个层中具有至少一种药学有效成分的基质，其特征在于，一个或多个层的形成结构的基础聚合物不封闭或者仅少量封闭，并且在至少一个聚合物层中分散有第二聚合物，所述第二聚合物不与基础聚合物混溶或者仅与基础聚合物极少量混溶并且具有低水蒸汽渗透性。
背衬层优选由纺织材料组成，特别是织物或非织物或其复合物。作为材料在此可以考虑例如棉、粘胶、聚酯、聚酰胺、聚氨酯或聚丙烯。聚氨酯也适合作为水蒸汽渗透性薄膜材料。
在使用时与皮肤接触的基质层的形成结构的基础聚合物优选为压敏粘合剂。合适的压敏聚合物为例如聚丙烯酸酯粘合剂或有机硅粘合剂。基质优选以单层构造。
具有低水蒸汽渗透性的聚合物可以例如为聚异丁烯、苯乙烯-异戊二烯-苯乙烯-嵌段聚合物或苯乙烯-丁二烯-苯乙烯-嵌段聚合物。聚合物的分散相优选具有5至50μm，特别是7至40μm，非常特别优选10至30μm的平均粒径。基质中分散的颗粒的含量通常在5和50重量％，优选7和40重量％，特别是10和30重量％之间。
基质的单位面积重量通常在50和400g/m2之间，优选在60和300g/m2之间，特别是在70和200g/m2之间。
药学有效成分可以为非类固醇抗炎药(非类固醇抗炎药的德文缩写为NSAR，非类固醇抗炎药的英文缩写为NSAID)。非类固醇抗炎药通常在关节，特别是四肢关节的区域中局部外用。恰恰在这些经受强烈机械应力的使用位置上，根据本发明的TTS被证明是特别有利的。非穷尽地，非类固醇抗炎药为双氯芬酸或其药学可接受的盐、酪洛芬、布洛芬、氟比洛芬、萘普生、噻洛芬酸、吲哚美辛、吡罗昔康、替诺昔康、美洛昔康、氟芬那酸或甲芬那酸。优选的双氯芬酸盐为例如双氯芬酸-钠盐、双氯芬酸-钾盐、双氯芬酸-二乙基铵盐或双氯芬酸的二羟乙基-吡咯烷盐。
作为有效成分还可以考虑外用有效的止痛剂，例如利多卡因或丁卡因。
除了已经描述的聚合物和有效成分之外，还可以使用大量其它助剂，如本领域已知用于TTS的助剂。
因此可以优选在基质的内部相中使用例如渗透强化剂。作为渗透强化剂，可以考虑选自如下的化合物：低分子量一元或多元醇、脂肪酸(优选油酸)、脂肪醇、脂肪醇醚、聚氧乙基化的脂肪醇、脂肪酸酯(特别是单甘油酯和与丙二醇的单酯)、失水山梨醇脂肪酸酯和聚氧乙基化的失水山梨醇脂肪酸酯以及二甲基异山梨醇。
还可以考虑能够通过降低界面能积极影响两相基质层的稳定性的界面活性表面活性剂。
无水蒸汽渗透性的聚合物嵌入基质。因此其实际上不与皮肤接触并且因此不损害压敏粘合剂在皮肤上的粘附能力。
水蒸汽渗透性的降低基于水分子的有效扩散路径的延长。这也意味着，效果的大小取决于分散的聚合物的量并且当然取决于基质层的总厚度。
对聚丙烯酸酯粘合剂和低分子量聚异丁烯进行实验研究所述关系。为此，制备不同厚度和不同聚异丁烯含量的粘合剂膜并且根据DIN-方法EN 13726-2以20cm2的样品尺寸在37℃和18％的相对湿度下测量水蒸汽渗透性。样品组成和所测得的水蒸汽渗透性示于表1并且水蒸汽渗透性还示于图3。水蒸汽渗透性通常在50和600g/(m2x24h)之间，优选在100和500g/(m2x 24h)之间，特别是在150和400g/(m2x 24h)之间。
表1：样品组成和水蒸汽渗透性
1)387-2353，Henkel 2)B 10，BASF
可见，10重量％的聚异丁烯实际上还没有效果，20重量％已经具有明显的效果，40重量％时渗透性几乎减半。正如预期的，渗透性也取决于层的厚度，即渗透性由于厚度加倍而减半。
还研究聚异丁烯含量对贴剂系统的渗透速度的影响。为此选择双氯芬酸-钠盐作为有效成分，并且将其引入具有纺织背衬层的单层基质系统。假设亲水性有效成分的盐仅以可忽略的量溶于聚异丁烯，有效成分的量这样选择，使得尽管外部聚丙烯酸酯相中的聚异丁烯含量不同，有效成分的浓度在所有样品中保持相同。因此排除了如下情况：渗透速度的不同不仅基于不同强度的封闭，而且基于不同的热力学活性。
通过使用本领域技术人员公知的Franz-扩散池和人类表皮进行渗透研究。表中的数值为4次独立实验的平均值。
样品的组成和相应的渗透速度列于表2和3并且渗透速度还示于图4。
表2：用于渗透研究的样品的组成
1)为样品3层厚度的双倍
表3：使用人类表皮的渗透速度
1)为样品3的层厚度的双倍
渗透研究的结果清楚显示了，渗透速度取决于聚异丁烯的含量和因此而升高的封闭。其他的解释不考虑，因为含有效成分的相的组成在所有样品中相同并且聚异丁烯的加入甚至降低了该相在基质中的相对含量。然而，聚异丁烯的最佳含量为30重量％，因为40重量％显示出与20重量％大致相同的结果。在更高的含量下，含有效成分的相的变小的含量和有效成分的变长的有效扩散路径起不利作用。
如图5中所示，由于内部相与外部相分离并且分子水平上没有混合，具有低水蒸汽渗透性的内部相的加入不会影响由聚丙烯酸酯或有机硅组成的外部相中的有效成分的饱和溶解度。这意味着，在这种系统中，有效成分的递送不受含有效成分的相中的饱和溶解度的变化的影响，如例如在示例性提及US专利6,235,306中那样。在表2中所示和在渗透研究表3中所使用的配制剂中，丙烯酸酯粘合剂和有效成分的比例保持相同，即所测得的渗透速度的不同仅可通过随着聚异丁烯的量而升高的封闭来解释。
如下制备实施例用于说明本发明，而不限制本发明。
实施例1
根据配制剂1、2、3、4和5制备具有双氯芬酸-钠盐的贴剂
通过搅拌将90g聚异丁烯(B 10，BASF)溶于110g正庚烷。得到200g固体含量为45％g/g的聚异丁烯溶液。
伴随搅拌将20g双氯芬酸-钠盐溶于774g387-2353(固体含量36％)、150g乙酸乙烯酯和33g油酸。得到929g固体含量为34％g/g的含有效成分的聚丙烯酸酯溶液。通过将表4中给出的量的聚异丁烯溶液加入100g含有效成分的聚丙烯酸酯溶液中从而制得涂覆物料。
表4：配制剂1至5的组成
通过以400U/min迅速机械搅拌10分钟从而制得分散体。通过将所述分散体涂覆在100μm厚的硅化聚酯薄膜上然后在50℃下干燥25分钟除去溶剂从而制得基质。仍含溶剂的涂覆膜的厚度这样选择，使得干燥基质膜具有110g/m2的单位面积重量。通过使已经干燥的配制剂3的基质膜与自身层合一次从而获得配制剂4的基质。
使干燥的膜与无弹性聚酯织物层合从而获得整个层合物。
由整个层合物中冲裁用于渗透研究的成品贴剂或样品。
实施例2
含利多卡因的贴剂的制备
在搅拌下将50g利多卡因溶于1164g聚丙烯酸酯溶液(387-2052，Henkel，固体含量47％g/g)、74g乙醇、110g乙酸乙烯酯、6g薄荷醇、100g油酸。在溶液中分散631g聚异丁烯溶液(在正庚烷中48％g/g)。将物料以一定厚度涂覆在硅化聚酯薄膜上，使得在除去溶剂(室温下10分钟，50℃下25分钟)之后得到135g/m2的单位面积重量。使干燥的膜与无弹性聚酯织物层合从而获得整个层合物。
附图和附图标记的简要说明
图1：具有无水蒸汽渗透性背衬层的封闭贴剂
1无水蒸汽渗透性背衬层
2含有效成分的基质
3可揭式保护薄膜
图2：根据本发明的具有可调节封闭性的贴剂
4纺织材料背衬层
5形成结构的基础聚合物
6具有低水蒸汽渗透性的聚合物颗粒
7可揭式保护薄膜
图3：水蒸汽渗透性与聚异丁烯的含量和基质层的厚度的关系
图4：聚异丁烯的含量和双氯芬酸-钠盐的累积渗透量
图5：分散在聚丙烯酸酯粘合剂相中的聚异丁烯颗粒(比例：500:1)。

Claims (20)

1.经皮或外用的含有效成分的贴剂，所述贴剂具有由纺织材料组成的非封闭背衬层，由一个或多个聚合物层形成并且在一个或多个所述层中具有至少一种药学有效成分的基质，其特征在于，在使用时与皮肤接触的基质层的一个或多个层的形成结构的基础聚合物不封闭或者仅少量封闭并为压敏粘合剂，其中所述压敏粘合剂为聚丙烯酸酯粘合剂或有机硅粘合剂，并且在至少一个聚合物层中分散有第二聚合物，所述第二聚合物不与基础聚合物混溶或者仅与基础聚合物极少量混溶并且具有低水蒸汽渗透性，所述第二聚合物为聚异丁烯、苯乙烯-异戊二烯-苯乙烯-嵌段聚合物或苯乙烯-丁二烯-苯乙烯-嵌段聚合物，其中第二聚合物的分散的颗粒的含量在7和40重量％之间，第二聚合物嵌入基质中，基质的单位面积重量在50和400g/m2之间且药学有效成分为非类固醇抗炎药。
2.根据权利要求1所述的经皮或外用的贴剂，其特征在于，基质为单层的。
3.根据权利要求1所述的经皮或外用的贴剂，其特征在于，分散在基础聚合物中的具有低水蒸汽渗透性的聚合物相具有5至50μm的平均粒径。
4.根据权利要求3所述的经皮或外用的贴剂，其特征在于，分散在基础聚合物中的具有低水蒸汽渗透性的聚合物相具有7至40μm的平均粒径。
5.根据权利要求3所述的经皮或外用的贴剂，其特征在于，分散在基础聚合物中的具有低水蒸汽渗透性的聚合物相具有10至30μm的平均粒径。
6.根据权利要求1或3所述的经皮或外用的贴剂，其特征在于，具有低水蒸汽渗透性的聚合物的分散的颗粒的含量在10和30重量％之间。
7.根据权利要求1至3任一项所述的经皮或外用的贴剂，其特征在于，基质的单位面积重量在60和300g/m2之间。
8.根据权利要求1至3任一项所述的经皮或外用的贴剂，其特征在于，基质的单位面积重量在70和200g/m2之间。
9.根据权利要求1至3任一项所述的经皮或外用的贴剂，其特征在于，根据DIN-方法EN13726-2以20cm2的样品尺寸在37℃和18％的相对湿度下测得的其水蒸汽渗透性在50和600g/(m2x24h)之间。
10.根据权利要求9所述的经皮或外用的贴剂，其特征在于，根据DIN-方法EN 13726-2以20cm2的样品尺寸在37℃和18％的相对湿度下测得的其水蒸汽渗透性在100和500g/(m2x24h)之间。
11.根据权利要求9所述的经皮或外用的贴剂，其特征在于，根据DIN-方法EN 13726-2以20cm2的样品尺寸在37℃和18％的相对湿度下测得的其水蒸汽渗透性在150和400g/(m2x24h)之间。
12.根据权利要求1至3任一项所述的经皮或外用的贴剂，其特征在于，药学有效成分为双氯芬酸或其药学可接受的盐、酮洛芬、布洛芬、氟比洛芬、萘普生、噻洛芬酸、吲哚美辛、吡罗昔康、替诺昔康、美洛昔康、氟芬那酸或甲芬那酸。
13.根据权利要求12所述的经皮或外用的贴剂，其特征在于，药学有效成分为双氯芬酸盐。
14.根据权利要求13所述的经皮或外用的贴剂，其特征在于，药学有效成分为双氯芬酸-钠盐、双氯芬酸-钾盐、双氯芬酸-二乙基铵盐或双氯芬酸的二羟乙基-吡咯烷盐。
15.根据权利要求1至3任一项所述的经皮或外用的贴剂，其特征在于，药学有效成分为外用有效的止痛剂。
16.根据权利要求15所述的经皮或外用的贴剂，其特征在于，外用有效的止痛剂为利多卡因或丁卡因。
17.根据权利要求1至3任一项所述的经皮或外用的贴剂，其特征在于，基质包含至少一种渗透强化剂。
18.根据权利要求17所述的经皮或外用的贴剂，其特征在于，在形成结构的基础聚合物中，基质包含至少一种渗透强化剂。
19.根据权利要求17所述的经皮或外用的贴剂，其特征在于，一种或多种渗透强化剂为低分子量一元或多元醇、脂肪酸、脂肪醇、脂肪醇醚、聚氧乙基化的脂肪醇、脂肪酸酯、失水山梨醇脂肪酸酯、聚氧乙基化的失水山梨醇脂肪酸酯和/或二甲基异山梨醇。
20.根据权利要求19所述的经皮或外用的贴剂，其特征在于，所述脂肪酸为油酸。
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US20140234395A1 (en) 2014-08-21
KR20140072128A (ko) 2014-06-12
IN2014CN02984A (zh) 2015-07-03
EP2760436B1 (de) 2019-09-18
CA2849956A1 (en) 2013-04-04
AU2012314560C1 (en) 2016-10-06
WO2013045420A1 (de) 2013-04-04
RU2616524C2 (ru) 2017-04-17
DE102011114411A1 (de) 2013-03-28
AU2012314560A1 (en) 2014-05-15
JP6033309B2 (ja) 2016-11-30
US9180103B2 (en) 2015-11-10
ES2755728T3 (es) 2020-04-23
RU2014116821A (ru) 2015-11-10
AU2012314560B2 (en) 2016-02-18
KR101945573B1 (ko) 2019-02-07
CA2849956C (en) 2019-09-03
EP2760436A1 (de) 2014-08-06
JP2014526546A (ja) 2014-10-06

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