CN1349794A - 经皮吸收制剂 - Google Patents
经皮吸收制剂 Download PDFInfo
- Publication number
- CN1349794A CN1349794A CN01131289.0A CN01131289A CN1349794A CN 1349794 A CN1349794 A CN 1349794A CN 01131289 A CN01131289 A CN 01131289A CN 1349794 A CN1349794 A CN 1349794A
- Authority
- CN
- China
- Prior art keywords
- adhesive phase
- transdermal formulation
- binding agent
- key
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
本发明提供了一种经皮吸收制剂,该经皮吸收制剂包括载体和具有释放控制层的粘合剂层,该粘合剂层形成在载体的至少一面上,其中粘合剂层含有粘合剂和0.5~60wt%的除1,2-乙二醇衍生物外的药物。
Description
技术领域
本发明涉及一种经皮吸收制剂,该制剂含有特定量的除1,2-乙二醇衍生物外的药物,该制剂可使药物持续地经皮吸收进入体内,并且该制剂可抑制由药物引起的对皮肤的刺激。
背景技术
对于给药,药物粘合片形式的制剂,即所谓的经皮吸收制剂,由于其具有可行的给药方法,易于控制给药等优点,最近几年已引起大家的注意,其中制剂是通过粘合剂的作用粘贴到皮肤上的。
但是,皮肤的功能本来是作为一个屏障体系,来保护身体不受外部环境的影响,并能有效地阻止外界物质对身体的入侵。为了使经皮吸收的药物的药理学作用完全发挥出来,需要开发一种具有穿越这种屏障功能的皮肤渗透性的经皮吸收制剂。
为改善皮肤的渗透性,人们做了如下尝试:经常向粘合剂中加入一种经皮吸收促进剂;使用离子电渗疗法,其中通过向皮肤通电而使离子化的药物被经皮吸收;通过利用超声波作用的扩音听诊器使药物被物理经皮吸收;等。
另一方面,已报道有很多化合物在被经皮吸收时会引起对皮肤的刺激。因为经皮吸收制剂的目标是将药物经皮吸收进入体内,所以会引起对皮肤的刺激的药物的经皮吸收,要求在不会对皮肤产生刺激的浓度下,身体能够经皮吸收足够量的药物,这意味着该制剂应具有相反的作用。
发明内容
发明概述
因此本发明的一个目的是提供一种经皮吸收制剂,该制剂能够持续地使药物经皮吸收进入体内,足以产生所需的药理学效果,并且该制剂能够抑制由药物引起的对皮肤的刺激。
根据本发明,具有释放控制层的粘合剂层形成在载体的至少一侧,以控制粘合剂层中含有的药物的释放量和释放速率,由此实现药物的持续经皮吸收,其吸收量足以发挥药理学作用,并提供一种药物对皮肤刺激较小的经皮吸收制剂。
因此,本发明提供如下的经皮吸收制剂:(1)一种经皮吸收制剂,含有载体和具有释放控制层的粘合剂层,该粘
合剂层形成在载体的至少一侧,其中粘合剂层含有粘合剂和0.5-
60wt%的除1,2-乙二醇衍生物以外的药物。(2)上述(1)中的经皮吸收制剂,其中所述的粘合剂选自下列粘合剂中
至少之一:丙烯酸粘合剂,该粘合剂含有一种聚合物作为主要组分,
该聚合物含有作为聚合组分的(甲基)丙烯酸C2-18烷基酯,其含量
不低于40wt%;橡胶粘合剂,该粘合剂含有选自聚异丁烯,聚异戊
二烯,和苯乙烯-二烯-苯乙烯共聚物中的至少一种作为主要组分;
和硅氧烷粘合剂,该粘合剂包含含有二甲基硅氧烷单元的聚有机硅
氧烷作为主要组分。(3)上述(1)中的经皮吸收制剂,其中粘合剂层含有至少一种选自二元
醇,脂肪和油脂,脂肪酸,醇和脂肪酸酯的有机液体组分。(4)上述(1)中的经皮吸收制剂,其中粘合剂是含有聚异丁烯作为主要
组分的橡胶粘合剂,并且粘合剂层还含有高级脂肪酸的低级烷基
酯。(5)上述(1)中的经皮吸收制剂,其中释放控制层是多孔塑料薄膜。(6)上述(5)中的经皮吸收制剂,其中多孔塑料薄膜是由高分子量聚乙
烯制成的。(7)上述(5)或(6)中的经皮吸收制剂,其中多孔塑料薄膜的孔隙率为
20-60%。(8)上述(1)中的经皮吸收制剂,其中具有释放控制层的粘合剂层,从
载体一侧开始具有由粘合剂层A/释放控制层/粘合剂层B构成的层压
结构。(9)上述(8)中的经皮吸收制剂,其中粘合剂层B的药物含量不超过
200μg/cm2。
附图说明
图1是显示测试实施例1中的水下释放试验结果的曲线。
发明详述
本发明的经皮吸收制剂含有载体和具有释放控制层的粘合剂层,该粘合剂层形成在载体的至少一侧,其中的粘合剂层含有粘合剂和除1,2-乙二醇衍生物外的药物。
用于本发明的药物可以是除1,2-乙二醇衍生物外的任何药物,并依治疗的目的而定。其实例包括皮质类固醇(例如氢化可的松,强的松龙,倍氯美松丙酸酯(becloinetasone propionate),氟甲松,去炎松,去炎松丙酮,氟轻松,氟轻松丙酮,醋酸氟轻松丙酮,丙酸氯氟美松等),抗炎镇痛剂(例如对乙酰氨基酚,甲灭酸,氟灭酸,消炎痛,1-薄荷醇,樟脑,苏灵大,联苯丁酮酸,保泰松,布洛芬,甲苯酰吡酸钠,双氯酚酸,双氯酚酸钠,烯氯苯乙酸,羟基保泰松,萘普生,氟联苯丙酸,酮丙酸,水杨酸,水杨酸甲酯等),hypnosedatives(例如苯巴比妥,异戊巴比妥,环巴比妥,氯羟去甲安定,氟哌啶醇等),镇静剂(例如氟非那嗪,甲硫哒嗪,安定,氟硝安定,氯丙嗪等),抗高血压剂(例如可乐定,盐酸可乐定,心得静,心得安(盐酸盐),氯甲苯心安,茚心安,布库洛尔,硝苯吡啶等),利尿降血剂(例如双氢氯噻嗪,下氟噻嗪,环戊氯噻嗪等),抗生素(例如青霉素,四环素,土霉素,硫酸新霉素,红霉素,氯霉素等),麻醉剂(例如利多卡因,苯佐卡因,氨苯甲酸乙酯等),抗菌剂(例如氯苄烷铵,呋喃西林,制霉菌素,磺胺乙酰钠,克霉唑等),防霉剂(例如pentimycin,两性霉素B,硝吡咯菌素,克霉唑等),维生素(例如维生素A,维生素D2,维生素D3,辛硫胺,丁酸核黄素等),冠状血管舒张剂(例如硝酸甘油,硝酸乙二醇,硝酸异山梨醇酯等),抗组胺剂(例如苯海拉明(盐酸盐),氯苯吡胺等),止咳药(例如美沙芬,叔丁喘宁,麻黄碱,麻黄碱盐酸盐等),性激素(例如黄体酮,雌二醇等),抗抑郁剂(例如丙咪嗪(盐酸盐),阿密曲替林盐酸盐等),改善大脑循环的制剂,止吐药物(例如灭吐灵,哌双咪酮等),抗癌制剂(例如5-氟尿嘧啶等),抗癫病药(例如硝基安定,安宁,氯硝安定,2-丙基戊酸钠等),抗头晕药(例如甲胺乙吡啶等)等。这些药物可单独使用或组合使用。
上面提到的不能用在本发明中的1,2-乙二醇衍生物具有如下的通式(I):其中R1是任选取代的杂环基,R2为氢原子,低级烷基,低级烷氧基或任选保护羟基,R3为氢原子或低级烷基,在数字n内的R4和R5可相同,也可不同,并且各自为氢原子或低级烷基,R6为任选取代的氨基或含氮的杂环基,或氨复盐基,并且n为0-6的整数。
在上述通式(I)中,除非另外特别指出,每个符号代表下列含义:
卤原子是指氟原子,氯原子,溴原子或碘原子。
低级烷基是指C1-6烷基,如甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,戊基和己基。
低级烯基是指C2-6烯基,如乙烯基,丙烯基,丁烯基,戊烯基和己烯基。
低级链烯氧基是指C2-6烯基-O-基。
环烷基是指C3-6环烷基,如环丙基,环丁基,环戊基和环己基。
低级烷氧基是指C1-6烷基-O-基。
低级烷硫基是指C1-6烷基-S-基。
芳基是指苯基,萘基,2,3-二氢化茚基或茚基。
芳氧基是指芳基-O-基。
芳基(低级)烷基是指芳基(C1-4)烷基,例如苄基,二苯甲基,三苯甲基和苯乙基。
芳基(低级)烯基是指芳基(C2-6)烯基,例如苯乙烯基,肉桂基等。
芳基(低级)烷氧基是指芳基(C1-4)烷基-O-基。
芳基(低级)烷硫基是指芳基(C1-4)烷基-S-基。
低级亚烷基二氧基是指C1-4亚烷基二氧基,例如亚甲基二氧基和亚乙基二氧基。
低级酰基是指C1-6烷基-CO-基,例如甲酰基,乙酰基和丁酰基。
芳酰基是指芳基-CO-基。
低级烷基磺酰基是指C1-6烷基-SO2-基。
芳基(低级)烷基磺酰基是指芳基(C1-6)烷基-SO2-基。
芳基磺酰基是指芳基-SO2-基。
低级烷基磺酰氧基是指C1-6烷基-SO2-O-基。
芳基磺酰氧基是指芳基-SO2-O-基。
芳基磺酰氨基是指芳基-SO2NH-基。
低级烷基磺酰氨基是指C1-6烷基-SO2NH-基。
二低级烷基氨基是指二C1-6烷基氨基。
氨复盐基是指三C1-6烷基氨复盐基,如三甲基氨复盐基和三乙基氨复盐基。
含氮的杂环基是指5元或6元稠合环或桥联环的杂环基,其含有一个或多个氮原子和一个或多个氧原子或硫原子作为形成环的杂原子,实例有吡咯基,吡咯烷基,哌啶基,哌嗪基,咪唑基,吡唑基,吡啶基,四氢吡啶基,嘧啶基,吗啉基,硫代吗啉基,喹啉基,喹嗪基,四氢喹啉基,四氢异喹啉基,奎宁环基,噻唑基,四唑基,噻二唑基,吡咯啉基,咪唑啉基,咪唑烷基,吡唑啉基,吡唑烷基,嘌呤基和吲唑基。
杂环基是指上述含氮杂环基,或含有一个或多个氧原子和/或硫原子作为形成环的杂原子的5元或6元稠合环或桥联环的杂环基,其实例有呋喃基,噻吩基,苯并呋喃基,苯并噻吩基,异苯并呋喃基,吡喃基,苯并二氢吡喃基,苯并吡喃基,黄嘌呤基,硫代吡喃基,噻蒽基,吩黄嘌呤基等。
杂环羰基是指杂环-CO-基。
在通式(I)中“任选取代的杂环基”R1的取代基的实例为卤原子;任选取代的氨基,低级烷基,芳基,芳基(低级)烷基,低级烷氧基,芳基(低级)烷氧基,芳氧基,氨基甲酰氧基,低级烷硫基,低级烯基,低级链烯氧基,芳基(低级)烷硫基,芳基(低级)烷基磺酰基,芳基磺酰基,低级烷基磺酰氨基,芳基磺酰氨基和杂环基;保护的氨基;任选保护的羟基;硝基;氧基;和低级亚烷基二氧基,这些取代基可单独使用或组合使用。
作为在通式(I)中“任选取代的杂环基”R1的取代基的“任选取代的低级烷基,芳基,芳基(低级)烷基,低级烷氧基,芳基(低级)烷氧基,芳氧基,氨基甲酰氧基,低级烷硫基,低级烯基,低级链烯氧基,芳基(低级)烷硫基,芳基(低级)烷基磺酰基,芳基磺酰基,低级烷基磺酰氨基,芳基磺酰氨基和杂环基”的取代基,及在通式(I)中“任选取代的含氮的杂环基”R6的取代基的实例有卤原子,任选保护的羟基,保护的羧基,任选保护的氨基,用任选保护的羟基任选取代的低级烷基,用卤原子任选取代的芳基,用卤原子任选取代的芳酰基,用低级烷氧基任选取代的低级烷氧基,低级酰基,芳基(低级)烷基,芳基(低级)烯基,杂环基,杂环羰基,氧基,低级烷基磺酰基和芳基磺酰基,这些取代基可单独使用或组合使用。
作为在通式(I)中“任选取代的杂环基”R1的取代基的“任选取代的氨基”的取代基,及在通式(I)中“任选取代的氨基”R6的取代基的实例有任选保护的羟基,用任选保护的羟基和/或保护的羧基任选取代的低级烷基,环烷基,芳基,低级酰基,芳基(低级)烷基,杂环基,被氧基任选取代的杂环羰基,金刚烷基,低级烷基磺酰基和芳基磺酰基,这些取代基可单独使用或组合使用。
在通式(I)中“任选保护的羟基”R2,作为在通式(I)中“任选取代的杂环基”R1的取代基的“保护的氨基”和“任选保护的羟基”,及所有作为在通式(I)中“任选取代的氨基或含氮的杂环基”R6的取代基的“任选保护的羟基”,“保护的羧基”,“任选保护的氨基”,“任选保护的羟基”或“被任选保护的羟基任选取代的低级烷基”,及“用保护的羧基任选取代的低级烷基”中的“保护的羧基”的保护基,可以是在“Protective Groups in Organic Synthesis” [TheodraW.Creen(1991),John Wiley & Sons.Inc.]中描述的羟基,羧基和氨基的典型的保护基。具体而言,羟基的保护基是例如低级烷基,低级酰基,2-四氢吡喃基,或芳基(低级)烷基,例如任选取代的苄基。
当本发明中使用的药物可以形成盐时,其可以是自由形式或药物可接受的盐。药物可接受的盐的实例包括与酸形成的盐,所述酸可以是例如无机酸(例如盐酸,氢溴酸,硫酸,磷酸等),有机酸(例如羧酸,如甲酸,乙酸,草酸,琥珀酸,富马酸,马来酸,乳酸,苹果酸,酒石酸,天冬氨酸等;磺酸,如甲磺酸,苯磺酸,对甲苯磺酸,萘磺酸等)等,碱盐,例如钠盐,铵盐等。
在本发明中,药物可接受的盐可以通过加一种盐的释放剂,而在粘合剂层中释放出来。释放剂的实例包括碱,例如氢氧化钠,氢氧化钾,三乙胺,四乙基铵,氨,辛酸钠等,酸,例如盐酸,琥珀酸,乙酸等。对于经皮吸收,包含在粘合剂层中的药物的经皮吸收性能的顺序为:自由形式的药物>在粘合剂层中释放的药物>药物的可接受的盐。
本发明中使用的药物在粘合剂层中的含量为0.5~60wt%,优选1~30wt%。当含量少于0.5wt%时,很难有有效量的药物被吸收以发挥药效。相反,当含量超过60wt%时,所述粘合剂层对皮肤的粘合力很低,不能确保粘合在皮肤上,或者不能得到药物量增加所带来的药效提高的效果,而这在经济上是不利的。
在本发明的粘合剂层中包含的粘合剂是一种粘合剂膏,该粘合剂膏可以粘合到皮肤上,使粘合剂层中包含的药物可以从皮肤表面经皮给药,并且该粘合剂膏在常温下具有粘性。
作为这类粘合剂,使用的是在涂敷到皮肤上后对皮肤无刺激性等的药用粘合剂,例如丙烯酸粘合剂,天然橡胶粘合剂,合成橡胶粘合剂(含有作为主要组分的合成橡胶组分,例如合成异戊二烯橡胶,聚异丁烯橡胶,苯乙烯/丁二烯橡胶,苯乙烯/异戊二烯/苯乙烯橡胶,苯乙烯/丁二烯/苯乙烯橡胶等),硅氧烷粘合剂,乙烯酯粘合剂,乙烯醚粘合剂等是优选的。
在上述粘合剂中,考虑到性能的稳定和粘合剂性能控制的容易性,优选使用选自如下粘合剂中的至少一种粘合剂:丙烯酸酯粘合剂,该粘合剂含有一种聚合物作为主要组分,该聚合物含有作为聚合组分的(甲基)丙烯酸C2-18烷基酯,其含量不低于40wt%;橡胶粘合剂,该粘合剂含有聚异丁烯,聚异戊二烯,和苯乙烯-二烯-苯乙烯共聚物中的至少一种作为主要组分;和硅氧烷粘合剂,该粘合剂含有具有二甲基硅氧烷单元的聚有机硅氧烷作为主要组分。特别地,考虑到药物的稳定性,优选使用含有聚异丁烯作为主要组分的橡胶粘合剂。
上述丙烯酸粘合剂没有任何特别的限制,只要其具有上述组成。从粘合剂性能容易控制等角度考虑,由50~98wt%的一种或多种(甲基)丙烯酸C2-18烷基酯,和2~50wt%的一种或多种共聚单体共聚得到的共聚物是优选的。
上述(甲基)丙烯酸C2-18烷基酯的实例包括:由含有2~18,优选4~12个碳原子的烷基的一级,二级,或三级醇,和丙烯酸或甲基丙烯酸得到的酯。
上述共聚单体的实例包括具有至少一个参与共聚反应的不饱和双键,并且在侧链上具有官能团的单体,所述官能团是例如羧基[例如(甲基)丙烯酸,衣康酸,马来酸,马来酸酐等];羟基[例如(甲基)丙烯酸羟乙酯,(甲基)丙烯酸羟丙酯等];磺基[例如苯乙烯磺酸,烯丙基磺酸,(甲基)丙烯酸磺基丙基酯,(甲基)丙烯酰氧基萘磺酸,丙烯酰胺甲基丙磺酸等];氨基[例如(甲基)丙烯酸氨乙酯,(甲基)丙烯酸二甲胺乙基酯,(甲基)丙烯酸叔丁基氨乙酯等];酰胺基(例如(甲基)丙烯酰胺,二甲基(甲基)丙烯酰胺,N-丁基丙烯酰胺,N-羟甲基(甲基)丙烯酰胺,N-羟甲基丙烷(甲基)丙烯酰胺等);烷氧基[例如(甲基)丙烯酸甲氧基乙基酯,(甲基)丙烯酸乙氧基乙基酯,(甲基)丙烯酸甲氧基乙二醇酯,(甲基)丙烯酸甲氧基二乙二醇酯,(甲基)丙烯酸甲氧基聚乙二醇酯,(甲基)丙烯酸四氢化糠基酯等]等。
除上述外的其它共聚单体的实例包括(甲基)丙烯腈,醋酸乙烯酯,丙酸乙烯酯,N-乙烯基-2-吡咯烷酮,甲基乙烯基吡咯烷酮,乙烯基吡啶,乙烯基哌啶酮,乙烯基嘧啶,乙烯基哌嗪,乙烯基吡嗪,乙烯基吡咯,乙烯基咪唑,乙烯基己内酰胺,乙烯基噁唑,乙烯基吗啉等。
可以使用一种或多种上述共聚单体。考虑到粘合剂的粘性和内聚力,包含在粘合剂层中的药物的释放性能等,共聚物中至少包括含羧基的单体和含羟基的单体中的一种,含量为1~50wt%,优选3~20wt%,并且在需要时,共聚物中优选含有上面列举的其它共聚单体,例如乙烯基单体(如醋酸乙烯酯,和N-乙烯基-2-吡咯烷酮),含量不超过40wt%,优选不超过30wt%。
丙烯酸粘合剂的实例包括丙烯酸(2-乙基己基)酯和丙烯酸的共聚物,丙烯酸(2-乙基己基)酯和丙烯酸(2-羟乙基)酯的共聚物,丙烯酸(2-乙基己基)酯和丙烯酸(2-甲氧基乙基)酯,醋酸乙烯酯的共聚物,丙烯酸(2-乙基己基)酯和乙烯基吡咯烷酮的共聚物,丙烯酸(2-乙基己基)酯和乙烯基吡咯烷酮和丙烯酸的共聚物,等等。
按照本发明,所述粘合剂层优选含有至少一种有机液体组分,该有机液体组分选自二元醇,脂肪和油,脂肪酸,醇和脂肪酸酯。当粘合剂层含有有机液体组分时,可进一步改善对皮肤的粘性,药物的皮肤渗透性,和在剥离时对皮肤刺激性的降低等。换句话说,可以改善药物的皮肤渗透性;由于有机液体组分与粘合剂层中的粘合剂增塑剂的相容性,使粘合剂制备物在粘合到皮肤上时产生一种软的感觉;通过交联处理赋予合适的内聚力,并且可以降低使用后剥离时对皮肤的刺激。
上述二元醇的实例包括乙二醇,二甘醇,三甘醇,聚乙二醇,丙二醇,聚丙二醇等。具有高分子量的那些二元醇,例如聚乙二醇,聚丙二醇等,优选重均分子量为200~1000。
上述脂肪和油的实例包括橄榄油,蓖麻油,角鲨烯,角鲨烷,橙油,矿物油等。
上述脂肪酸的实例包括总碳数为6~20的一癸酸,油酸,辛酸,月桂酸,十一碳烯酸,异硬脂酸,亚油酸等。
上述醇的实例包括除上述二元醇外的,具有1~20个碳原子的醇,例如乙醇,甲醇,辛醇,乙氧化十八烷醇,1,3-丁二醇,癸醇,桉树脑,油醇等。
上述脂肪酸酯的实例包括总碳数为6~20的肉豆蔻酸异丙酯,癸二酸二乙酯,油酸乙酯,邻苯二甲酸二乙酯,己二酸二异丙酯,丙二醇脂肪酸酯,烟酸月桂酯,吡咯烷酮羧酸月桂酯等。
上述有机液体组分的含量优选为:每100份(重量)粘合剂,含有3~200份(重量),更优选10~180份(重量),最优选20~100份(重量)。当有机液体组分的含量太低时,将起不到效果。当含量太高时,粘合剂层塑化太严重,这将造成低的内聚力。这样还有一个结果,即交联处理将不可避免地在皮肤表面留下胶状残留物,并且可能增加在剥离时对皮肤的刺激。
如上所述,为了药物的稳定性,本发明优选使用含有聚异丁烯作为主要组分的橡胶粘合剂。在这种情况下,优选含有高级脂肪酸的低级烷基酯作为上述有机液体组分。
具体而言,对于涂敷到皮肤上后粘合剂性能(粘合力,内聚力,粘着性等)的平衡,优选一种合适的组合物,该组合物包括作为聚异丁烯的粘均分子量(Mv)为900,000~2,100,000的高分子量的聚异丁烯,Mv为10,000~200,000的中分子量的聚异丁烯,Mv为500~4,000的低分子量的聚异丁烯。
上述各聚异丁烯的混合比优选为:高分子量聚异丁烯,10~80wt%,优选20~70wt%;中分子量聚异丁烯,0~90wt%,优选10~80wt%;低分子量聚异丁烯,0~80wt%,优选0~60wt%。通过使各聚异丁烯的含量在上述范围内,得到的聚异丁烯粘合剂具有优异的粘合剂性能平衡,这将有效实现本发明药物的经皮吸收。
作为有机液体组分的高级脂肪酸低级烷基酯的实例包括具有10~14个碳原子的高级脂肪酸与具有1~3个碳原子的低级醇的酯化产物,例如肉豆蔻酸异丙酯,癸二酸二乙酯等。这些有机液体组分的含量优选为3~80份(重量),更优选10~40份(重量),基于每100份(重量)含有聚异丁烯作为主要组分的橡胶粘合剂。在这一范围内的含量,将降低药物对皮肤的刺激性,并改善药物的经皮吸收性能。
而且按照本发明,当需要增加粘合剂层的粘度时,可以与粘合剂一起使用一种增粘剂。增粘剂的实例包括松香,松香衍生物,多萜树脂,苯并二氢吡喃-茚树脂,石油树脂,萜苯酚树脂等。
在本发明中,当需要时,粘合剂层可以含有添加剂,例如抗氧化剂,颜料,填料,经皮吸收促进剂,药物稳定剂,药物加溶剂,药物降溶剂等。一般地,这些添加剂的含量通常为粘合剂层的约0.1~50wt%,优选1~10wt%。
按照本发明,所述粘合剂层含有一个释放控制层。该释放控制层的目的是,在粘合剂层中含有的药物由于铺展扩散,从粘合剂层的表面释放到与该层接触的皮肤表面时,控制药物的释放量和释放速度,并具有防止自由扩散的屏障功能。
本发明的含有释放控制层的粘合剂层,具有一种层叠结构,例如粘合剂层A/释放控制层/粘合剂层B,该顺序是从载体侧开始。在这种结构中,粘合剂层A和粘合剂层B的组成可以相同或不同,其中所包含的粘合剂,有机液体组分等的种类和量,及加入的药物的量可以变化。
上述释放控制层可以是纸,无纺布,纺织布,有孔的塑料薄膜等,并且如果药物可以溶解在其中,也可以使用没有孔的塑料薄膜(例如聚乙烯薄膜,聚丙烯薄膜,乙烯/醋酸乙烯酯共聚物薄膜)。当使用无孔塑料薄膜时,所述药物从粘合剂层A的释放速度可能降低,降低粘合剂层A中的药物的有效利用率,并且所述薄膜会由于有机液体组分的作用而溶涨,这样会产生皱纹。因此,优选使用有孔的塑料薄膜,特别是多孔的塑料薄膜。尽管对多孔塑料薄膜的厚度没有特别的限制,但是优选不超过100微米,以降低将其粘合在皮肤上所产生的不舒适感,即硬感。
可用于本发明的多孔塑料薄膜的例子为由如下材料制成的多孔薄膜:聚乙烯,聚丙烯,聚四氟乙烯,乙烯/醋酸乙烯酯共聚物,醋酸乙烯酯/氯乙烯共聚物,塑性氯乙烯,聚氨酯,聚(1,1-二氯乙烯),聚酯等。在这些材料中,优选使用高分子量的聚乙烯,超高分子量的聚乙烯等,它们对上述有机液体组分具有足够的抵抗力(例如非溶涨性等)。
为了控制药物的释放,上述多孔塑料薄膜的孔隙率优选为约20~60%,更优选25~55%。孔的大小优选不超过50微米,更优选为20~35微米。
按照本发明,所述粘合剂层有一个释放控制层。通过这种结构,可以按照本发明的目标控制释放的量和释放的速度,由此实现药物被身体持续经皮吸收,并且可以抑制药物对皮肤的刺激。具体而言,药物在粘合剂层B(与皮肤接触一侧)的含量优选控制为不超过200μg/cm2,更优选为75~150μg/cm2,并且药物从粘合剂层A(载体侧)迁移到粘合剂层B的速率优选控制为不超过120μg/cm2/t1/2,更优选为70~120μg/cm2/t1/2。
因为粘合剂层B位于与皮肤接触的一侧,所以在粘合剂层B中包含的药物,在敷于皮肤上后立即释放到皮肤上。当粘合剂层B的药物含量太高时,将很难控制其释放到皮肤上的量。因此,粘合剂层B的药物含量优选设定为不超过200μg/cm2。另外,药物从粘合剂层B的释放速度优选控制为不超过180μg/cm2/t1/2,更优选不超过10~150μg/cm2/t1/2。通过调节粘合剂层的厚度和组成,药物的总含量和浓度,及有机液体组分的含量,可以控制释放速度。
在粘合剂层A中包含的药物在释放到皮肤上前,需要通过释放控制层,这涉及到持续的释放。当释放控制层的透过率太高时,在短时间内大量的药物释放到皮肤上,不能实现持续释放。因此,药物从粘合剂层A迁移到粘合剂层B的速度优选控制为不超过120μg/cm2/t1/2,更优选为70~120μg/cm2/t1/2。通过调节粘合剂层的组成,释放控制层的材料和厚度,可以控制迁移速度。
对本发明中使用的载体没有任何特别的限制,只要其可以承载粘合剂层并改善粘合性能。其实例包括:由聚酯,聚乙烯,聚丙烯,聚氯乙烯,聚(1,1-二氯乙烯),乙烯/醋酸乙烯酯共聚物,乙酸纤维素,乙基纤维素,醋酸乙烯/氯乙烯共聚物,聚氨酯等制成的塑料薄膜,纸,纺织布,无纺布,及其层压物,这些材料和金属箔的层压物,等。
上述载体的厚度为,当本发明的经皮吸收制剂附着在皮肤表面时,不会引起不舒适感,并且在从皮肤表面剥离该制剂时能够提供足够的机械强度以保持该制剂完整的厚度。该厚度一般为1~50微米,优选1~30微米。
按照本发明,含有上述释放控制层的粘合剂层,优选通过包藏涂敷技术等,直接或间接形成在载体的至少一面上,以改善操作性能,对皮肤的粘接性,经皮吸收性,所述间接形成是指通过用于改善固定效果的底物等。
本发明的经皮吸收制剂可以按照如下方法得到。将一种形成粘合剂层的涂敷溶液涂布在脱模衬(例如经过脱模处理后的薄膜等)上并干燥(形成粘合剂层B)。分开地,将一种形成粘合剂层的涂敷溶液涂布在载体上并干燥(形成粘合剂层A)。将在脱模衬上的粘合剂层B和在载体上的粘合剂层A分别粘附在释放控制层的两面,并除去脱模衬,给出一种结构为载体/粘合剂层A/释放控制层/粘合剂层B的经皮吸收制剂。
尽管对本发明的经皮吸收制剂的形状无特殊的限制,但是优选具有优异可操作性的带状。
具体实施方式
下面参考实施例详细阐述本发明。无论如何,本发明不局限于这些实施例,而是可以做各种改变,只要这些改变未脱离本发明的技术概念。在下列叙述中,份数是指重量份,%是指wt%。
实施例1
将丙烯酸粘合剂(75份,丙烯酸(2-乙基己基)酯/丙烯酸共聚物,丙烯酸(2-乙基己基)酯/丙烯酸=95/5(重量比))溶解在乙酸乙酯中。向其中加入癸二酸二乙酯(20份)和自由形式的甲胺乙吡啶(5份),得到形成粘合剂层的涂敷溶液。将该涂敷溶液涂布到经过脱模处理的聚酯薄膜上,使干燥后的厚度为30微米,并干燥(形成粘合剂层B)。分开地,将上述涂敷溶液涂布在载体无纺布(6微米厚的聚酯薄膜和基础重量为8g/m2的聚酯无纺布的层压物)上,使干燥后的厚度为60微米,并干燥(形成粘合剂层A)。
作为释放控制层,使用一个50微米厚的高分子量多孔聚乙烯薄膜(孔隙率:45%,由NITTO DENKO CORPORATION生产的聚乙烯薄膜,商标为BREATHRON)。在该薄膜的两面粘附经过脱模处理的聚酯薄膜上的粘合剂层B,和在载体上的粘合剂层A,并剥离该经过脱模处理的聚酯薄膜,得到结构为载体/粘合剂层A/释放控制层/粘合剂层B的经皮吸收制剂。
实施例2
将一种聚异丁烯粘合剂(60份,为粘均分子量为1,400,000的聚异丁烯(100份)与粘均分子量为60,000的聚异丁烯(100份)的混合物)溶解在己烷中。加入肉豆蔻酸异丙酯(30份)和自由形式的甲胺乙吡啶(10份),得到形成粘合剂层的涂敷溶液。将该涂敷溶液涂布到经过脱模处理的聚酯薄膜上,使干燥后的厚度为20微米,并干燥(形成粘合剂层B)。分开地,将上述涂敷溶液涂布在载体无纺布(6微米厚的聚酯薄膜和基础重量为8g/m2的聚酯无纺布的层压物)上,使干燥后的厚度为30微米,并干燥(形成粘合剂层A)。
作为释放控制层,使用一个50微米厚的超高分子量多孔聚乙烯薄膜(孔隙率:30%,由NITTO DENKO CORPORATION生产的超高分子量聚乙烯薄膜,商标为SUNMAP)。在该薄膜的两面粘附经过脱模处理的聚酯薄膜上的粘合剂层B,和在载体上的粘合剂层A,并剥离该经过脱模处理的聚酯薄膜,得到结构为载体/粘合剂层A/释放控制层/粘合剂层B的经皮吸收制剂。比较实施例1
制备如实施例1的形成粘合剂层的涂敷溶液,并将该涂敷溶液涂布到如实施例1的载体无纺布上,使干燥后的厚度为90微米,并干燥,得到结构为载体/粘合剂层的经皮吸收制剂。比较实施例2
将丙烯酸粘合剂(95份,丙烯酸(2-乙基己基)酯/丙烯酸共聚物,丙烯酸(2-乙基己基)酯/丙烯酸=95/5(重量比))溶解在乙酸乙酯中,并加入自由形式的甲胺乙吡啶(5份),得到形成粘合剂层的涂敷溶液。将该溶液涂布到如实施例1的载体无纺布上,使干燥后的厚度为90微米,并干燥,得到结构为载体/粘合剂层的经皮吸收制剂。比较实施例3
制备如实施例2的形成粘合剂层的涂敷溶液,并将该涂敷溶液涂布到如实施例2的载体无纺布上,使干燥后的厚度为50微米,并干燥,得到结构为载体/粘合剂层的经皮吸收制剂。比较实施例4
将一种聚异丁烯粘合剂(90份,为粘均分子量为1,400,000的聚异丁烯(100份)与粘均分子量为60,000的聚异丁烯(100份)的混合物)的混合物溶解在己烷中。加入自由形式的甲胺乙吡啶(10份),得到形成粘合剂层的涂敷溶液。将该涂敷溶液涂布到载体无纺布上,使干燥后的厚度为50微米,并干燥,得到结构为载体/粘合剂层的经皮吸收制剂。
在实施例1~2和比较实施例1~4中得到的经皮吸收制剂进行如下试验。测试实施例1(释放性试验)
在上述各实施例和比较实施例中得到的经皮吸收制剂冲压成10cm2圆形物,并根据日本药典,扩散试验方法2(水坑方法)进行水下释放试验。结果示于图1。图1的结果清楚地表明,在粘合剂层中释放控制层的存在可得到所需的药物释放控制模式。测试实施例2(皮肤刺激性试验)
在上述各实施例和比较实施例中得到的经皮吸收制剂冲压成10cm2圆形物,并粘贴在Wistar大鼠(8周大)的背上,该鼠的皮肤表面已进行了剪毛,剃刮和清洁。在粘贴18h后剥离该制剂,按照Draize等的标准评价在粘合剂涂敷部位是否有由药物引起的刺激性的存在。结果列于表1。评价标准如下。<对皮肤的刺激性>
○:对皮肤无刺激
△:对皮肤有弱刺激
×:对皮肤有中等或中等以上的刺激测试实施例3(通过蛇皮的渗透性)
在上述各实施例和比较实施例中得到的经皮吸收制剂冲压成直径为6cm的圆形物,并粘贴在网状巨蟒皮的一面上。网状巨蟒皮的没有经皮吸收制剂的一面上,放置直径6mm的渗滤池,并测定渗透到渗滤池的药物的量,以评价渗透性。渗透的药物的量采用HPLC测定,并计算每单位面积的渗透量(24h累积)和每单位面积的最大药物渗透速率。结果列于表1。
【表1】
对皮肤的刺激性 | 渗透量(μg/cm2)(24h累积) | 最大渗透速率(μg/cm2/h) | |
实施例1 | ○ | 380 | 18.5 |
比较实施例1 | × | 410 | 63.0 |
比较实施例2 | ○ | 105 | 5.2 |
实施例2 | ○ | 200 | 15.0 |
比较实施例3 | × | 220 | 65.0 |
比较实施例4 | ○ | 100 | 7.5 |
如上表1所清楚表明的那样,实施例1-2的制剂几乎没有表现出药物对皮肤的刺激性,并且在药物渗透性方面没有实际问题。相反,比较实施例1-4的没有释放控制层的制剂,在药物对皮肤的刺激性和渗透性方面,实际上不能令人满意。比较实施例1和3的制剂含有有机液体组分,但是没有释放控制层。结果,所述药物显示最大的渗透速率,引起药物对皮肤的刺激。比较实施例2和4的制剂没有释放控制层,但是由于缺少有机液体组分,药物的渗透量很小。
上述说明清楚表明,本发明可以提供一种经皮吸收制剂,该制剂可以提供药物的持续经皮吸收,以在长时间内发挥需要的药效。另外,本发明的制剂具有经皮可吸收性和低的皮肤刺激性,其中抑制了药物对皮肤的刺激性。
本申请是基于在日本提交的专利申请No.2000-268899,其内容结合在此作为参考。
Claims (10)
1.一种经皮吸收制剂,包括载体和具有释放控制层的粘合剂层,该粘合剂层形成在载体的至少一面上,其中粘合剂层含有粘合剂和0.5~60wt%的除1,2-乙二醇衍生物外的药物。
2.权利要求1的经皮吸收制剂,其中所述的粘合剂选自下列粘合剂中至少之一:丙烯酸粘合剂,该粘合剂含有一种聚合物作为主要组分,该聚合物含有作为聚合组分的(甲基)丙烯酸C2-18烷基酯,其含量不低于40wt%;橡胶粘合剂,该粘合剂含有选自聚异丁烯,聚异戊二烯,和苯乙烯-二烯-苯乙烯共聚物中的至少一种作为主要组分;和硅氧烷粘合剂,该粘合剂包含含有二甲基硅氧烷单元的聚有机硅氧烷作为主要组分。
3.权利要求1的经皮吸收制剂,其中所述粘合剂层含有选自二元醇,脂肪和油,脂肪酸,醇和脂肪酸酯的至少一种有机液体组分。
4.权利要求1的经皮吸收制剂,其中所述粘合剂是橡胶粘合剂,包括聚异丁烯作为主要组分,并且所述粘合剂层还含有高级脂肪酸的低级烷基酯。
5.权利要求1的经皮吸收制剂,其中所述释放控制层是多孔塑料薄膜。
6.权利要求5的经皮吸收制剂,其中所述多孔塑料薄膜由高分子量聚乙烯制成。
7.权利要求5的经皮吸收制剂,其中所述多孔塑料薄膜的孔隙率为20~60%。
8.权利要求6的经皮吸收制剂,其中所述多孔塑料薄膜的孔隙率为20~60%。
9.权利要求1的经皮吸收制剂,其中所述含有释放控制层的粘合剂层具有一种层压结构,该层压结构从载体侧开始,由粘合剂层A/释放控制层/粘合剂层B构成。
10.权利要求9的经皮吸收制剂,其中所述粘合剂层B的药物含量不超过200μg/cm2。
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DE60116202D1 (de) | 2006-02-02 |
EP1188436A2 (en) | 2002-03-20 |
JP2002080349A (ja) | 2002-03-19 |
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CA2356743C (en) | 2009-04-21 |
CN100418579C (zh) | 2008-09-17 |
DE60116202T2 (de) | 2006-08-24 |
US7029693B2 (en) | 2006-04-18 |
US20020106401A1 (en) | 2002-08-08 |
EP1188436B1 (en) | 2005-12-28 |
EP1188436A3 (en) | 2003-06-04 |
JP4358978B2 (ja) | 2009-11-04 |
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