CN1252004A - 经皮吸收用基质组合物及含有该基质组合物的可经皮吸收的制剂 - Google Patents
经皮吸收用基质组合物及含有该基质组合物的可经皮吸收的制剂 Download PDFInfo
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- CN1252004A CN1252004A CN 98804063 CN98804063A CN1252004A CN 1252004 A CN1252004 A CN 1252004A CN 98804063 CN98804063 CN 98804063 CN 98804063 A CN98804063 A CN 98804063A CN 1252004 A CN1252004 A CN 1252004A
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- hexanediol
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Abstract
一种经皮吸收用基质组合物,该组合物含有苯乙烯-异戊二烯-苯乙烯嵌段共聚物、软化剂、增稠树脂和已二醇;以及一种含有该组合物和一种药物的可经皮吸收制剂。
Description
本发明的技术领域
本发明属于经皮治疗的药物领域并涉及经皮可吸收的制剂,其特征在于所说制剂使用了一种苯乙烯-异戊二烯-苯乙烯共聚物、一种软化剂、一种增稠树脂和己二醇作为经皮吸收的基质组合物的成分,该药物的溶解性和皮肤渗透性很好,可以对病人精确和安全地给服预定的药物量。背景技术
卵泡激素中所含的***在妇女具有生殖能力的阶段由卵巢分泌。因此绝经期前后的妇女大部分都缺乏***,引起绝经期病症、月经不规律等症状。为了改善这些症状,目前一般通过口服给药等进行治疗。但是其成分会很快引起代谢,并被消化器官如胃和肠以及肝等灭活,因此为了达到有效的药理学效果,必须给服高剂量的***。另外由于该高剂量而存在副作用增加的可能性。
在此情况下,人们已经尝试过很少产生***的代谢从而能很好地将其输送至血液并进行治疗的经过皮肤(经皮)的给药方法。另一方面,对另一种激素黄体激素经皮吸收以抑制由***给药所引起的副作用的研究也已进行。在已公开的日本专利342532/1992中,提出了一种可经皮吸收的制剂,其中***和黄体激素为有效成分,由丙烯酸2-乙基己基酯和N-乙烯基-2-吡咯烷酮组成的丙烯酸粘合剂是作为粘合剂的主要成分。但是该丙烯酸粘合剂释放能力低,对皮肤具有强刺激性,并且不能持久地进行长时间连续给药。
在已公开的日本专利51623/1994中提出了一种方法,其中药物成分***和醋酸炔诺酮溶解在由羟丙基纤维素和乙醇所组成的凝胶中,该溶液被制备成一种储器形式,药物成分的释放通过调节膜的渗透性来控制。但是存在副作用的问题,因为乙醇对皮肤有强的刺激性,经常导致施用区域潮红。同时在已公开的国际专利公开文本WO91/17752和已公开的日本专利148145/1993中提出了一种由苯乙烯-异戊二烯-苯乙烯嵌段共聚物组成的可经皮吸收的片剂,其中克罗米能被用作增溶剂。但是当克罗米能被用作增溶剂时,在稳定性方面存在问题,因为苯乙烯-异戊二烯-苯乙烯嵌段共聚物本身可溶于克罗米能中,并且预期的内聚力不能获得。
己二醇(属名,其化学名称为2-甲基-2,4-戊二醇)一般用作增湿剂,溶剂,工业清洗剂,液压油,皮革和织物柔软剂,墨水添加剂,以及感光添加剂等。在已公开的日本专利109220/1995和53338/1996中提出了一种外用试剂,其中己二醇被用作一种抗菌剂。
此外在已公开的国际专利公开文本WO 96/19976和已公开的日本专利138153/1995中提出了一种外用试剂,其中己二醇被用作一种吸附加速剂。但是己二醇与丙烯酸基质具有高的相溶性,为了获得有效的吸附加速效果,必须使用大剂量的己二醇。存在的另一个问题是使用大剂量的己二醇会降低粘合性,并破坏制剂的基本物理性质。
考虑到上述问题,本发明者为了提供一种可经皮吸收的制剂或基质组合物的目的进行了持续的广泛研究并完成了本发明,该制剂或组合物具有:
1)改善的药物成分的溶解性和稳定性;
2)改善的药物成分的皮肤渗透性;
3)对皮肤的低的刺激性;和
4)稳定的基质材料的物理性质。
为解决上述问题所进行的广泛研究的结果,本发明者发现,当将苯乙烯-异戊二烯-苯乙烯嵌段共聚物、软化剂、增稠树脂和己二醇用于基质组合物的成分时,便能够提供一种具有良好的内聚力,稳定的物理性质以及良好的药物成分的溶解性、稳定性和皮渗透性的可经皮吸收的基质组合物,据此得到本发明。
本发明的公开
本发明涉及含有对经皮吸收表现出加速作用或溶解药物的有效量的苯乙烯-异戊二烯-苯乙烯嵌段共聚物、软化剂、增稠树脂和己二醇的基质组合物。
本发明还涉及含有一种药物和所说可经皮吸收的基质组合物的一种可经皮吸收制剂。
更具体地说,本发明涉及含有苯乙烯-异戊二烯-苯乙烯嵌段共聚物、软化剂、增稠树脂和己二醇的可经皮吸收的基质组合物并涉及含有所说可经皮吸收的基质组合物和一种药物的可经皮吸收的片剂。
在将本发明的可经皮吸收的片剂施用于病人的皮肤后,治疗有效量的药物可以精确并安全地释放,本发明的目的是提供一种可经皮吸收的片剂。
附图的简要说明
图1表示使用无毛老鼠测得的实施例3以及对比例2和3的制剂中***(E2)的皮渗透性。
图2表示使用无毛老鼠测得的实施例3以及对比例2和3的制剂中醋酸炔诺酮(NETA)的皮渗透性。
图3表示实施例3以及对比例1和6的制剂中***(E2)的释放试验的结果。
图4表示实施例3以及对比例1和6的制剂中醋酸炔诺酮(NETA)的释放试验的结果。
实施本发明的最好方式
作为本发明的可经皮吸收制剂中的有效成分的药物是一种生理活性物质并具有可经皮吸收的能力。或者,它可以是一种在经皮吸收后表现出生理活性的所谓前药剂(pro-drug)。而且,它可以是一种药物可接收的无机或有机的加合盐。
用于本发明的可经皮吸收制剂的药物的优选例子是***如卵泡激素、黄体激素以及它们的衍生物。在卵泡激素的情况下活性成分的例子是***、雌酮、雌三醇、马烯雌酮、马萘雌酮以及它们的衍生物。在本发明的可经皮吸收制剂中,优选使用***。在黄体激素的情况下,活性成分的例子是孕酮、己酸羟孕酮、醋酸甲羟孕酮、地屈孕酮、醋酸氯地孕酮、炔孕酮、地美孕酮、炔诺酮、醋酸炔诺酮、庚酸炔诺酮、炔诺醇醋酸酯、醋酸甲地孕酮和丙烯基雌烯三醇,在本发明的可经皮吸收制剂中最优选的是使用醋酸炔诺酮。
除了上述例子以外,在本发明的可经皮吸收制剂中有效的药物的例子有止吐剂(如格兰西龙,azasetron,奥丹亚龙和ramosetron),治疗尿频药剂(如奥昔布宁),用于抑制血管紧张素I转化为酶的抑制剂(如卡托普利和地拉普利),钙拮抗物(如心痛定),冠状血管扩张剂(如地尔硫和尼可地尔),局部麻醉剂(如利多卡因和普鲁卡因),胸腺激素(如血清胸腺因子),肌肉弛缓药(如替托尼定,乙苯哌丁酮和丹曲林),***,抗高血压药剂(如阿普洛尔和心痛定),消肿剂,治疗精神病药剂(如丙咪嗪,芬太尼和***),抗生素物质,抗帕金森氏综合症的药剂(如金刚烷胺和左旋多巴),抗组胺药剂,抗眩晕药剂(如地芬尼多和倍他司汀),催眠止痛剂,消炎止痛剂(如消炎痛,酮洛芬,双洛芬酸,布洛芬,氟比洛芬,联苯乙酸和酮咯酸),自主药剂,用于心脏和血管的药物(如苯并硫代丫庚因),镇咳祛痰剂(如酮替芬,妥洛特罗和曲尼司特),用于改善脑循环和新陈代谢的药剂(如长春西汀),维他命,多肽类激素(如促黄体生成激素释放激素和促甲状腺激素释放激素),周血管扩张剂,免疫调节剂(如多糖,金洛芬和氯苯扎利),利胆药(如熊去氧胆酸),利尿剂(如氢氟噻嗪),抗糖尿病药剂(如甲苯磺丁脲),治疗痛风的药剂(如秋水仙硷),等等。它们的治疗有效量根据复合的目的而变化,但一般来说优选使用0.1~10重量%的复合量。在没有因其相互作用而产生不利的情况下,必要时可将这些药物的两种或多种结合使用。
在本发明的可经皮吸收的基质组合物中,苯乙烯-异戊二烯-苯乙烯嵌段共聚物、软化剂、增稠树脂和己二醇的结合可以含有不能从常规的橡胶型基质组合物来预知的大量的药物,而且能够释放在单独使用丙烯酸型组合物时所不能达到的高剂量的药物。
另外,己二醇可以在基本不溶解该基质组合物的成分特别是苯乙烯-异戊二烯-苯乙烯嵌段共聚物或者其溶解性本质上可以忽略的范围内使用,从而获得良好的内聚力和稳定性。
这些成分相对于制剂的总量的含量如下所列。
即,10~30重量%,优选13~27重量%,或者更优选15~25重量%的苯乙烯-异戊二烯-苯乙烯嵌段共聚物;10~60重量%,优选12~55重量%,或者更优选15~50重量%的软化剂;以及20~60重量%,优选23~57重量%,或者更优选25~50重量%的增稠树脂。上述范围的结合对达到本发明的目的是最有效的。
当苯乙烯-异戊二烯-苯乙烯嵌段共聚物的含量低于上述范围时,内聚力不够,而当高于上述范围时,制剂的柔韧性很差,导致粘合性产生问题。当软化剂的含量低于上述范围时,制剂的柔韧性很差,导致粘合性产生问题,而当高于上述范围时,柔韧性变得很大但制剂的内聚力存在问题。增稠树脂在上述范围内时具有合适的厚度和与己二醇的相溶性。如果增稠树脂超出上述范围,则不能获得有效的己二醇的复合和有效的己二醇的吸附加速效应。
本发明的成分之一己二醇已被用于作为化妆品材料的增湿剂和抗菌剂,但是在本发明中,己二醇是作为药物成分的吸附加速剂和/或增溶剂以有效量进行复合,且其复合量为1~10重量%,优选1.5~8重量%,或者更优选2~7重量%。当复合量低于1重量%时,其对基质组合物的稳定性和对药物成分的溶解性和吸附加速性的效果不足,而当大于10重量%时,会产生己二醇的渗出。
虽然不使用其它吸附加速剂或增溶剂而单独使用己二醇是优选的,但与本发明的可经皮吸收的基质组合物复合的己二醇也可以与其它的吸附加速剂和/或增溶剂结合使用。
在本发明的可经皮吸收制剂中片剂是优选的,而且本发明的可经皮吸收片剂可以按照这样的方式制备,即由药物和可经皮吸收基质组合物组成的含药物的层基本上是以单层的形式形成,但如果对药物的吸收没有影响,也可以形成其它层以得到多层产品。
关于本发明可经皮吸收片剂的剂型,硬膏剂是优选的,而基本无水的硬膏剂是特别优选的。
苯乙烯-异戊二烯-苯乙烯嵌段共聚物的例子是由壳牌化学品公司生产的产品(商标名为Cariflex TR-1107和Cariflex TR-1111),由日本合成橡胶公司生产的产品(商标名为JSR 5000和JSR5100),以及由Nippon Zeon公司生产的产品(商标名为Quintac 3421)。
软化剂的例子是液体石蜡,聚丁烯,蓖麻油,棉籽油,棕榈油,椰子油和加工油。
增稠树脂的例子是脂环饱和烃树脂(如Arkon P-100(商标名)),甘油松香酯(如KE-311和KE-100(商标名));以及Super Ester S-100(商标名),氢化脂环烃(如Escorez 5300(商标名)),萜烯类的加氢树脂(如Clearon P-105(商标名))和加氢甘油松香酯(如Foral 105(商标名))。
作为本发明中的载体的薄膜具有优良的防止药物的泄漏、挥发和吸附的所谓屏障性能。当该薄膜施用于皮肤上时具有合适的柔韧性也是优选的。只要上述条件得到满足,对该载体的材料没有特别的限制,该材料的具体例子是铝、乙烯-醋酸乙烯酯共聚物或其皂化产物、醋酸纤维素、纤维素、尼龙、聚酯、聚乙烯、聚偏二氯乙烯、聚碳酸酯、聚乙烯醇和聚丙烯。这些材料可以制成薄膜状,或者如果需要可制成纸或布的形式然后用一种薄膜制成箔以得到层状薄膜,或者用铝或陶瓷进行蒸气沉积以使其屏障性能能够改善。
关于作为可释放衬垫层的薄膜,其必须在制剂保存期间能抑制药物层的泄漏、挥发等,另外当制剂使用时所说可释放衬垫层能够被释放和去除。可以使用的用于可释放衬垫薄膜的材料的具体例子是铝、纤维素、聚酯、聚乙烯和聚丙烯,必要时该薄膜可以为层状。而且其表面可以用硅氧烷或氟碳化合物或已知的可以复合在该衬垫材料中的添加剂进行处理,以调节其释放能力或屏障性能。也可以对可释放衬垫上的释放进行挤压,以使释放的控制更容易。
另外为了粘合性、安全性和稳定性的调节,必要时可以复合已知的添加剂。例如其中可以含有合适量的增稠剂或粘合剂(如聚异丁烯),抗氧化剂(如二丁基羟基甲苯),吸水聚合物(如SumikagelSP-520(商标名),Aquakeep 10SH(商标名),Arasorb 800F(商标名)和Sunwet 1M-1000MPS(商标名)),无机填充剂(如氧化锌,碳酸钙,二氧化钛和硅胶),溶解助剂(如甘油脂肪酸酯(例如Excel(商标名))和克罗米能),吸附加速剂(如脂肪醇(例如Kalcohl(商标名))),以及增湿剂(如柠檬酸三乙酯,聚乙二醇和甘油)。
下面将描述本发明的可经皮吸收制剂的制备方法。该可经皮吸收制剂可以,例如,用这样一种方式制备,即,除了药物成分和己二醇以外的用于基质组合物的所有成分都在加热下溶解,然后将药物成分和己二醇加入其中并混合均匀,将所得混合物铺展在上述载体上,必要时再用一种衬垫覆盖,然后将其切成所希望的形状而得产品。或者当铺展在一种已经过可释放处理的薄膜上以后,将其用压力转移到一种合适的载体上而得产品。也可以将所有成分溶解在一种有机溶剂如己烷、甲苯或乙酸乙酯中,将该溶液铺展在上述载体上,从其中除去有机溶剂,将残留物用一种衬垫覆盖,并切成所希望的形状而得产品,或者也可以当铺展在一种已经过可释放处理的薄膜上以后,将其用压力转移到一种合适的载体上而得产品。
本发明的可经皮吸收制剂,优选可经皮吸收片剂的优点是,药物成分的溶解性、稳定性和皮肤渗透性得到加强,并获得了基质组合物的良好的内聚力和稳定的物理性质。
本发明的可经皮吸收制剂在药物的组成方面具有很高的自由度,因此对药物功效的合适的设计具有很大的优点。实施例
本发明的可经皮吸收片剂将通过下面的实施例和测试例得到更详细的说明,但本发明并不局限于此。
在这些实施例和测试例中所有的含量都以重量%表示。实施例1
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 10
液体石蜡 60
增稠剂(脂环饱和烃树脂;商标名为Arkon P-100) 20
聚异丁烯 7.4
己二醇 1
二丁基羟基甲苯 1
*** 0.1
炔洛酮醋酸酯 0.5
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例2
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 30
液体石蜡 10
增稠剂(甘油松香酯;商标名为KE-311) 24
聚异丁烯 10
己二醇 10
二丁基羟基甲苯 1
*** 5
炔洛酮醋酸酯 10
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例3
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 29
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 10
己二醇 7
二丁基羟基甲苯 1
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例4
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 35
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 10
己二醇 1
二丁基羟基甲苯 1
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例5
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 24
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 12
己二醇 10
二丁基羟基甲苯 1
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例6
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 21
增稠剂(加氢甘油松香酯;商标名为Foral 105) 25
聚异丁烯 10
己二醇 8
二丁基羟基甲苯 1
*** 5
炔洛酮醋酸酯 10
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例7
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 15
液体石蜡 15
增稠剂(加氢甘油松香酯;商标名为Foral 105) 60
聚异丁烯 7.4
己二醇 1
二丁基羟基甲苯 1
*** 0.1
炔洛酮醋酸酯 0.5
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。实施例8
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 30
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 10
己二醇 7
二丁基羟基甲苯 1
奥昔布宁 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到奥昔布宁的制剂。实施例9
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 35
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 10
己二醇 1
二丁基羟基甲苯 1
替托尼定 3
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到替托尼定的制剂。实施例10
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 24
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 12
己二醇 10
二丁基羟基甲苯 1
酮洛芬 3
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到酮洛芬的制剂。实施例11
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 28
增稠剂(加氢甘油松香酯;商标名为Foral 105) 25
聚异丁烯 15
己二醇 8
二丁基羟基甲苯 1
枯兰西龙 3
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到枯兰西龙的制剂。实施例12
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 15
液体石蜡 15
增稠剂(加氢甘油松香酯;商标名为Foral 105) 58.6
聚异丁烯 7.4
己二醇 1
二丁基羟基甲苯 1
妥洛特罗(Tulobuterol) 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到妥洛特罗的制剂。对比例1(没有复合己二醇)
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 36
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 10
二丁基羟基甲苯 1
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。对比例2(用克罗米能作为增溶剂)
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 29
增稠剂(加氢甘油松香酯;商标名为Foral 105) 30
聚异丁烯 10
克罗米能 7
二丁基羟基甲苯 1
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。对比例3(丙烯酸基质组合物)
TS-620(丙烯酸甲酯和丙烯酸2-乙基己基酯的共聚 89
树脂的乳剂;由日本碳化物公司制造)
己二醇 8
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。对比例4
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 5
液体石蜡 65
增稠剂(加氢甘油松香酯;商标名为Foral 105) 10
聚异丁烯 3.4
己二醇 15
二丁基羟基甲苯 1
*** 0.1
炔洛酮醋酸酯 0.5
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。对比例5
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 35
液体石蜡 5
增稠剂(加氢甘油松香酯;商标名为Foral 105) 32
聚异丁烯 3
己二醇 7
二丁基羟基甲苯 1
*** 6
炔洛酮醋酸酯 11
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。对比例6
苯乙烯-异戊二烯-苯乙烯嵌段共聚物 20
液体石蜡 29
增稠剂(加氢甘油松香酯;商标名为Foral 105) 36.5
聚异丁烯 10
己二醇 0.5
二丁基羟基甲苯 1
*** 1
炔洛酮醋酸酯 2
对该配方使用前面描述的制备方法,然后切成所希望的大小,得到***和醋酸炔诺酮的混合制剂。测试例
测试例1(基质组合物中药物成分的溶解性的稳定性试验)
将实施例1,2,3,4,5,6,7和对比例1,4,6的试验片分别在50℃下保存三个月,并观察其从片中的渗液情况或晶体的析出情况。其结果列于表1中。观察到对比例1和6的片析出晶体,对比例4的片渗出己二醇。而所有实施例的片没有观察到晶体的析出现象或者渗液现象。
表1
测试例2(性质的验证)
50℃保存三个月所观察到的晶化情况 | 50℃保存三个月所观察到的渗液情况 | |
实施例1 | 没有晶体析出 | 没有渗液 |
实施例2 | 没有晶体析出 | 没有渗液 |
实施例3 | 没有晶体析出 | 没有渗液 |
实施例4 | 没有晶体析出 | 没有渗液 |
实施例5 | 没有晶体析出 | 没有渗液 |
实施例6 | 没有晶体析出 | 没有渗液 |
实施例7 | 没有晶体析出 | 没有渗液 |
对比例1 | 有晶体析出 | 没有渗液 |
对比例4 | 没有晶体析出 | 有渗液 |
对比例6 | 有晶体析出 | 没有渗液 |
将实施例3和对比例2,4的试验片分别在50℃下保存三个月,并观察每个试验片的外观和性质。其结果列于表2中。在实施例3的片中没有观察到基质组合物的流出,而对比例2和4的片观察到了基质的流出。
表2
测试例3(皮肤渗透试验)
50℃保存三个月 | |
实施例3 | 没有变化 |
对比例2 | 观察到流出 |
对比例4 | 观察到流出 |
将实施例3和对比例2,3的试验片分别用无毛老鼠(6个星期大;雌性)背部的皮用Franz型渗滤池进行渗透试验(温度为37℃)。在试验开始后的每个预定时间收集接收池的溶液并在其后立即补充接收池的溶液。进入接收池溶液的药物的渗透量用高效液相色谱进行测定。每个测试片的样品数为3。其结果如图1和图2所示。与对比例2和3的样品相比,实施例3的样品表现出更好的药物渗透性。测试例4(释放试验)
用圆筒旋转法对实施例3和对比例1,6的试验片进行释放试验。测试条件为:测试溶液900毫升,测试溶液温度32.0±0.5℃,圆筒转速50转/分。其结果如图3和图4所示。与对比例1和6的试验片相比,实施例3的试验片具有良好的药物成分释放性能。测试例5(粘合性试验)
按照下列方法对实施例1,2,3和对比例4,5的试验片进行粘合性试验。即将一种试验片在10个人(健康的正常人;男性)的臂上施用24小时,然后评价其粘合力。其结果列于表3中。在对比例中大多数情况下观察到1/2以上的剥落,而在实施例中大多数情况下没有观察到剥落。
表3
没有剥落 | 边缘剥落 | 1/4剥落 | 1/2剥落 | 3/4剥落 | 散开 | 总数 | |
实施例1 | 9 | - | 1 | - | - | - | 10 |
实施例2 | 8 | 1 | 1 | - | - | - | 10 |
实施例3 | 9 | 1 | - | - | - | - | 10 |
对比例4 | - | - | - | 1 | 3 | 6 | 10 |
对比例5 | - | - | 1 | 7 | 1 | 1 | 10 |
Claims (9)
1.一种经皮吸收用基质组合物,该组合物含有苯乙烯-异戊二烯-苯乙烯嵌段共聚物、软化剂、增稠树脂和己二醇。
2.按照权利要求1的经皮吸收用基质组合物,其中己二醇的含量为1~10重量%。
3.按照权利要求1或2的经皮吸收用基质组合物,其中相对于制剂的总量含有10~30重量%的苯乙烯-异戊二烯-苯乙烯嵌段共聚物,10~60重量%的软化剂,20~60重量%的增稠树脂,以及1~10重量%的己二醇。
4.按照权利要求1~3中任意一种的经皮吸收用基质组合物,其中己二醇是一种对药物的吸收加速剂和/或增溶剂。
5.一种可经皮吸收的制剂,该制剂是在按照权利要求1~4中任意一种的经皮吸收用基质组合物中含有药物。
6.按照权利要求5的可经皮吸收制剂,其中复合有0.1~10重量%的药物。
7.按照权利要求5或6的可经皮吸收制剂,其中的药物为卵泡激素和/或黄体激素。
8.按照权利要求7的可经皮吸收制剂,其中的卵泡激素为***或其衍生物,其复合量为0.1~5重量%。
9.按照权利要求7的可经皮吸收制剂,其中的黄体激素为炔诺酮、醋酸炔诺酮、或者它们的衍生物,其复合量为0.5~10重量%。
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JP11525497 | 1997-04-16 | ||
JP115254/1997 | 1997-04-16 |
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EP (1) | EP0976405A4 (zh) |
CN (1) | CN1252004A (zh) |
AU (1) | AU723018B2 (zh) |
BR (1) | BR9808594A (zh) |
CA (1) | CA2287463A1 (zh) |
ID (1) | ID23512A (zh) |
NO (1) | NO995032D0 (zh) |
WO (1) | WO1998046267A1 (zh) |
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EP1278778A2 (en) * | 2000-05-03 | 2003-01-29 | Amgen Inc., | Modified peptides, comprising an fc domain, as therapeutic agents |
US6914169B1 (en) | 2000-05-19 | 2005-07-05 | Hisamitsu Pharmaceutical., Inc. | Patch agent |
DE10236319A1 (de) * | 2002-08-08 | 2004-02-19 | Beiersdorf Ag | Hautfreundliche Wirkstoffpflaster auf der Basis von SBC mit mindestens einem pharmazeutischen Wirkstoff mit einem Gehalt von mindestens 34 Gew.-% und dessen Herstellung |
EA008098B1 (ru) | 2003-02-21 | 2007-02-27 | Шеринг Акциенгезельшафт | Стойкий к уф-излучению трансдермальный пластырь |
JP4422430B2 (ja) | 2003-05-14 | 2010-02-24 | 帝國製薬株式会社 | エストロゲン及び/又はプロゲストゲン含有外用貼付剤 |
US8668925B2 (en) | 2003-12-12 | 2014-03-11 | Bayer Intellectual Property Gmbh | Transdermal delivery of hormones without the need of penetration enhancers |
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ATE120368T1 (de) * | 1990-05-17 | 1995-04-15 | Hisamitsu Pharmaceutical Co | Estradiol enthaltende transdermale zubereitung. |
JP2971224B2 (ja) * | 1991-11-30 | 1999-11-02 | 久光製薬株式会社 | エストラジオール経皮吸収貼付剤 |
JPH0853338A (ja) * | 1994-08-11 | 1996-02-27 | Shiseido Co Ltd | 皮膚外用剤 |
EP0746311B1 (en) * | 1994-12-24 | 2001-07-11 | Pacific Corporation | Medicinal patches for percutaneous administration |
-
1998
- 1998-04-16 AU AU68525/98A patent/AU723018B2/en not_active Ceased
- 1998-04-16 ID IDW991380A patent/ID23512A/id unknown
- 1998-04-16 WO PCT/JP1998/001745 patent/WO1998046267A1/ja not_active Application Discontinuation
- 1998-04-16 BR BR9808594-8A patent/BR9808594A/pt not_active Application Discontinuation
- 1998-04-16 CN CN 98804063 patent/CN1252004A/zh active Pending
- 1998-04-16 EP EP98914050A patent/EP0976405A4/en not_active Withdrawn
- 1998-04-16 CA CA002287463A patent/CA2287463A1/en not_active Abandoned
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1999
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EP0976405A1 (en) | 2000-02-02 |
EP0976405A4 (en) | 2000-12-06 |
BR9808594A (pt) | 2000-05-23 |
NO995032L (no) | 1999-10-15 |
ID23512A (id) | 2000-04-27 |
WO1998046267A1 (fr) | 1998-10-22 |
AU6852598A (en) | 1998-11-11 |
AU723018B2 (en) | 2000-08-17 |
CA2287463A1 (en) | 1998-10-22 |
NO995032D0 (no) | 1999-10-15 |
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