CN105939729A - 皮肤渗透促进组合物、经皮给药制剂及贴附制剂 - Google Patents
皮肤渗透促进组合物、经皮给药制剂及贴附制剂 Download PDFInfo
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Abstract
本发明提供能够不必使药物成形为颗粒结构等、不伴有皮肤组织的破坏地飞跃性地提高药物的皮肤渗透性的皮肤渗透促进组合物。另外,还提供含有该皮肤渗透促进组合物的经皮给药制剂及贴附制剂。所述皮肤渗透促进组合物含有类黄酮化合物,被用于促进药物的皮肤渗透。
Description
技术领域
本发明涉及用于促进药物的皮肤渗透的皮肤渗透促进组合物,特别涉及能够不必使药物成形为颗粒结构等、不伴有皮肤组织的破坏地飞跃性地提高药物的皮肤渗透性的皮肤渗透促进组合物。另外,本发明还涉及含有该皮肤渗透促进组合物的经皮给药制剂及贴附制剂。
背景技术
经皮给药制剂是以实现非侵入性给药、回避肝脏首过效应、减轻消化道副作用等作为目的而受到关注的剂型。
对于经皮给药,主药为了显示出药效需要渗透最坚固的生物屏障即皮肤组织,因此,使用各种物质作为药物的渗透促进剂。作为供于经皮给药的制剂,例如,已知有含有烷醇胺、表面活性剂、醇或其酯类或者其醚类、脂肪酸或其酯类、萜类等作为渗透促进剂的经皮吸收型贴附剂(专利文献1);含有克罗米通作为渗透促进剂的经皮吸收贴附剂(专利文献2)。
但是,即使使用这些渗透促进剂,也仍然存在对很多生理活性药物的皮肤渗透的促进不充分、或者若配混可发挥充分的促进效果的渗透促进剂量则会发生皮肤组织的破坏的问题,使药物的皮肤渗透性提高是非常困难的。
作为其它方法,例如,还提出了使用微针等来破坏一部分皮肤结构的方法(专利文献3)、通过将药物制成平均粒径为规定值以下的微粒来使其容易通过角质的间隙的方法(专利文献4)等。
但是,对于以往的使用强力的渗透促进剂的方法及使用微针等破坏一部分皮肤结构的方法而言,若要提高促进效果,则会伴随其使皮肤的结构明显变化,因此,为了获得治疗效果,对需要维持皮肤的正常功能的体系而言并不优选,而且有产生皮肤刺激等副反应的担心。另外,使药物颗粒化的方法局限在能够成形为颗粒结构的药物,而且在颗粒化的过程中有破坏药物的结构、活性等的担心。
现有技术文献
专利文献
专利文献1:日本特开2013-79220号公报
专利文献2:日本特开平10-279474号公报
专利文献3:日本特许第5032121号公报
专利文献4:日本特开2012-206979号公报
发明内容
发明要解决的问题
鉴于上述现状,本发明的目的在于,提供能够不必使药物成形为颗粒结构等、不伴有皮肤组织的破坏地飞跃性地提高药物的皮肤渗透性的皮肤渗透促进组合物。另外,本发明的目的还在于,提供含有该皮肤渗透促进组合物的经皮给药制剂及贴附制剂。
用于解决问题的方案
为了解决上述课题,本发明人等着眼于使用类黄酮化合物作为药物的渗透促进剂。关于类黄酮化合物对皮肤的作用,例如,公开了由促进胶原蛋白产生而获得的皮肤保护作用(日本特开2008-260747号公报),但尚不清楚对生理活性药物的皮肤渗透性的效果。
本发明人等进行了深入研究,结果发现,通过将类黄酮化合物与药物一起配混到经皮给药制剂中,能够基本不伴有对皮肤的刺激性及伤害性地、飞跃性地提高药物的皮肤渗透性,从而完成了本发明。
即,本发明为含有类黄酮化合物的用于促进药物的皮肤渗透的皮肤渗透促进组合物。
上述类黄酮化合物优选为具有下述化学式(1)所示的黄酮骨架的化合物。
具有上述化学式(1)所示的黄酮骨架的化合物优选为选自由槲皮素、芹菜素及杨梅酮组成的组中的至少1种。
另外,本发明为含有药物和本发明的皮肤渗透促进组合物的经皮给药制剂。
另外,本发明为具有含有药物和本发明的皮肤渗透促进组合物的含药层的贴附制剂。
以下对本发明详细地进行说明。
本发明为含有类黄酮化合物的用于促进药物的皮肤渗透的皮肤渗透促进组合物。
通过含有上述类黄酮化合物,本发明的皮肤渗透促进组合物能够不伴有皮肤组织的破坏地飞跃性地提高药物的皮肤渗透性。
作为上述类黄酮化合物,例如可列举出具有黄酮骨架的化合物、具有异黄酮骨架的化合物、儿茶素化合物等。其中,优选具有下述化学式(1)所示的黄酮骨架的化合物。
作为具有上述化学式(1)所示的黄酮骨架的化合物,没有特别限定,可以适宜地使用黄酮、黄酮醇、黄烷酮、羟基黄酮、甲氧基黄酮、二羟基黄酮、黄芩素、三羟基黄酮、羟基黄酮醇、高良姜素、漆黄素、桑色素、异鼠李素、刺槐亭、栎草亭、柚皮素、柚皮苷、圣草酚、橙皮素(Hesperetin)、刺芒柄花素、绿脓菌素A、芹菜素、白杨素、花青素、橙皮苷、山奈酚、杨梅酮、川陈皮素、槲皮素、芸香苷、硫磺菊素、桔皮素(Tangeretin)、木犀草素及它们的药学上可接受的盐。这些具有黄酮骨架的化合物可以单独使用,也可以组合使用2种以上。其中,优选选自由槲皮素、芹菜素及杨梅酮组成的组中的至少1种。
作为上述具有异黄酮骨架的化合物,没有特别限定,例如可列举出:异黄酮、染料木黄酮、黄豆苷(Daidzin)、染料木苷、黄豆黄苷(Glycitin)、黄豆苷元、黄豆黄素(Glycitein)、6”-O-乙酰黄豆苷、6”-O-乙酰染料木苷、6”-O-乙酰黄豆黄苷、6”-O-丙二酰黄豆苷、6”-O-丙二酰染料木苷、6”-O-丙二酰黄豆黄苷等。这些具有异黄酮骨架的化合物可以单独使用,也可以组合使用2种以上。
作为上述儿茶素化合物,没有特别限定,例如可列举出:儿茶素、表儿茶素、没食子儿茶素、表没食子儿茶素、儿茶素没食子酸酯、表儿茶素没食子酸酯、没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯等。这些儿茶素化合物可以单独使用,也可以组合使用2种以上。
本发明的皮肤渗透促进组合物还可以含有表面活性剂。通过组合使用上述类黄酮化合物和表面活性剂,药物的皮肤渗透性会进一步提高。
作为上述表面活性剂,没有特别限定,可列举出离子性表面活性剂、非离子性表面活性剂等。
对于本发明的皮肤渗透促进组合物的用途而言,只要是用于促进药物的皮肤渗透的用途就没有特别限定,优选将本发明的皮肤渗透促进组合物与药物混合来供于经皮给药。
另外,含有药物和本发明的皮肤渗透促进组合物的经皮给药制剂也是本发明的1个方面。
从药物的皮肤渗透效果的观点出发,本发明的经皮给药制剂中的上述类黄酮化合物的含量优选相对于药物100重量份为0.1~10000重量份。上述类黄酮化合物的含量的更优选的下限为1重量份、更优选的上限为1000重量份、进一步优选的下限为10重量份。
对上述药物没有特别限定,例如可列举出:镇静剂、祛痰剂、泻剂、抗癌剂、糖尿病药、抗帕金森病药、抗抑郁药、镇静药、痴呆症药、降压剂、高脂血症药、偏头痛药、骨质疏松治疗药、低血压治疗药、镇咳剂、消化性溃疡用剂、尿频排尿障害药、尿失禁药、抗溃疡药、抗过敏药、5-HT3受体拮抗药(止吐药)、抗原肽、抗原蛋白质、核酸等。上述药物适宜为没有皮肤刺激性的药物,但即使是有皮肤刺激性的药物,也可以通过使其同时含有消炎药来适宜地使用。其中,更适宜使用酸性药物或形成水溶性盐的药物。这是因为:这些药物不易与上述类黄酮化合物中富含的酚性羟基相互作用,不易阻碍上述类黄酮化合物的效果。
作为本发明的经皮给药制剂的剂型,没有特别限定,例如,可列举出:软膏剂、乳膏剂、液体制剂、洗剂、搽剂、巴布剂、硬膏剂(plaster剂)、贴附剂(例如薄膜、带等)等。其中,优选贴附剂。
另外,具有包含药物和本发明的皮肤渗透促进组合物的含药层的贴附制剂也是本发明的1个方面。
对上述含药层中的上述类黄酮化合物的含量没有特别限定,优选为上述含药层中所含有的固体成分总重量中的0.01~80重量%。上述含量小于0.01重量%时,有时上述类黄酮化合物不到达皮肤,不会充分显示出药物的皮肤渗透促进作用。上述含量超过80重量%时,有时上述含药层无法保持上述类黄酮化合物,贴附制剂向皮肤表面的贴附变困难。上述含量的更优选的下限为0.05重量%、更优选的上限为30重量%。
上述药物可以溶解在上述含药层中,也可以分散在上述含药层中。
对上述含药层中的上述药物的含量没有特别限定,因使用的药物的性质等而不同,优选为上述含药层中所含有的固体成分总重量中的0.01~60重量%。上述含量小于0.01重量%时,有时上述药物不到达皮肤,不会显示出充分的药效。上述含量超过60重量%时,有时上述含药层无法保持上述药物,贴附制剂向皮肤表面的贴附变困难。
对上述含药层的厚度没有特别限定,优选为10~1000μm、更优选20~500μm、进一步优选30~200μm。上述含药层的厚度小于10μm时,有时难以使其含有有效量的上述药物及上述类黄酮化合物,或者在上述含药层需要粘合性的情况下难以获得充分的粘合力。上述含药层的厚度超过1000μm时,有时会对上述含药层的形成造成障碍(涂布困难)。
本发明的贴附制剂优选为如下的贴附制剂:上述含药层为含药粘合层且在支承体的单面具有该含药粘合层的贴附制剂(所谓骨架型贴附制剂)。其中,本发明的贴附制剂也可以是上述含药层为药物贮藏层且在支承体的单面具有该药物贮藏层和粘合层的贴附制剂(所谓贮库型贴附制剂)。在贮库型贴附制剂的情况下,优选在上述药物贮藏层与上述粘合层之间还设置有药物渗透控制膜。
需要说明的是,出于保护、保存性等目的可以在上述含药粘合层或上述粘合层上层叠剥离衬垫。
图1为示意性地示出本发明的贴附制剂(骨架型贴附制剂)的一例的截面图。如图1所示,在本发明的贴附制剂(骨架型贴附制剂)1中,在支承体6的单面层叠有含有药物和本发明的皮肤渗透促进组合物的含药粘合层7、剥离衬垫2。
作为构成上述含药粘合层的树脂,优选粘合性聚合物。
作为上述粘合性聚合物,没有特别限定,可列举出:包括(甲基)丙烯酸酯系聚合物在内的丙烯酸系聚合物;苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物、聚异戊二烯、聚异丁烯、聚丁二烯等橡胶系聚合物;有机硅橡胶、以二甲基硅氧烷为基础、以二苯基硅氧烷为基础等的有机硅系聚合物;聚乙烯基甲基醚、聚乙烯基乙基醚、聚乙烯基异丁基醚等乙烯基醚系聚合物;乙酸乙烯酯-乙烯共聚物等乙烯基酯系聚合物;对苯二甲酸二甲酯、间苯二甲酸二甲酯、邻苯二甲酸二甲酯等由羧酸成分和多元醇成分(乙二醇等)形成的酯系聚合物等。其中,从上述类黄酮化合物的保持性优异的方面考虑,优选橡胶系聚合物。
作为上述丙烯酸系聚合物,优选以(甲基)丙烯酸烷基酯作为主要成分且使其与官能性单体共聚而得到的聚合物。即,优选以下的共聚物:含有优选50~99重量%(更优选为60~95重量%)的由上述(甲基)丙烯酸烷基酯构成的单体成分、且剩余的单体成分由官能性单体构成的共聚物。此处所说的主要成分是指在构成共聚物的单体成分的总重量之中占50重量%以上的单体成分。
上述(甲基)丙烯酸烷基酯优选具有碳数4~13的直链或支链烷基(例如丁基、戊基、己基、庚基、辛基、2-乙基己基、壬基、癸基、十一烷基、十二烷基、十三烷基等)作为烷基。这些(甲基)丙烯酸烷基酯可以单独使用,也可以组合使用2种以上。
上述官能性单体在分子内具有至少1个参与共聚反应的不饱和双键并且在侧链具有官能团,例如可列举出:(甲基)丙烯酸、衣康酸、马来酸、马来酸酐等含羧基的单体;(甲基)丙烯酸羟乙酯、(甲基)丙烯酸羟丙酯等含羟基的单体;苯乙烯磺酸、烯丙基磺酸、(甲基)丙烯酸磺丙酯、(甲基)丙烯酰氧基萘磺酸、丙烯酰胺甲基丙磺酸等含磺酸基的单体;(甲基)丙烯酸氨基乙酯、(甲基)丙烯酸二甲基氨基乙酯、(甲基)丙烯酸叔丁基氨基乙酯等含氨基的单体;(甲基)丙烯酰胺、二甲基(甲基)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、N-乙烯基乙酰胺等含酰胺基的单体;(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)丙烯酸甲氧基聚丙二醇酯、(甲基)丙烯酸四氢呋喃酯等含烷氧基的单体。这些官能性单体可以单独使用,也可以组合使用2种以上。其中,从上述含药粘合层的压敏粘合性、聚集性、上述含药粘合层中所含有的药物的释放性等观点出发,优选含羧基的单体,特别优选(甲基)丙烯酸。
作为上述丙烯酸系聚合物,也可以使用使上述(甲基)丙烯酸烷基酯和上述官能性单体进一步共聚其它单体而得到的聚合物。
作为上述其它单体,例如可列举出:(甲基)丙烯腈、乙酸乙烯酯、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、乙烯基吡咯、乙烯基咪唑、乙烯基己内酰胺、乙烯基噁唑等。这些其它单体可以单独使用,也可以组合使用2种以上。
上述其它单体的使用量相对于上述(甲基)丙烯酸烷基酯和上述官能性单体的总重量通常优选为0~40重量%左右、更优选为10~30重量%左右。
作为上述丙烯酸系聚合物的具体例,从对人皮肤的粘接性良好、粘接及剥离的重复容易的观点出发,优选作为(甲基)丙烯酸烷基酯的丙烯酸2-乙基己酯与丙烯酸与N-乙烯基-2-吡咯烷酮的三元共聚物,更优选使丙烯酸2-乙基己酯与丙烯酸与N-乙烯基-2-吡咯烷酮以40~99.8:0.1~10:0.1~50的重量比、优选50~89:1~8:10~40的重量比共聚而得到的共聚物。
上述橡胶系聚合物优选为将选自由聚异丁烯、聚异戊二烯及苯乙烯-二烯-苯乙烯嵌段共聚物(苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS)等)组成的组中的至少1种作为主要成分的橡胶系聚合物。其中,从药物稳定性高、能够兼顾所需的粘接力及聚集力的观点出发,特别优选将粘均分子量优选为180万~550万、更优选为200万~500万的高分子量聚异丁烯和粘均分子量优选为4万~8万5千、更优选为4万5千~6万5千的低分子量聚异丁烯以95:5~5:95的重量比进行配混而得到的混合物。
在含有上述橡胶系聚合物的情况下,上述含药粘合层优选还含有增粘剂。通过进一步配混增粘剂,能够提高常温下的上述含药粘合层的粘合性。
对上述增粘剂没有特别限定,适宜选择本技术领域中公知的物质来使用即可,例如可列举出:石油系树脂(例如芳香族系石油树脂、脂肪族系石油树脂等)、萜系树脂、松香系树脂、香豆酮-茚树脂、苯乙烯系树脂(例如苯乙烯树脂、聚(α-甲基苯乙烯)等)、氢化石油树脂(例如脂环族饱和烃树脂等)等。这些增粘剂可以单独使用,也可以组合使用2种以上。其中,为了使药物的稳定性良好,适宜的为脂环族饱和烃树脂。
上述增粘剂的含量相对于上述橡胶系聚合物的总重量通常优选为33~300重量%、更优选为50~200重量%。
上述含药粘合层优选还含有增塑剂。
上述增塑剂只要具有使上述粘合性聚合物塑化从而对上述含药粘合层赋予柔和感、能够减少由从皮肤剥离贴附制剂时的皮肤粘接力所引起的疼痛、皮肤刺激性的作用,就没有特别限定。
作为上述增塑剂,可列举出:橄榄油、蓖麻油、角鲨烯、羊毛脂等油脂类;癸基甲基亚砜、甲基辛基亚砜、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、甲基吡咯烷酮、十二烷基吡咯烷酮等有机溶剂类;山梨糖醇酐脂肪酸酯、聚氧乙烯脂肪酸酯等表面活性剂类;邻苯二甲酸二丁酯、邻苯二甲酸二庚酯、邻苯二甲酸二辛酯等邻苯二甲酸酯类;癸二酸二乙酯、癸二酸二丁酯、癸二酸二辛酯等癸二酸酯类;液体石蜡等烃类;油酸乙酯、己二酸二异丙酯、棕榈酸异丙酯、棕榈酸辛酯、肉豆蔻酸异丙酯、肉豆蔻酸异十三烷基酯、月桂酸乙酯等脂肪酸酯类;甘油脂肪酸酯、丙二醇脂肪酸酯、乙氧基化硬脂醇、吡咯烷酮羧酸脂肪酸酯等。这些增塑剂可以单独使用,也可以组合使用2种以上。
上述增塑剂优选在上述含药粘合层100重量%中含有1~70重量%,更优选含有20~60重量%。
可以在上述含药粘合层中导入交联结构。在这种情况下,可以对上述含药粘合层实施基于紫外线照射、电子射线照射等辐射线照射的物理交联处理、或者实施使用了异氰酸酯系化合物(例如三官能性异氰酸酯等)、有机过氧化物、有机金属盐、金属醇盐、金属螯合物、多官能性化合物(例如多官能性外部交联剂、二(甲基)丙烯酸酯等多官能性内部交联用单体等)等交联剂的化学交联处理。
在实施化学交联处理的情况下,将上述交联剂与药物和本发明的皮肤渗透促进组合物一起配混到含药粘合剂溶液或分散液中,在支承体的单面涂布含药粘合剂溶液或分散液,进行干燥从而形成含药粘合层后,将剥离衬垫的剥离处理面粘贴在含药粘合层上,在优选60~90℃、更优选60~70℃下放置24~48小时来促进交联反应,从而形成导入了交联结构的含药粘合层。需要说明的是,也可以在剥离衬垫的剥离处理面涂布含药粘合剂溶液或分散液并将形成的含药粘合层转印到支承体。
对上述支承体没有特别限定,具体而言,可列举出:聚酯(例如聚对苯二甲酸乙二醇酯(PET)等)、尼龙、聚氯乙烯、聚乙烯、聚丙烯、乙烯-乙酸乙烯酯共聚物、聚四氟乙烯、离子键树脂等的单独薄膜、金属箔、及将选自它们中的1种或2种以上薄膜层叠而得到的层压薄膜等。其中,为了提高上述支承体与上述含药粘合层的粘接性(锚固性),优选的是,采用由上述材质形成的无孔性薄膜和后述多孔性薄膜层叠而得到的层压薄膜作为上述支承体,并在多孔性薄膜侧形成上述含药粘合层。上述无孔性薄膜的厚度优选为1~100μm、更优选为2~50μm。
作为上述多孔性薄膜,只要可提高与上述含药粘合层的锚固性就没有特别限定,例如可列举出:纸、织布、无纺布(例如聚酯(例如聚对苯二甲酸乙二醇酯(PET)等)无纺布等)、对由上述材质形成的薄膜(例如聚酯、尼龙、Saran(商品名)、聚乙烯、聚丙烯、乙烯-乙酸乙烯酯共聚物、聚氯乙烯、乙烯-丙烯酸乙酯共聚物、聚四氟乙烯、金属箔、聚对苯二甲酸乙二醇酯等的单独薄膜、及将选自它们之中的1种或2种以上薄膜层叠而得到的层压薄膜等)进行机械穿孔处理而得到的薄膜等。其中,从柔软性的方面考虑,优选纸、织布、无纺布(例如聚酯无纺布、聚对苯二甲酸乙二醇酯无纺布等)。
上述多孔性薄膜例如为织布或无纺布的情况下,从提高锚固性的方面考虑,优选将它们的单位面积重量设为5~30g/m2。
上述支承体的层压薄膜可以通过干式层压法、湿式层压法、挤出(extrusion)层压法、热熔层压、共挤出(coextrusion)层压法等公知的层压薄膜的制造方法来制造。
对上述支承体的厚度没有特别限定,优选为1~200μm、更优选为2~100μm。上述支承体的厚度小于1μm时,有自身支承性等操作性降低的倾向。上述支承体的厚度超过200μm时,产生不协调感(rough feel),有追随性降低的倾向。
作为上述剥离衬垫,可列举出:在剥离衬垫用基材的表面形成有由剥离处理剂形成的剥离处理剂层的剥离衬垫、其自身剥离性高的塑料薄膜、在剥离衬垫用基材的表面形成有由上述剥离性高的塑料薄膜形成的剥离层的剥离衬垫等。上述剥离衬垫的剥离面可以仅为剥离衬垫用基材的单面,也可以为两面。
作为上述剥离处理剂,没有特别限制,例如,可列举出含有长链烷基的聚合物、有机硅聚合物(有机硅系剥离剂)、氟系聚合物(氟系剥离剂)等。
作为上述剥离衬垫用基材,例如可列举出:聚对苯二甲酸乙二醇酯(PET)薄膜、聚酰亚胺薄膜、聚丙烯薄膜、聚乙烯薄膜、聚碳酸酯薄膜、聚酯(除PET以外)薄膜等塑料薄膜及在这些薄膜上蒸镀有金属的金属蒸镀塑料薄膜;日本纸、洋纸、牛皮纸、玻璃纸、优质纸等纸类;由无纺布、布等纤维质材料得到的基材;金属箔等。
作为上述其自身剥离性高的塑料薄膜,例如可列举出:由聚乙烯(低密度聚乙烯、线性低密度聚乙烯等)、聚丙烯、乙烯-丙烯共聚物等乙烯-α-烯烃共聚物(嵌段共聚物或无规共聚物)及它们的混合物形成的聚烯烃系薄膜;Teflon(注册商标)制薄膜等。
需要说明的是,在上述剥离衬垫用基材的表面形成的剥离层可以通过将上述剥离性高的塑料薄膜的原材料层压或涂布到上述剥离衬垫用基材上来形成。
作为上述剥离衬垫的厚度,没有特别限定,通常优选为200μm以下、更优选为25~100μm。
本发明的贴附制剂可以通过例如以下方法来制造。首先,使规定量的粘合性聚合物溶解于溶剂(例如乙酸乙酯、甲苯、己烷、二甲基亚砜、乙醇、丙醇、丙酮等)。使药物和本发明的皮肤渗透促进组合物分散或溶解于所得到的溶液中,从而制备含药粘合剂溶液或分散液。然后,在支承体的单面涂布含药粘合剂溶液或分散液,进行干燥从而形成含药粘合层后,将剥离衬垫的剥离处理面粘贴在含药粘合层上。需要说明的是,也可以在剥离衬垫的剥离处理面涂布含药粘合剂溶液或分散液并将形成的含药粘合层转印到支承体。
在上述含药粘合剂溶液或分散液的制备中产生泡的情况下,优选放置一夜或进行真空脱泡。含药粘合剂溶液或分散液向支承体的单面或剥离衬垫的涂布通过例如浇铸法、印刷、其它本领域技术人员所公知的技术方法来实施即可。
发明的效果
根据本发明,可以提供能够不必使药物成形为颗粒结构等、不伴有皮肤组织的破坏地飞跃性地提高药物的皮肤渗透性的皮肤渗透促进组合物。另外,根据本发明,还能够提供含有该皮肤渗透促进组合物的经皮给药制剂及贴附制剂。
附图说明
图1为示意性地示出本发明的贴附制剂(骨架型贴附制剂)的一例的截面图。
图2为示出在实施例及比较例中得到的贴附制剂的皮肤渗透性试验的结果的图。
图3为示出在实施例及比较例中得到的贴附制剂的皮肤渗透性试验的结果的图。
图4为示出在实施例及比较例中得到的贴附制剂的皮肤渗透性试验的结果的图。
图5为示出在实施例及比较例中得到的贴附制剂的皮肤渗透性试验的结果的图。
具体实施方式
根据以下的实施例对本发明进行具体说明,但本发明不限定于这些实施例。
(实施例1~3)
以按照组合物中的固体成分计算为63.0重量份的方式称取溶解于甲苯中的聚异丁烯和增粘剂的混合物(将聚异丁烯B200(粘均分子量400万)、聚异丁烯B12(粘均分子量5万5千)、脂环族饱和烃树脂ARKON P-100以按照固体成分计分别为24、36、40重量份的量混合而得到的混合物:以下称为PIB共混物)。接着,分别称取肉豆蔻酸异丙酯(以下称为IPM)27.0重量份作为增塑剂、聚氧乙烯(7)油烯基醚(以下称为BO-7)4.0重量份作为表面活性剂、洛索洛芬钠(形成了水溶性盐的药物)3.0重量份作为药物、下述表1所示的类黄酮化合物(槲皮素、芹菜素或杨梅酮)3.0重量份,对它们进行搅拌使它们充分脱泡,从而制备含药粘合剂分散液。
将该含药粘合剂分散液在聚酯剥离薄膜上拉伸干燥而形成厚度约60μm的含药粘合层,将其转印到厚度6μmPET薄膜-20g/m2无纺布的粘贴型的支承体,得到薄膜。将所得到的薄膜切断成0.7cm2的长方形,得到含有洛索洛芬钠的贴附制剂。
(比较例1、2)
更改为下述表1所示的组成,除此以外,与实施例1同样地操作,得到含有洛索洛芬钠的贴附制剂。需要说明的是,在比较例2中,使用类黄酮化合物以外的属于多元酚的姜黄素。
[表1]
(实施例4~6、比较例3、4)
更改为下述表2所示的组成,除此以外,与实施例1同样地操作,得到含有HER2/neu-A24肽的贴附制剂。需要说明的是,在比较例4中,使用类黄酮化合物以外的属于多元酚的姜黄素。
[表2]
(实施例7~9、比较例5~7)
更改为下述表3所示的组成,除此以外,与实施例1同样地操作,得到含有酸性药物或碱性药物的贴附制剂。
[表3]
(实施例10、比较例8)
更改为下述表所示的4组成,除此以外,与实施例1同样地操作,得到不含表面活性剂的贴附制剂。
[表4]
(实施例11~15、比较例9~13)
以按照组合物中的固体成分计算为下述表5所示的重量份的方式称取溶解于甲苯中的聚异丁烯和增粘剂的混合物(将聚异丁烯B200(粘均分子量400万)、聚异丁烯B12(粘均分子量5万5千)、脂环族饱和烃树脂ARKONP-100以按照固体成分计分别为24、36、40重量份的量混合而得到的混合物:以下称为PIB共混物)、或聚丙烯酸钠粘合剂。接着,分别称取下述表5所示的重量份的增塑剂(IPM、IPP或液体石蜡)、作为药物的洛索洛芬钠(形成了水溶性盐的药物)3.0重量份、下述表5所示的重量份的类黄酮化合物(槲皮素),对它们进行搅拌使它们充分脱泡,从而制备含药粘合剂分散液。
将该含药粘合剂分散液在聚酯剥离薄膜上拉伸干燥而形成厚度约60μm的含药粘合层,将其转印到厚度6μmPET薄膜-20g/m2无纺布的粘贴型的支承体,得到薄膜。将所得到的薄膜切断成0.7cm2的长方形,得到含有洛索洛芬钠的贴附制剂。
[表5]
<评价>
对在实施例及比较例中所得到的贴附制剂进行以下评价。
皮肤渗透性试验
通过以下的小鼠皮肤渗透性试验,对贴附制剂中所含有的药物的皮肤渗透性进行评价。
将自9周龄的C57/BL6♀采取的背部皮肤在溶解有酶抑制剂的磷酸缓冲液(以下称为接收液)中浸渍2小时。将浸渍的背部皮肤固定在Franz型渗透池中,去除多余的液滴后,将在实施例及比较例中所得到的贴附制剂贴附到背部皮肤,在Franz型渗透池中填满接收液。24小时后,回收接收液,用PTFE膜滤器将接收液过滤后,用UPLC/MS法对接收液中的药物量(药物渗透量)进行定量。
图2、3、4、5为示出在实施例及比较例中所得到的贴附制剂的皮肤渗透性试验的结果的图。
与在比较例1中所得到的不含类黄酮化合物的贴附制剂及在比较例2中所得到的含有类黄酮化合物以外的多元酚的贴附制剂相比,实施例1~3中所得到的含有类黄酮化合物的贴附制剂的洛索洛芬钠(形成了水溶性盐的药物)的皮肤渗透性提高(图2)。在使用HER2/neu-A24肽作为药物的情况下也观察到同样的倾向(图3、实施例4~6、比较例3、4)。另外,在使用酸性药物阿司匹林、碱性药物咪喹莫特或肾上腺素作为药物的情况下,通过使用槲皮素作为类黄酮化合物,皮肤渗透性也提高(图4、实施例7~9、比较例5~7)。另外,在不含有BO-7作为表面活性剂的情况下,通过使用槲皮素作为类黄酮化合物,皮肤渗透性也提高(图5、实施例10、比较例8)。需要说明的是,与不含有类黄酮化合物的贴附制剂相比,即使含有类黄酮化合物的贴附制剂改变增塑剂的种类,皮肤渗透性也提高。
产业上的可利用性
根据本发明,可以提供能够不必使药物成形为颗粒结构等、不伴有皮肤组织的破坏地飞跃性地提高药物的皮肤渗透性的皮肤渗透促进组合物。另外,根据本发明,还能够提供含有该皮肤渗透促进组合物的经皮给药制剂及贴附制剂。
附图标记说明
1 本发明的贴附制剂(骨架型贴附制剂)
2 剥离衬垫
6 支承体
7 含药粘合层
Claims (6)
1.一种皮肤渗透促进组合物,其特征在于,含有类黄酮化合物,该皮肤渗透促进组合物被用于促进药物的皮肤渗透。
2.根据权利要求1所述的皮肤渗透促进组合物,其中,类黄酮化合物为具有下述化学式(1)所示的黄酮骨架的化合物,
3.根据权利要求2所述的皮肤渗透促进组合物,其中,具有化学式(1)所示的黄酮骨架的化合物为选自由槲皮素、芹菜素及杨梅酮组成的组中的至少1种。
4.一种经皮给药制剂,其特征在于,含有药物和权利要求1、2或3所述的皮肤渗透促进组合物。
5.一种贴附制剂,其特征在于,具有含药层,所述含药层含有药物和权利要求1、2或3所述的皮肤渗透促进组合物。
6.根据权利要求5所述的贴附制剂,其中,含药层为含药粘合层,并且,在支承体的单面具有所述含药粘合层。
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