CN113710238A - 透皮治疗系统 - Google Patents
透皮治疗系统 Download PDFInfo
- Publication number
- CN113710238A CN113710238A CN202080029020.5A CN202080029020A CN113710238A CN 113710238 A CN113710238 A CN 113710238A CN 202080029020 A CN202080029020 A CN 202080029020A CN 113710238 A CN113710238 A CN 113710238A
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- CN
- China
- Prior art keywords
- acid
- transdermal therapeutic
- therapeutic system
- matrix layer
- ketamine
- Prior art date
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Abstract
本发明涉及一种透皮治疗系统,包含对活性成分不可渗透的背衬层和在背衬层一侧上的基质层,其中所述基质层包含至少一种压敏粘合剂和氯胺酮或其药学上可接受的盐或溶剂化物,其中至少一种压敏粘合剂具有游离羟基,及其用作药物,特别是用于治疗抑郁症和疼痛。
Description
本发明涉及包含氯胺酮作为活性成分的透皮治疗系统(TTS)。本发明还涉及这种系统作为药物的用途,特别是用于治疗抑郁症和/或疼痛。
在过去的几年中,透皮治疗系统作为治疗多种疾病的剂型变得日益重要,因为它们比普通剂型更具优势。例如,那些为精确和恒定的药物释放,这是血浆中活性成分浓度恒定所必需的。此外,可以避免首过效应,并且增加依从性,因为患者不需要定期服用片剂。与其他局部应用系统(例如软膏剂或霜剂)相比,透皮治疗系统的优势在于,它们的应用区域准确,且由此剂量准确,并且不存在因其他区域污染而偶然擦掉软膏剂的风险。此外,软膏剂或片剂必须定期施用,因为否则通常无法实现活性成分的持续释放。
几年前,人们认为活性成分在透皮治疗系统中的实施是很容易实现的,使得这种应用形式将可供大量活性成分可利用。然而,事实证明这是不正确的,因为成分经由皮肤的分子传输产生了限制因素。因此,始终需要深入研究,以提供用于施用新活性成分的透皮治疗系统。
活性成分氯胺酮以治疗疼痛而闻名。近来,还发现氯胺酮适合于治疗心理障碍,尤其是抑郁症。
透皮治疗系统为氯胺酮的施用提供了一个有吸引力的选项。
用于施用氯胺酮的透皮治疗系统是现有技术已知的。
例如,WO 2017/003935 A1和WO 2018/195318 A1公开了用于施用氯胺酮的TTS,其中采用包含游离羧基的压敏粘合剂以及结晶抑制剂。
然而,现有技术中已知的用于施用氯胺酮的TTS需要在活性成分的通量和基质层中所含活性成分的利用方面进行优化。此外,提供其中氯胺酮以稳定形式存在而不使用结晶抑制剂的制剂是有利的。
因此,本发明的一个目的在于提供一种用于施用氯胺酮的TTS,其具有最佳的,即尽可能高的活性成分通量,尤其是在施用后的最初2-12小时内,并且其中基质层中含有的氯胺酮以最佳方式得到利用。此外,TTS中所含的氯胺酮应在化学和物理方面尽可能稳定的条件下存在。此外,TTS应设计简单,并且以经济方式生产。
令人惊讶地,通过权利要求1的透皮治疗系统解决了该任务。
优选实施方案在从属权利要求中给出。
在本公开中,表述“包含”或“含有”还可以指“由…组成”。
本发明涉及一种透皮治疗系统,其包含对活性成分不可渗透的背衬层,以及在背衬层一侧上的至少一个基质层,其中所述基质层包含至少一种压敏粘合剂和氯胺酮或其药学上可接受的盐或溶剂化物,其特征在于所述至少一种压敏粘合剂含有游离羟基。
通常,本领域技术人员知晓几种类型的透皮治疗系统。存在DIR(贮库(reservoir)中的药物)-系统,其包含背衬层、贮库层、粘合剂层和可剥离保护层。在这些系统中,药物活性成分仅存在于贮库层中,而不存在于包含至少一种粘合剂聚合物的粘合剂层中。
此外,DIA(粘合剂中的药物)-系统是已知的,其中省略了贮库层并且药物活性成分直接存在于包含至少一种粘合剂聚合物的粘合剂层(也称作基质层)中。
DIA系统相对于DIR系统的优势在于更简单的生产过程和更低的滥用风险。更低的滥用风险与活性成分氯胺酮密切相关。
因此,本发明的透皮治疗系统优选为DIA-系统。即活性成分氯胺酮或其药学上可接受的盐或溶剂化物优选与至少一种压敏粘合剂共同存在于一层和相同层中。
这种TTS的特征在于其相对简单的设计和由此具有经济上有利的生产。此外,与包含不含游离羟基的压敏粘合剂的已知TTS相比,本发明的这类TTS具有更高的活性成分通量。此外,基质层中所含的氯胺酮可以以最佳方式得到利用。
此外,本发明的TTS具有高皮肤耐受性。
术语“以最佳方式使用”表示在将TTS施用于患者皮肤期间,基质层中所含的氯胺酮尽最广泛可能的程度从基质层扩散到患者皮肤中,以便在施用后尽可能少地将“未利用的”活性成分保留在基质层中。
术语“活性成分不可渗透的背衬层”表示背衬层基本上、优选完全不渗透活性成分氯胺酮。
适合的背衬层材料包含聚酯,例如聚对苯二甲酸乙二醇酯,聚对苯二甲酸丁二醇酯,聚萘二甲酸乙二醇酯,聚烯烃,例如聚乙烯或聚丙烯,乙烯-乙酸乙烯酯,聚氯乙烯,聚酰胺(尼龙)和/或聚氨基甲酸酯(polyurethane)。背衬层也可以由复合材料构成并且优选地包含铝涂覆的膜和上述给定材料中的一种。
压敏粘合剂为聚合物,其自身作为压敏粘合剂起作用,如DIN EN 923:2016-03中所定义的。
正如公知的,羟基(hydroxyl-group)和羟基基团(hydroxy-group)分别为–OH基团。
氯胺酮为(S)-(+)-2-(2-氯苯基)-2-(甲基氨基)环己-1-酮((S)-氯胺酮)、(R)-(-)-2-(2-氯苯基)-2-(甲基氨基)环己-1-酮((R)-氯胺酮)以及外消旋体(RS)-(±)-2-(2-氯苯基)-2-(甲基氨基)环己-1-酮。还包含这些化合物的药学上可接受的盐和溶剂化物。还包含这些化合物的混合物。特别优选的盐为氯胺酮·HCl。
更优选地,本发明的透皮治疗系统中至少一种药物活性成分包含(S)-氯胺酮和/或其药学上可接受的盐或溶剂化物,优选(S)-氯胺酮·HCl。
本发明的透皮治疗系统优选的特征在于,至少一种压敏粘合剂包含含有游离羟基的丙烯酸共聚物。
此外,本发明的透皮治疗系统优选的特征在于,至少一种压敏粘合剂包含丙烯酸共聚物,其选自2-乙基己基丙烯酸乙酸酯(2-ethylhexyl acrylic acetate)、乙酸乙烯酯和丙烯酸2-羟乙酯(其含有游离羟基)。
此外,本发明的透皮治疗系统优选的特征在于,至少一种压敏粘合剂得自下述:60-80wt.-%丙烯酸2-乙基己酯、1-10wt.-%丙烯酸2-羟乙酯和20-30wt.-%乙酸乙烯酯,优选65-70wt.-%丙烯酸2-乙基己酯、3-7wt.-%丙烯酸2-羟乙酯和25-30wt.-%乙酸乙烯酯,最优选68wt.-%丙烯酸2-乙基己酯、5wt.-%丙烯酸2-羟乙酯和27wt.-%乙酸乙烯酯作为起始单体。
聚合优选用0.1-0.5wt.-%,优选0.3wt.-%(基于单体wt.-%)偶氮二异丁腈(azodiisobutyronitril)引发。
此外,本发明的透皮治疗系统优选的特征在于,至少一种压敏剂(pressuresensitive)包含60-80wt.-%丙烯酸2-乙基己酯、1-10wt.-%丙烯酸2-羟乙酯和20-30wt.-%乙酸乙烯酯,优选65-70wt.-%丙烯酸2-乙基己酯、3-7wt.-%丙烯酸2-羟乙酯和25-30wt.-%乙酸乙烯酯,最优选68wt.-%丙烯酸2-乙基己酯、5wt.-%丙烯酸2-羟乙酯和27wt.-%乙酸乙烯酯作为单体。
至少一种压敏剂中的残留单体优选小于0.2wt.-%丙烯酸2-乙基己酯、小于0.2wt.-%丙烯酸2-羟乙酯和小于4.0wt.-%乙酸乙烯酯,优选小于或等于0.1wt.-%丙烯酸2-乙基己酯、小于或等于0.1wt.-%丙烯酸2-羟乙酯和小于或等于4.0wt.-%乙酸乙烯酯。
在另一个实施方案中,本发明的透皮治疗系统优选的特征在于,至少一种压敏粘合剂得自下述:60-80wt.-%丙烯酸2-乙基己酯、1-10wt.-%丙烯酸2-羟乙酯和15-30wt.-%丙烯酸甲酯,优选65-75wt.-%丙烯酸2-乙基己酯、3-7wt.-%丙烯酸2-羟乙酯和20-25wt.-%丙烯酸甲酯,最优选72wt.-%丙烯酸2-乙基己酯、5wt.-%丙烯酸2-羟乙酯和23wt.-%丙烯酸甲酯作为起始单体。
聚合优选用0.1-0.5wt.-%、优选0.2wt.-%(基于单体wt.-%)偶氮二异丁腈引发。
在另一个实施方案中,本发明的透皮治疗系统优选的特征在于,至少一种压敏剂包含60-80wt.-%丙烯酸2-乙基己酯、1-10wt.-%丙烯酸2-羟乙酯和15-30wt.-%丙烯酸甲酯,优选65-75wt.-%丙烯酸2-乙基己酯、3-7wt.-%丙烯酸2-羟乙酯和20-25wt.-%丙烯酸甲酯,最优选72wt.-%丙烯酸2-乙基己酯、5wt.-%丙烯酸2-羟乙酯和23wt.-%丙烯酸甲酯作为单体。
至少一种压敏剂中的残留单体优选小于0.2wt.-%丙烯酸2-乙基己酯、小于0.02wt.-%丙烯酸-羟乙酯和小于0.1wt.-%丙烯酸甲酯,优选小于或等于0.1wt.-%丙烯酸2-乙基己酯、小于或等于0.01wt.-%丙烯酸-羟乙酯和小于0.05wt.-%丙烯酸甲酯。
令人惊奇地,已发现在基质层中使用这类共聚物实现活性成分的高通量和以最佳方式利用基质层中所含的氯胺酮。
此外,令人惊讶地发现,本发明的透皮治疗系统具有良好至足够的粘合强度,不过,避免使用以高粘合性著称的基质聚合物,特别是包含羧基的丙烯酸酯聚合物。
适合的压敏粘合剂为已知的,商品名为DURO-TAK,特别是Henkel Germany的DURO-TAK 87-4287、DURO-TAK 87-2516、DURO-TAK 2287或DURO-TAK 2510。
由于游离羧基的存在可以降低活性成分的通量和本发明活性成分的利用率,因此,本发明的透皮治疗系统优选的特征在于,至少一种压敏粘合剂包含小于4wt.%、优选1-3wt.%、更优选小于1%的游离羧基。
由于游离羧基的存在会降低活性成分的通量和本活性成分的利用率,因此,本发明的透皮治疗系统优选的特征在于,至少一种压敏成分不含游离羧基。
此外,本发明的透皮治疗系统优选的特征在于,含有游离羟基的至少一种压敏粘合剂不使用交联剂得到。
交联剂为一种化学化合物,它可以实现治疗系统的单层的更高的内聚力和更高的坚固性。这种交联剂通常包含金属螯合物。
在压敏粘合剂的生产过程中省略交联剂也可以增加活性成分的通量。
此外,本发明的透皮治疗系统优选的特征在于,含有游离羟基的至少一种压敏粘合剂使用交联剂得到。
交联剂为一种化学化合物,它可以实现治疗系统的单层的更高的内聚力和更高的坚固性。这种交联剂通常包含金属螯合物。
在压敏粘合剂的生产过程中使用交联剂也可以增加活性成分的通量。
此外,本发明的透皮治疗系统优选的特征在于,含有游离羟基的至少一种压敏粘合剂占整个基质重量的60-90wt.-%,优选70-85wt.-%。
此外,本发明的透皮治疗系统优选的特征在于,基质层包含一种渗透促进剂。
至少一种渗透促进剂为这样的一种化合物,其稳定溶解形式的活性成分且由此提供活性成分经由皮肤的相对高的和长时间期限内的稳定的吸收。术语“渗透促进剂”由此可以被术语“增溶剂”替换。
渗透促进剂优选自羧酸、脂肪酸和/或脂肪酸酯,例如乙酰丙酸、戊酸、己酸、辛酸、壬酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、3-甲基丁酸、新庚酸、新壬酸(neonanonic acid)、异硬脂酸、油酸、棕榈油酸、亚麻酸、11-十八碳烯酸(vaccenic acid)、岩芹酸、反油酸、油酸、花生四烯酸、鳕油酸(gadoleic acid)、芥酸、丙酸甲酯、戊酸甲酯、癸二酸二乙酯、月桂酸甲酯、月桂酸乙酯、油酸乙酯、癸酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯和/或油酸异丙酯。
此外,化合物例如二乙甲苯酰胺(DEET)(diethyltoluamide)、丙二醇单辛酸酯、丙二醇、聚乙二醇、己二酸二异丙酯、丁香酚、卡必醇(transcutol)、乳酸月桂酯和/或油醇适合于作为渗透促进剂。
本发明的透皮治疗系统的特征更优选在于,至少一种渗透促进剂选自乙酰丙酸和/或月桂酸甲酯。
甚至更优选的至少一种渗透促进剂包含乙酰丙酸和月桂酸甲酯的混合物,且甚至进一步优选的至少一种渗透促进剂为乙酰丙酸和月桂酸甲酯的混合物。
此外,本发明的透皮治疗系统优选的特征在于,至少一种渗透促进剂在基质层中的存在量为占基质层的重量的1-15wt.-%,优选4-10wt.-%。
本发明的透皮治疗系统预期的施用时间优选至少6小时,更优选至少12小时,甚至更优选至少24小时。活性成分的量优选适合于期望的施用时间。
优选本发明的透皮治疗系统包含在基质层中的氯胺酮,其用量占基质层重量的1-25wt.-%,优选5-15wt.-%。
本发明的透皮治疗系统的特征优选进一步在于基质层包含至少一种抗氧化剂。
至少一种抗氧化剂为一种化学化合物,其可防止或减少其他物质、特别是活性成分的氧化,且由此起防止治疗系统老化的作用。特别地,抗氧化剂的特征在于它们作为自由基清除剂的作用以及它们防止敏感分子、特别是受空气中的氧气影响的活性成分的氧化分解。至少一种抗氧化剂优选自α-生育酚、抗坏血酸棕榈酸酯和/或二丁基羟基甲苯。
优选地,本发明的透皮治疗系统包含至少一种在基质层中的抗氧化剂,其用量占基质层总重的0.001-5wt.-%,优选0.01-2wt.-%。
除上述举出的组分外,基质层还可以包含常用添加剂。根据它们的功能,它们可分为软化剂/增塑剂、增粘剂、稳定剂、载体和/或填充剂。相关的、生理上不重要的物质是本领域技术人员已知的。
软化剂/增塑剂可以选自具有6-20个碳原子的直链或支链、饱和或不饱和醇、甘油三酯和聚乙二醇。
增粘剂可以选自甘油三酯、双丙甘醇、树脂、树脂酯、萜烯及其衍生物、乙烯乙酸乙烯酯粘合剂、二甲基聚硅氧烷和聚丁烯。
稳定剂可以选自生育酚及其酯衍生物和抗坏血酸及其酯衍生物,且更优选选自脂肪酸抗坏血酸酯与生育酚,且更优选抗坏血酸棕榈酸酯或α-生育酚。
载体和/或填充剂例如硅胶、二氧化钛和氧化锌可以与聚合物结合使用,以便以期望的方式影响某些物理参数,例如内聚力和粘合强度。
此外,可以将滥用威慑剂(abuse deterrent)加入透皮治疗系统以防止或至少降低其滥用的可能性。可用作滥用威慑剂的物质的实例为苦味剂、凝胶形成剂、刺激剂、导致急性胃肠道、心脏或呼吸效应的物质、导致剧烈恶心或呕吐的物质、导致令人厌恶的气味的物质、诱导睡眠的物质、尝试提取时导致活性成分失活或降解的物质。
此外,透皮治疗系统还可以包含滥用威慑部件(feature),当以不同于其预期用途、即透皮施用的任何其他方式使用时,该部件使得活性物质和/或系统无效。
此外,可以在透皮治疗系统中加入另外的活性成分,以抵消氯胺酮的潜在副作用或增强氯胺酮的作用。另外的活性成分可以选自非类固醇抗炎药(NSAID,例如布洛芬、酮洛芬、美洛昔康、吡罗昔康、吲哚美辛)、COX-2抑制剂(例如塞来昔布、依托昔布)、阿片类药物(芬太尼、丁丙诺啡、吗啡、可待因、羟考酮、氢可酮、二氢吗啡、哌替啶)、MAOI(不可逆和非选择性,例如苯乙肼、反苯环丙胺、异卡波肼)、MAOI(MAO-A的可逆抑制剂,例如吗氯贝胺)、MAOI(MAO-B的优先抑制剂,例如德普尼林(deprenyl))、三环(和四环)抗抑郁药(例如氯米帕明、丙咪嗪、阿米替林、去甲替林、普罗替林、马普替林、阿莫沙平、多塞平、地昔帕明、曲米帕明)、选择性5-羟色胺再摄取抑制剂(氟西汀、舍曲林、帕罗西汀、氟伏沙明、西酞普兰、依他普仑)、选择性去甲肾上腺素再摄取抑制剂(例如瑞波西汀、阿托西汀)、去甲肾上腺素和多巴胺再摄取抑制剂/释放剂(例如安非他酮)、血清素和去甲肾上腺素再摄取抑制剂(例如文拉法辛、米那普仑、度洛西汀)、血清素拮抗剂/再摄取抑制剂(例如奈法唑酮、曲唑酮)、α2-肾上腺素受体拮抗剂(例如米氮平(mitazapine))。
优选地,本发明的透皮治疗系统的特征进一步在于,基质层具有30-400g/m2、优选100-275g/m2的面积重量。
优选地,本发明的透皮治疗系统的特征进一步在于,透皮治疗系统包含在基质层的未设置背衬层的一侧上的可剥离保护层。
与基质接触并在应用之前剥离的可剥离保护层包含例如与用于生产背衬层相同的材料,只要它们是可剥离的,例如通过硅酮处理。其他可剥离的保护层为聚四氟乙烯、处理过的纸、玻璃纸、聚氯乙烯等。
此外,本发明涉及如上所述的透皮治疗系统,用作药物。
此外,本发明涉及用于治疗重度抑郁症(MDD)(也简称为抑郁症)的如上所述的透皮治疗系统。
特别地,所述透皮治疗系统可以用于降低自杀风险和/或治疗难治性抑郁症(TRD)。
重度抑郁症(MDD)是一种精神障碍,其特征在于普遍和持续的低情绪并且伴随低自尊和对通常愉快的活动失去兴趣或乐趣。重度抑郁症是一种致残疾病,其会对个人的家庭、工作或学校生活、睡眠和饮食习惯以及整体健康产生不良影响。
难治性抑郁症(TRD)描述了一种影响重度抑郁症(MDD)患者的病症,这些患者在一定时间内对适当的抗抑郁药物疗程无充分反应。
美国精神病学协会的精神疾病诊断和统计手册(The American PsychiatricAssociation’s Diagnostic and Statistical Manual of Mental Disorders)(DSM-5)认可的其他亚型是郁型抑郁症(melancholic depression)、非典型抑郁症、紧张性抑郁症(catatonic depression)、具有焦虑困扰的抑郁症、围产期发作的抑郁症和季节性情感障碍。
此外,本发明优选涉及如上所述的透皮治疗系统,其用于治疗疼痛。
疼痛是一种令人痛苦的感觉,通常由强烈或破坏性的刺激引起。持续很长时间的疼痛称作慢性或持续性疼痛,而快速消退的疼痛称作急性痛。
伤害性疼痛由对接近或超过有害强度的刺激(伤害感受器)产生反应的感觉神经纤维受到刺激引起,并且可以根据有害刺激的方式进行分类。最常见的类别是热、机械和化学。一些伤害感受器对这些模式中的超过一种有反应,且由此被指定为多模式。
伤害性疼痛还可分为“内脏”、“深部躯体”和“浅部躯体”疼痛。
神经性疼痛由影响与身体感觉相关的神经系统任何部分(躯体感觉系统)的损伤或疾病引起。神经性疼痛可分为周围性、中枢性或混合性(外周性和中枢性)神经性疼痛。周围神经性疼痛通常被描述为“灼痛”、“刺痛”、“电痛”、“刺痛感”或“针刺痛”。
此外,本发明的透皮治疗系统可以用于不同施用方案,例如连续或交错施用。
在连续施用中,以持续至少12h的间隔施用透皮系统,以在血浆中达到单个活性成分的浓度。
反复施用优选无延迟地连续进行,即,当在施用间隔结束时去除一种或多种本发明的TTS时,立即施用用于随后施用间隔的一种或多种本发明的TTS。优选地,可以根本不存在施用于身体的本发明TTS的时间间隔不超过10分钟,更优选不超过5分钟。
在交错施用中,透皮系统以持续至少4h的间隔施用,以在血浆中达到单个活性成分的浓度。
交错施用优选每天一次、每周两次或每周一次进行,即,当在施用间隔结束时除去本发明的一种或多种TTS时,施用用于后续施用间隔的本发明的一种或多种TTS,考虑到了至少18小时的无剂量间隔。
在一个优选的实施方案中,在整个时间期限内在个体的相同皮肤区域上施用本发明的所有TTS,即,用本发明的TTS反复覆盖或涂抹个体的给定皮肤区域。
在另一个优选的实施方案中,在整个时间期限内,在个体的不同皮肤区域上每次施用本发明的所有TTS,即,没有用本发明的TTS反复覆盖或涂抹个体的给定皮肤区域。
下面使用非限制性实施例进一步描述本发明。
实施例:
实施例1
将实施例1a-c的含S-氯胺酮的涂覆组合物的制剂概括在下表1中。制剂基于重量百分比,如表1中所示。
表1:
DURO-TAK 387-2516:基于具有包含羟基的丙烯酸酯乙酸乙烯酯共聚物的压敏粘合剂,使用交联剂得到。
DURO-TAK 387-4287:基于含有游离羟基的丙烯酸酯乙酸乙烯酯共聚物的压敏粘合剂,不使用交联剂得到。
DURO-TAK 387-2052:基于包含游离羧基的丙烯酸酯乙酸乙烯酯共聚物的压敏粘合剂,使用交联剂得到。
对于实施例1a和1b,在烧杯中装入S-氯胺酮碱和溶剂(乙酸乙酯),以及乙酰丙酸和月桂酸甲酯(实施例1b)。加入丙烯酸压敏粘合剂聚合物DURO-TAK 387-4287,然后将该混合物以至多300rpm的速度搅拌直至得到均匀的混合物(搅拌时间为约60min)。
对于实施例1c,在烧杯中装入S-氯胺酮碱和溶剂(乙酸乙酯)以及乙酰丙酸。加入丙烯酸压敏粘合剂聚合物(DURO-TAK 387-2052),然后将该混合物以至多300rpm的速度搅拌直至得到均匀的混合物(搅拌时间为约60min)。
对于实施例1d,在烧杯中装入S-氯胺酮碱和溶剂(乙酸乙酯)以及乙酰丙酸。加入丙烯酸压敏粘合剂聚合物(DURO-TAK 387-2516),然后将该混合物以至多300rpm的速度搅拌直至得到均匀的混合物(搅拌时间为约60min)。
将所得的含S-氯胺酮的涂覆组合物涂覆在聚对苯二甲酸乙二醇酯薄膜(硅化处理,75μm厚,可用作隔离衬垫(release liner))上并在室温下干燥约15min,在60℃下15min。涂层厚度使基质层的面积重量分别为136.5g/m2(实施例1a)、132.8g/m2(实施例1b)、130.0g/m2(实施例1c)和122.8g/m2(实施例1d)。将干燥的薄膜与聚对苯二甲酸乙二醇酯背衬层(23μm厚)一起层压,得到含S-氯胺酮的自粘层结构。
然后从含有S-氯胺酮的自粘层结构中冲压出单个系统。在特定的实施方案中,如上所述的TTS可以配备具有更大表面积的另外的自粘合层,优选具有圆角,其包含不含活性剂的压敏粘合剂基质层。当TTS仅基于其物理特性不能充分粘附在皮肤上和/或当含S-氯胺酮的基质层出于避免浪费的目的而具有明显的角(正方形或矩形)时,这具有优势。然后冲压出系统并密封到初级包装材料的小袋中。
使用实施例1a、实施例1b和实施例1d进行局部耐受性评估和S-氯胺酮血浆水平测
定的临床前设置(preclinical set up)
实施例1a和实施例1d的临床前设置
TTS尺寸:10cm2
实施例1b的临床前设置
TTS尺寸:10cm2
根据DRAIZE评估局部不耐受反应(即特殊强调水肿、红斑或焦痂形成)在用透皮贴剂治疗的任何动物的施用部位均未显示出任何水肿或红斑。
去除贴剂后,任何动物在任何施用部位均未注意到其他局部不耐受迹象(例如变色或肿胀)。
S-氯胺酮血浆水平测定结果如图1中所示。
皮肤渗透率的测定
根据OECD指南(2004年4月13日修订)和EMA透皮贴剂质量指南(EMA/CHMP/QWP/608924/2014,2014年10月23日修订),通过使用7.0ml Franz扩散池进行的体外实验测定根据实施例1a-1c制备的TTS的渗透量和相应的皮肤渗透率。使用分裂厚度人腹部皮肤(女性)。使用生皮节(dermatome)制备厚度为500μm的皮肤,其中所有TTS均具有完整的表皮。从TTS冲压出面积为1.152cm2的模切件(diecut)。测量S-氯胺酮在32±1℃温度下在Franz池受体介质(包含0.1%叠氮化物盐水作为抗菌剂的磷酸盐缓冲溶液pH 5.5)中的渗透量,并计算出相应的皮肤渗透率[μg/cm2*h]。结果如表2和图2中所示。
表2
S-氯胺酮的利用率
基于24h和48h后TTS的残留量和初始S-氯胺酮含量计算S-氯胺酮在24h和48h时的利用率。结果如表3和图3中所示。
表3:
在图1-图3中概括的结果显示活性成分的改进利用率和活性成分的改进通量。
实施例2
使用本发明和现有技术的系统的皮肤渗透的比较
实施例2a-c的含S-氯胺酮的涂覆组合物的制剂按照实施例1中所述类似地制备并概括于下表4中。制剂基于重量百分比,也如表4中所示。
表4:
Eutanol HD:油醇(促进剂)
卡比醇:二甘醇单乙醚(促进剂)
Plastoid B:甲基丙烯酸丁酯和甲基丙烯酸甲酯的共聚物
皮肤渗透率按照与实施例1类似的方式测定,并概括在图4中。本实施例的皮肤渗透性在于本发明(实施例2a和实施例2b)的优势,因为与参比例(实施例2c)相比,通量的开始(前8小时的通量)明显更高。
实施例3
使用具有不同涂层重量的本发明系统的皮肤渗透的比较
实施例3a-c的含S-氯胺酮的涂覆组合物的制剂按照与实施例1中所述类似的方式制备并概括在下表5中。制剂基于重量百分比,也如表5中所示。
表5
皮肤渗透率按照与实施例1类似的方式测定,并概括在图5中。本实施例的皮肤渗透性显示了涂层重量对通量开始和通量分布的影响。
实施例4
使用本发明的系统与交联剂和月桂酸甲酯或月桂酸乙酯的皮肤渗透性比较
实施例4a-c的含S-氯胺酮的涂覆组合物的制剂按照与实施例1中所述类似的方式制备,并概括在下表6中。制剂基于重量百分比,也如表6所示。
表6
皮肤渗透率按照与实施例1类似的方式测定,并概括在图6中。本实施例的皮肤渗透性显示交联剂乙酰丙酮铝不影响通量的开始,并且月桂酸甲酯在通量的开始方面比月桂酸乙酯更有利。
实施例5
使用应用不同聚合物的系统的皮肤渗透的比较
将实施例5a-f的含S-氯胺酮的涂覆组合物的制剂概括在下表7中。制剂基于重量百分比,也如表7中所示。
表7
DURO-TAK 87-4098:基于不含任何官能团的丙烯酸酯乙酸乙烯酯共聚物的压敏粘合剂,无需交联剂得到。
DURO-TAK 87-9301:基于不含任何官能团的丙烯酸酯聚合物的压敏粘合剂,无需使用交联剂得到。
DURO-TAK 87-4287:基于含有游离羟基的丙烯酸酯乙酸乙烯酯共聚物的压敏粘合剂,无需使用交联剂得到。
DURO-TAK 87-2054:基于包含游离羧基的丙烯酸酯乙酸乙烯酯共聚物的压敏粘合剂,无需使用交联剂得到。
DURO-TAK 87-6908:基于不含官能团的聚异丁烯聚合物的压敏粘合剂,无需使用交联剂得到。
Plastoid B:基于不含官能团的甲基丙烯酸丁酯和甲基丙烯酸甲酯的压敏粘合剂,无需使用交联剂得到。
对于实施例5a-d和5f,向烧杯中装入S-氯胺酮碱。加入粘合剂聚合物,然后以至多200rpm的速度搅拌该混合物直到得到均匀的混合物(搅拌时间约为90min)。
将所得的含S-氯胺酮的涂覆组合物涂覆在聚对苯二甲酸乙二醇酯薄膜(硅化处理,75μm厚,可用作隔离衬垫)上并在室温下干燥约15min,且在60℃下15min。涂层厚度得到基质层面积重量分别为109.2g/m2(实施例5a)、105.1g/m2(实施例5b)、106.0g/m2(实施例5c)、105.0g/m2(实施例5d)和100.2g/m2(实施例5f)。将干燥的薄膜与聚对苯二甲酸乙二醇酯背衬层(23μm厚)一起层压,得到含S-氯胺酮的自粘层结构。
对于实施例5e,向烧杯中装入S-氯胺酮碱。加入甲基丙烯酸丁酯和甲基丙烯酸甲酯共聚物溶液(50%;Plastoid B),然后以至多200rpm的速度搅拌该混合物直到得到均匀的混合物(搅拌时间约为90min)。
将所得的含S-氯胺酮的涂覆组合物涂覆在聚对苯二甲酸乙二醇酯薄膜(硅化处理,75μm厚,可用作隔离衬垫)上并在室温下干燥约15min,且在60℃下15min。涂层厚度得到基质层面积重量为107.3g/m2。将干燥的薄膜与聚对苯二甲酸乙二醇酯背衬层(23μm厚)一起层压,得到含S-氯胺酮的自粘层结构。
皮肤渗透率按照与实施例1类似的方式测定,并概括在图7中。本实施例的皮肤渗透性显示,就皮肤通量率而言,含有游离羟基的压敏粘合剂更为有利。
实施例6
使用应用不同聚合物的系统的探头粘性和粘附力的比较
实施例5a-d和5f的含S-氯胺酮涂覆组合物的制剂用于测量探头粘性和粘附力。
探头粘性的测量:
仪器:探头粘性测试仪,PT 1000(ChemInstruments,US)
探头直径:5.0mm
探头与基质的接触时间:1秒
样品大小:11.3cm2
用冲压工具按样品尺寸冲压层压条。此后,通过使用样品环将样品固定在探头粘性测试仪上并开始测量(每个层压板n=3次测量)。每次测量后,用汽油(沸程80/110)清洗样品环和探头。
报告3次测量的平均值。
粘附力的测量:
仪器:恒定伸长率(CRE)张力测试仪,zwicki-line Z5.0(Zwick-Roell AG,Germany)
测试板:根据DIN EN 1939/ASTM D3330/3330M-04的不锈钢板
样品大小:宽:25mm;长:约10cm
测量前路径/测量路径/测量后路径:5mm/50mm/5mm
测试速度:300mm/min
用冲压工具将层压板冲压成25mm宽的条。此后,将模切件制成约10cm长。隔离衬垫在下端被提升几毫米以将具有粘合剂侧的伸长胶带施加到开放基质侧。然后完全去除隔离衬垫并用手将样品施加到钢板上。10min后开始测量。平衡时间和钢板固定在仪器上后,调整到零,且伸长带的自由端附接在上夹具上。测量从上述参数开始。
报告3次测量的平均值。
Claims (15)
1.透皮治疗系统,其包含活性成分不可渗透的背衬层,以及在所述背衬层一侧的至少一个基质层,其中所述基质层包含至少一种压敏粘合剂和氯胺酮或其药学上可接受的盐或溶剂化物,其特征在于至少一种压敏粘合剂含有游离羟基。
2.权利要求1的透皮治疗系统,其特征在于
所述氯胺酮为(S)-氯胺酮或其药学上可接受的盐或溶剂化物。
3.前述权利要求任一项的透皮治疗系统,其特征在于至少一种压敏粘合剂包含含有游离羟基的丙烯酸共聚物。
4.前述权利要求任一项的透皮治疗系统,其特征在于至少一种压敏粘合剂包含丙烯酸共聚物,其选自2-乙基己基丙烯酸乙酸酯、乙酸乙烯酯和丙烯酸2-羟乙酯,其含有游离羟基。
5.前述权利要求任一项的透皮治疗系统,其特征在于至少一种压敏粘合剂包含小于4wt.%、优选1-3wt.%、更优选小于1%的游离羧基。
6.前述权利要求任一项的透皮治疗系统,其特征在于至少一种压敏粘合剂不含游离羧基。
7.前述权利要求任一项的透皮治疗系统,其特征在于所述基质层包含至少一种渗透促进剂。
8.权利要求7的透皮治疗系统,其特征在于至少一种渗透促进剂选自乙酰丙酸、戊酸、己酸、辛酸、壬酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、3-甲基丁酸、新庚酸、新壬酸、异硬脂酸、油酸、棕榈油酸、亚麻酸、11-十八碳烯酸、岩芹酸、反油酸、油酸、花生四烯酸、鳕油酸、芥酸、丙酸甲酯、戊酸甲酯、癸二酸二乙酯、月桂酸甲酯、月桂酸乙酯、油酸乙酯、癸酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、油酸异丙酯、二乙甲苯酰胺、丙二醇单辛酸酯、丙二醇、聚乙二醇、己二酸二异丙酯、丁香酚、卡必醇、乳酸月桂酯和/或油醇,更优选乙酰丙酸和/或月桂酸甲酯。
9.权利要求7或8的透皮治疗系统,其特征在于所述基质层包含占该基质层重量1-15wt.-%的量的至少一种渗透促进剂。
10.前述权利要求任一项的透皮治疗系统,其特征在于所述基质层包含占该基质层重量1-25wt.-%的量的氯胺酮。
11.前述权利要求任一项的透皮治疗系统,其特征在于所述基质层包含至少一种抗氧化剂,其优选选自α-生育酚、抗坏血酸棕榈酸酯和/或二丁基羟基甲苯。
12.前述权利要求任一项的透皮治疗系统,其特征在于所述基质层具有30-400g/m2的面积重量。
13.前述权利要求任一项的透皮治疗系统,其特征在于所述透皮治疗系统包含在所述基质层上未布置背衬层的一侧上的可分离保护层。
14.前述权利要求任一项的透皮治疗系统,其用作药物。
15.前述权利要求任一项的透皮治疗系统,其用于治疗抑郁症和/或疼痛。
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