CN114504566A - 含有大麻素的透皮贴剂 - Google Patents
含有大麻素的透皮贴剂 Download PDFInfo
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- CN114504566A CN114504566A CN202011287768.3A CN202011287768A CN114504566A CN 114504566 A CN114504566 A CN 114504566A CN 202011287768 A CN202011287768 A CN 202011287768A CN 114504566 A CN114504566 A CN 114504566A
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- cannabinoid
- transdermal
- patch
- transdermal patch
- sensitive adhesive
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Abstract
本发明涉及一种含有大麻素的透皮贴剂,该透皮贴剂不含有普通促渗剂,但其中含有天然或人工合成的温感剂,该温感剂可以显著促进贴剂中大麻素的透皮给药,从而提高了贴剂的功效。本发明所述含有大麻素的透皮贴剂可以用于多效镇痛,尤其是用于治疗慢性疼痛,如偏头痛、女性月经周期性疼痛等,此外还可用于大麻素能治疗的其他病症,如治疗罕见性癫痫。
Description
技术领域
本发明涉及含有大麻素的透皮贴剂,尤其是涉及含有大麻二酚的透皮贴剂。本发明还涉及上述含有大麻素尤其是大麻二酚的透皮贴剂的应用。
背景技术
虽然通过皮肤给药已经具有悠久的历史,但目前一般认为现代意义上的第一个透皮贴剂为1981年上市的东莨菪碱透皮贴剂,而在此之前的皮肤给药制剂均系传统型制剂,它们的给药途径和治疗效果均侧重于局部皮肤或皮下组织,而透皮贴剂则主要是着眼于皮肤给药而产生全身的治疗效果,这也是传统的皮肤给药剂型和现代透皮贴剂的根本区别所在。
经过数十年的制剂基础研究和产业化发展,目前全球已有数十种具有不同活性成分的透皮贴剂开发成功并且服务于人类健康,且随着透皮给药理论的完善和剂型产品的丰富,透皮贴剂已经形成了多样的体系化形态,如贮库型透皮贴剂和基质型透皮贴剂,被动型透皮贴剂和主动型透皮贴剂等。但如无特别说明,本发明中所述的透皮贴剂均是指被动型透皮贴剂,即主要依靠药物在制剂内和制剂—皮肤之间的浓度梯度推动给药的透皮贴剂。而现在材料学的发展则为透皮贴剂重要辅料尤其是药用压敏胶的系统化和系列化创造了条件,目前已经成功开发出了系列透皮贴剂用压敏胶辅料产品,如最常用的有聚丙烯酸酯压敏胶系列,聚异丁烯压敏胶系列,聚硅氧烷压敏胶系列,此外,还可用于透皮贴剂的压敏胶黏合剂类型包括氯丁橡胶、聚丁二烯、聚异戊二烯、乙酸乙烯酯、乙烯乙酸乙烯酯共聚物、苯乙烯-异戊二烯共聚物、聚氨酯等。
以上所述的系列药用压敏胶均可考虑应用于本发明中。
大麻(Cannabis sativ a L.)为桑科一年生草本植物, 又名麻、汉麻、火麻、山丝苗、黄麻等, 为重要的农用及药用作物。作为栽培植物, 很早的古籍上就有大麻的相关记载,如4000年前的《黄帝内经》中就有关于大麻的描述,公元2 世纪, 我国名医华佗曾用大麻作为麻醉药物用于临床治疗中;《本草纲目》中亦有大麻入药的记载;其成熟果实火麻仁也被收载于《中国药典》2005年版中。因其具有润燥、滑肠、通淋、活血作用, 中医用于治疗肠燥便秘、消渴、热淋、风痹、痢疾、月经不调、疥疮、癣癞等病。
近现代以来,由于毒品使用的泛滥所导致的严重社会不良后果,世界上的主要国家均对包括大麻在内的含有毒品成分的作物种植和栽培进行了严格的管制。然而由于大麻及其衍生物的重大经济价值和在临床上的重要性,尤其是在监管能力和监控技术的提高使得毒品的滥用得以控制,使得在世界范围内大麻作物的种植面积始终有增无减。
本发明涉及含有大麻素的透皮贴剂,其中可以含有一种纯的从大麻的花、叶、茎和根等部位提取物中经纯化而获得的大麻素类化合物或数种纯的大麻素类化合物的按照一定比例组成的混合物,也可以含有实质上含有数种到数十种大麻素类化合物而通过将上述的提取物经过一定工艺浓缩而成的浓缩液或膏状物的混合物。根据所含有的活性成分的不同,本发明中的含有大麻素的透皮贴剂可以用于镇痛、癫痫、失眠、减肥、美白等适应症或功效的发挥。
US20190282513A1公开了一种含有大麻二酚粉末、乙氧基乙二醇、精油和热感剂的组合物。根据其公开文件的说明书部分,该专利公开文件中的组合物,用于镇痛等领域,其实际上是利用了大麻二酚和精油同时作用于人体局部部位并发挥两者的协同作用来显现效果,或者是使得大麻二酚和乙氧基乙二醇同时作用于神经末梢从而发挥止痛作用甚至是同时发挥了大麻二酚、乙氧基乙二醇和香兰基丁基醚作用于神经末梢而发挥的止痛效果,更进而,该组合物是通过同时发挥大麻二酚、乙氧基乙二醇、精油和香兰基丁基醚的止痛效果。
发明内容
本发明涉及一种含有大麻素尤其是大麻二酚的透皮贴剂,对于本专利申请中的各个技术术语,如无特别说明,它们的含义均符合如下定义:
透皮贴剂:本发明中的透皮贴剂的定义符合《中国药典》2015年版中关于“贴剂”的定义,即系指原料药物与适宜的材料制成的供粘帖在皮肤上的可产生全身性或局部作用的一种薄片状制剂。在此,援引《中国药典》2015年版第四部“制剂通则”中的“0121 贴剂”部分,即本发明中所述的透皮贴剂(或贴剂)满足该部分中的技术要求。
贴膏剂:本发明中的贴膏剂的定义符合《中国药典》2015年版中关于“贴膏剂”的定义,即系指将原料药物与适宜的基质制成膏状物、涂布于背衬材料上供皮肤贴敷,可产生全身性或局部作用的一种薄片状制剂。
贴膏剂包括凝胶贴膏(原巴布膏剂或凝胶膏剂)和橡胶贴膏(原橡胶膏剂)。在此,援引《中国药典》2015年版第四部“制剂通则”中的“0122贴膏剂”部分,即本发明中所述的贴膏剂满足该部分中的定义和技术标准。
促渗剂:本发明所述的促渗剂是指普通促渗剂,即目前在教科书和技术手册中普遍定义的促渗剂,又名透皮促进剂(Transdermal enhancers)或穿透促进剂(Penetrationenhancers)。是指用于透皮贴剂系统中而能够帮助药物透过角质层和表皮扩散的物质。促渗剂存在着多种不同的分类,以下的例举只是根据其中的一种分类法所进行的阐述。透皮贴剂包括非极性类、极性类和表面活性类。其中非极性类包括高级脂肪醇(油醇、月桂醇等)、高级脂肪酸(油酸、月桂酸等)、高级脂肪酸酯(异丙基棕榈酸酯、异丙基肉豆蔻酸酯等)、萜烯(桉叶油素、薄荷醇等)、内酰胺(十二烷氮䓬酮等)、大环酮(樟脑);极性类包括一元醇(甲醇、乙醇等)、多元醇(甘油、异丙醇PEG-400等)、酚(百里酚等)、亚砜(二甲基亚砜等)、胆盐、酰胺(环乙月桂酰胺等)、尿素、多糖(环状糊精等)、吡咯烷酮(1-甲基-2-吡咯烷酮);表面活性类有阳离子型(N,N-二(α-羟乙基)油酰胺)、阴离子型(月桂醇硫酸钠等)、两性离子型(十二烷基二甲基丙基硫酸铵等)、非离子型(吐温-80等)。
大麻素:本发明中所述的大麻素是指大麻素类化合物(Cannabinoids),系指源自大麻提取物所获得的系列化合物中的经过纯化的单一组分,所述单一组分是指具有具体而确定的化学结构式的某一种化合物,既包括其光学异构体(如果其分子内存在手性中心),也包括其内消旋体和外消旋体。此外,如无特别说明,大麻素还包括上述的数种纯的单一组分的混合物,甚至包括源自大麻植株的苞片、根、茎、叶、花、种子等部位提取物直接经过浓缩而获得的混合物。另外,对于部分结构确定的大麻素纯的化合物,本发明中的大麻素也包括通过合成而获得的该纯品或其混合物。根据相关研究论文,当前,科学家已经从各种大麻提取物中确认了至少七十种大麻素类化合物,这些化合物中的很多在大麻植株中是以酸(尤其是羧酸)的形式存在,而在提取过程中则通过非酶促反应脱去羧基,所以如无特别说明,本发明中所述的各种大麻素化合物既包括了其酸,也包括了其碱,此外也可以是其可用于制备药品的盐。具体而言,本发明中可能涉及的纯的大麻素类化合物包括但不限于:四氢大麻酚(THC)、大麻二酚(Cannabidiol,CBD)、大麻环萜酚(Cannabichromene,CBC)、大麻酚(Cannabinol,CBN)、大麻萜酚(Cannabigerol,CBG)。
药用压敏胶:本发明中所述的药用压敏胶,是指在安全性和生物相容性等方面达到药用质量标准,能够用于医疗、化妆品、医疗器械等用途的药品级别的压敏胶产品,常用的如药用聚丙烯酸酯压敏胶、药用聚异丁烯压敏胶、药用聚硅氧烷压敏胶等。本发明中的药用压敏胶既包括已经在FDA、NMPA等EMA药监机构备案并激活的产品,也包括质量达到药用标准而尚未备案或备案未激活的产品。
本发明的目的在于,通过数据比对和实验验证的方法,从目前已知的大麻素类化合物中筛选出具有确切生理活性的成分或这些活性成分的定量组合,并将其制备成透皮贴剂,从而获得一种使用方便、副作用低、透皮给药量可控、性能优良的含有大麻素的透皮贴剂,在发挥其中含有的大麻素所具有的生理活性的同时,具有不良反应低和使用方便、安全等透皮贴剂的剂型优势,从而能够改善和提高患者或使用本产品的人们的生活质量。
在本发明的一个实施例中,活性成分为大麻二酚。具体而言,本发明中,发明人以大麻二酚作为标准化合物,研究了将大麻素类化合物制备成透皮贴剂的可行性及其特点,从而为获得高性能的含有大麻素类化合物的贴剂积累了相关数据和经验。更具体而言,发明人通过检索分析现有技术、实验设计、实验操作、样品制备、样品检验等工作,深入研究了大麻二酚的药理活性和理化性质及透皮贴剂成药性,然后根据以上信息筛选合适的特定型号的药用辅料,尤其是压敏胶粘合剂,如聚丙烯酸压敏胶、药用聚异丁烯压敏胶和药用聚硅氧烷压敏胶中的一种或几种或其组合,并配以其他必要辅料,根据在透皮贴剂研究中积累的理论知识和实践,完成初步的处方设计和样品制备方案及透皮贴剂各项性能的标准研究方案,从而确定了相关技术方案。
发明人发现,普通的透皮贴剂,常常容易引发使用者的皮肤过敏反应,而究其原因,除了压敏胶中的单体和其他配料(如引发剂、交联剂等)所致的过敏反应外,在制备透皮贴剂时经常性加入其中的促渗剂也是一个重要的导致皮肤过敏的原因。但是对于透皮贴剂而言,皮肤是给药的最主要屏障,对于大部分药物而言,如果不使用适宜的促渗剂,则难以获得满意的药物透过量,最后达不到治疗所需的血药浓度或局部药物浓度,所以对多数的透皮贴剂而言,促渗剂是不可或缺的,甚至有些品类的透皮贴剂的促渗剂使用量还较大。但如上所述,促渗剂的使用,尤其是过量使用所带来的不良影响也是亟待克服的问题。如何在减少促渗剂用量或者说最好在不使用促渗剂的前提下实现药物的促渗也是本领域的经常性研究课题,目前已有的方法主要是采用物理促渗法进行对化学促渗剂的替代,如红外线照射、微针、离子导入等,但是这些额外的措施和装置无疑又大大增加了透皮贴剂的成本或削弱了其易用性,导致难以获得市场的认可,阻碍了产品的市场化和产业良性发展。
本发明的发明人发现,在不加入普通的透皮促渗剂的情况下,即使在本发明的透皮贴剂体系中加入极少量的温感剂,也可以显著地提高活性成分即大麻素的透皮量,从而促进了人体对大麻素的吸收,并进而极大地提高了该透皮贴剂的大麻素透皮给药能力。此外,有很多温感剂,如来源于一些植物提取物的温感剂,还具有天然的芬芳,可以掩盖压敏胶黏胶剂和其他辅料的不良气味,增加了透皮贴剂的可接受度,提高了患者的用药依从性。这种温感剂的一个实例是香兰基丁基醚,其本身具有天然的花香,且温感效果温和而强度适当,而与此类似的温感剂还有很多。
具体而言,本发明中的温感剂可以选自但不限于如下所列的温感剂中的一种或二至三种的组合:辣椒素、香兰基丁基醚、薄荷醇、甲酮、烟酸维生素E、烟酸生育酚、肉桂樟脑叶薄荷油、沸石粉、薄荷油、留兰香油、决明子提取物。优选辣椒素、香兰基丁基醚,尤其优选香兰基丁基醚。
本发明中的透皮贴剂含有的温感剂对于透皮贴剂的基质而言,其含量范围可以为0.001-0.5%,尤其优选0.01%-0.1%,更优选0.02%-0.08%。
本发明中可以含有少量的抗氧化剂,所述的抗氧化剂优选源自天然植物或动物组织提取获得的抗氧化剂,包括但不限于生育酚(维生素E)和抗坏血酸(维生素C)或其酯,优选生育酚。抗氧化剂的含量为0%-0.1%,优选0.005%-0.05%。
本发明的透皮贴剂中的活性成分为大麻素,其含量范围为0.1%-20%,优选0.2-15%,更优选2%-15%。在本发明的至少一个实施例中,活性成分为大麻二酚。
本发明中的透皮贴剂不含有通常意义上的促渗剂,即其上述促渗剂的含量为0%。
本发明中的透皮贴剂的制备中使用了药用压敏胶黏合剂,这些压敏胶黏合剂可选自药用聚丙烯酸酯类压敏胶黏合剂,最常用的有可通过市场获得的Duro-tak系列,Gelva系列,Cotran系列,Cariflex系列等。以Duro-tak系列为例,可选择而用于本发明的压敏胶黏合剂包括但不限于Duro-tak 87-2051、Duro-tak 87-2052、Duro-tak 87-2054、Duro-tak87-2287、Duro-tak 87-2510、Duro-tak87-2516、Duro-tak 87-2525、Duro-tak 87-2825等。
本发明的透皮贴剂的制备还可以选用聚异丁烯压敏胶黏合剂,如Exxon公司的Vistanex NM L-100和BASF公司的Oppanol B10等型号的市售透皮贴剂用聚异丁烯压敏胶黏合剂。
聚硅氧烷类压敏胶黏合剂也常常被称为聚硅酮类压敏胶黏合剂。本发明的透皮贴剂可选用的聚硅氧烷类压敏胶黏合剂包括Dow Corning公司的Bio-PSA7-4204、Bio-PSA7-4202或7-4602等市售透皮贴剂用聚硅氧烷压敏胶黏合剂。
发明人对大麻素透皮贴剂中温感剂对大麻素透皮给药的影响进行了研究,发现仅极低含量的温感剂就能够显著提高大麻素的皮肤透过率,在温感剂含量较低时,温感剂的含量和透皮量呈现了线性相关性,而随着温感剂含量增加至某一阈值之上后,则其对药物的促渗效果进入所谓的平台期,即当温感剂含量大于一定的数值时,温感剂含量的继续增大并不会对药物的促渗产生持续的线性增量有益效果。如对于本发明中所涉及的大麻二酚聚丙烯酸酯基质(采用了聚丙烯酸酯压敏胶黏合剂)的透皮贴剂而言,当其中含有的香兰基丁基醚的含量满足如下的条件时,即:以其在基质中的质量含量计,当其中的香兰基丁基醚的含量为0.001%-0.5%时,则香兰基丁基醚的含量和大麻二酚的渗透基本上呈现了线性相关性,考虑到透皮贴剂的载药量和进入人体产生生理活性的大麻二酚浓度,上述的温感剂的含量范围尤其优选0.01%-0.1%,更优选0.02%-0.08%。
发明人对温感剂促进大麻二酚透皮的作用机理进行了初步的研究和理论推导,认为这主要是如下两个因素所带来的效果。首先,温感剂的使用可以加快贴剂部位的皮下毛细血管的血液循环,从而加快了药物的扩散速率。其次,这和以大麻二酚为代表的大麻素类化合物的理化性质密切相关,主要是大麻二酚的高脂溶性所决定的。我们已知,大麻二酚的辛烷/水的LogP值高达8.01,该数值表明其具有极强的脂溶性和极弱的水溶性。实际上,单纯从传统理论上来说,如此高的脂溶性的药物并不适合制备成透皮贴剂,因为一般认为,具有最好透皮给药性能的药物的LogP值应该是介于3-5之间,但是令人意外的是,实验数据表明,如果在透皮贴剂中加入一定量的温感剂如香兰基丁基醚,能够极大地改善大麻二酚的透皮性能,大大促进其单位时间和单位面积内透过皮肤的量,即其透皮性能得以大大改善。根据相关数据,我们推测可能是皮下组织中血液微循环的加快同时也改善了皮肤的角质层所在的表皮层及其下的真皮层的性质,从而使得其通过高脂溶性的大麻素如大麻二酚的渗入的效率大大提高,并在事实上改良了具有高的脂溶性的大麻二酚等大麻素类化合物通过角质层所在的表皮层和其下的真皮层的物理进程,且在皮下被迅速吸收进入血液循环或分布于局部组织,从而取得了意料之外的透皮效果。本发明正是基于以上的实验结果和理论推导而做出的,其为本发明的基础。
以下通过实施例对本发明进行进一步的说明,但是实施例只是为了进一步说明本发明而不构成对本发明的任何限制。
附图说明
附图1为实施例1-15中的大麻二酚透皮贴剂分别在豚鼠无毛皮肤上贴敷12小时候的药物释放量曲线(单位:μg/cm2)。从图中可以初略地判断出大麻二酚透皮贴剂药物释放量和其中含有的大麻二酚及香兰基丁基醚的浓度的线性关系。
具体实施方式
以下通过具体的实施例详细描述制备含有香兰基丁基醚的大麻二酚透皮贴剂。本部分只是为了通过实施例说明本发明中的具体技术方案的实施,但其不构成对本发明的任何限制。
本部分以制作聚丙烯酸酯压敏胶为基质的大麻二酚透皮贴剂为例对本发明进行更加具体的描述。本发明中的制备大麻二酚透皮贴剂的一般步骤如下:
1)将压敏胶黏合剂溶解于相应的溶剂中,如将聚丙烯酸酯压敏胶黏合剂Duro-tak87-2287溶解于纯的乙酸乙酯或环己烷中,优选溶解于乙酸乙酯中,最后制备获得澄清、均质的压敏胶黏合剂胶浆,适当调整其粘度至2000cP~20000cP左右为宜,经实测,满足以上条件的本压敏胶黏合剂胶浆的固含量约为60%。
2)将根据处方量计算所需量的香兰基丁基醚和抗氧化剂(如果有的话)加入到上述1)的黏合剂胶浆中,继续搅拌,获得均质的体系,待用。
3)将根据处方量计算所需量的大麻二酚溶解于少量的乙酸乙酯中,并加入2)中的均质体系中,继续搅拌,待其澄清均质后获得含药胶浆。
4)根据测算大麻二酚含量而拟定的涂布厚度,将3)中的含药胶浆涂布在薄的弹力布、铝箔或镀铝聚乙烯薄膜上,然后将具有含药胶浆涂布的上述弹力布、铝箔或镀铝聚乙烯薄膜置入温度为40℃-50℃的以约2米/秒的速率流动的干燥热空气中进行干燥处理约10分钟,使得体系中的挥发性溶剂基本挥发干净,仅留有少量残留溶剂,其余为由含药黏合剂组成的半固体基质。
5)将4)中的附着于弹力布、铝箔或镀铝聚乙烯薄膜的薄片状基质和经过防粘处理的聚酯膜防粘面复合,从而获得含药基质夹在上述的弹力布、铝箔或镀铝聚乙烯薄膜和防粘聚酯膜之间的产品。
6)使用手工或机器模切的方式,获得所需大小的透皮贴剂,如大小为10cm2、20cm2、30cm2或2cm2(本大小透皮贴剂用于下述实验例中测试释药性能,该面积的形状为圆形)的贴片,形状可以是正方形、长方形、圆形、椭圆形或异形,优选正方形或圆形。
实施例1
根据上述的步骤,按照如下的配方配制含有大麻二酚的涂布含药胶浆(湿基质):
Duro-tal 87-2287:500g
香兰基丁基醚:0.003g
大麻二酚:0.3g
乙酸乙酯:适量(使得含药胶浆的粘度在上述预设范围内,溶剂最终基本上从体系中挥发)
此时,获得了上述步骤3)中所述的含药胶浆,然后按照上述步骤的4)-6)操作,获得面积分别为10cm2、20cm2、30cm2、40cm2的大麻二酚透皮贴剂,其中的大麻二酚的含量为0.1mg/cm2。
实施例2-5
表1给出了实施例2-5的处方,其中透皮贴剂的制备方法基本上和实施例1相同。
表1 实施例2-5
实施例2-5中的贴剂,含有的大麻二酚的含量均为0.1mg/cm2。而其中含有的香兰基丁基醚的浓度则依次为0.004%、0.012%、0.048%和0.256%。
实施例6-10
表2给出了实施例6-10的处方,其中透皮贴剂的制备方法基本上和实施例1相同。
表2 实施例6-10
实施例11-15
表3给出了实施例11-15的处方,其中透皮贴剂的制备方法基本上和实施例1相同。
表3 实施例11-15
实施例16-18
表4给出了实施例16-18的处方,其中透皮贴剂的制备方法基本上和实施例1相同。
表4 实施例16-18
Claims (10)
1.一种含有大麻素的透皮贴剂,其中所述的大麻素为从大麻科植株中提取而获得的一种纯的大麻素化合物,该透皮贴剂的压敏胶黏合剂选自药用聚丙烯酸酯、药用聚异丁烯或药用聚硅氧烷中的一种,以质量百分含量计,该透皮贴剂的基质中的大麻素化合物的含量为0.1%-20%,温感剂的含量为0.001%-0.5%,抗氧化剂的含量为0%-0.1%,余量为药用压敏胶黏合剂。
2.权利要求1所述的含有大麻素的透皮贴剂,其中的压敏胶黏合剂为药用聚丙烯酸酯。
3.权利要求1所述的含有大麻素的透皮贴剂,其中的大麻素化合物的含量范围为0.2%-15%。
4.权利要求1所述的含有大麻素的透皮贴剂,其中的大麻素化合物的含量为2%-15%。
5.权利要求1-4任一项所述的含有大麻素的透皮贴剂,其中的温感剂的含量为0.01%-0.1%。
6.权利要求5所述的含有大麻素的透皮贴剂,其中的温感剂的含量0.02%-0.08%。
7.权利要求1-6之任一项所述的含有大麻素的透皮贴剂,其中的大麻素是大麻二酚。
8.权利要求1-6任一项所述的含有大麻素的透皮贴剂,其中的温感剂为香兰基丁基醚。
9.权利要求1-6任一项所述的含有大麻素的透皮贴剂,其中的抗氧化剂为生育酚或抗坏血酸。
10.权利要求9所述的含有大麻素的透皮贴剂,其中的抗氧化剂为生育酚。
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Application publication date: 20220517 |