CN103349643A - 透皮药物制剂 - Google Patents
透皮药物制剂 Download PDFInfo
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- CN103349643A CN103349643A CN2013102181280A CN201310218128A CN103349643A CN 103349643 A CN103349643 A CN 103349643A CN 2013102181280 A CN2013102181280 A CN 2013102181280A CN 201310218128 A CN201310218128 A CN 201310218128A CN 103349643 A CN103349643 A CN 103349643A
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- gel
- skin
- organosilicon
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Abstract
本发明涉及具有增强的稳定性和生物利用度的半固体透皮药物制剂,其中颗粒被挥发性硅油组分包被,并且由此得到的悬浮液分散在凝胶或乳膏基质中。
Description
技术领域
本申请是申请日为2010年2月5日、申请号为201080011106.1、发明名称为“透皮药物制剂”的中国发明专利申请的分案申请。
本发明涉及含有分散在凝胶基质或乳膏基质中的活性成分的包被颗粒的半固体透皮药物制剂及其制备方法。更特别地,本发明涉及用于透皮应用的制剂,其中活性成分被挥发性有机硅(silicones)(硅氧烷)包被,并且使由此得到的悬浮液分散在凝胶或乳膏媒介物基质中。根据本发明的透皮制剂的物理、化学和微生物学稳定性是优异的,其制备可以通过简单的操作以及选择适当的用于包被活性成分的挥发性有机硅组分进行,已经能够生产用于表面(topical)、局部或全身应用的透皮制剂。
背景技术
由于优异的化学惰性、耐热性和耐冷性、与生物***的相容性,以及由其化学结构决定的优异的机械性能,有机硅(也被称作硅氧烷(siloxane)、硅烷或聚硅氧烷)的应用领域特别广泛。有机硅可以含有具有高达700.000道尔顿分子量的线性聚硅氧烷链(例如硅油、弹性地蜡(caoutchoucs))、环状或支链(例如有机硅树脂)或网状结构。硅氧烷通常以不同粘度的硅油用于制药工业。
硅油的沸点和粘度主要取决于其聚合程度。具有较低聚合度的有机硅衍生物是自由流动的挥发性液体。沸点和粘度随聚合度增加而增加。在某一临界聚合度之上或由于交联形成网状结构,有机硅呈现为半固体或固体弹性物质,例如硅氧烷弹性地蜡和硅氧烷橡胶。
聚硅氧烷主要通过部分烷基取代的卤素-甲硅烷(silane)或其混合物的水解而产生。例如,根据欧洲专利No.980885,三甲基氯甲硅烷和二甲基二氯甲硅烷的混合物在存在盐酸水溶液的情况下水解,从而得到有机硅聚合物的混合物,其通过蒸馏和分馏而精制。
在药物中引入有机硅由于生产这些具有医药用途所必须的质量的化合物的特别昂贵且复杂这一事实而延迟。例如,常常发现用于眼科的硅油含有单体或寡聚体,其使该油对预期目的的适用性降低,并发现对健康有潜在伤害。有机硅聚合物在用于含药或手术植入物、假体和医疗装置目的的医药中使用。
高挥发性有机硅属于硅油的组。术语“挥发性有机硅”是指那些用作药物助剂的硅油,其在不到六小时内从人类皮肤上蒸发并且此后不留任何残留物。此类挥发性有机硅可以以适合生产药物的质量生产。
使用不同聚合度的有机硅以配制化妆品和药物制剂以及营养制剂是现有技术已知的。硅油以及高分子量弹性地蜡通常用作媒介物、膜形成剂,而现有技术中硅油已经用作分散剂或稳定剂。
根据现有技术使用挥发性有机硅用于在化妆品或药物乳液或悬浮液中的连续液相中部分分散可混溶的液体或固体。欧洲专利No.639372中的制剂是化妆品或药物气溶胶,其中六甲基二硅氧烷用作分散剂以使活性成分、触变性(tixotropic)助剂和固体媒介物,例如滑石粉均匀化。
欧洲专利申请No.1472263已经公开了将某些挥发性有机硅用作化妆品制剂中的媒介物。
英国专利No.2064363公开了一种适合增加向皮肤上表皮层渗透的液体媒介物***,含有水、挥发性有机硅和选自乙氧基化脂肪酸或乙氧基化去水山梨糖醇酯的乳化剂。国际专利申请WO2005053666公开了一种含有维生素D作为药物活性成分的相似的制剂,其中附加的非挥发性烃或酯用作媒介物的组分。
已公布的国际专利申请WO2006100489公开了一种乳液形式的液体制剂,其含有活性成分、渗透促进剂、渗透调节剂和挥发性媒介物。在渗透促进剂中提及了苄醇,在渗透调节剂中提及了挥发性有机硅。媒介物是短链醇的混合物。该制剂适合给予预期产生全身效应的药物活性成分。
液体药物制剂的缺点在于由于液体状态,应用周期和给药剂量都难以重复和复制。因此,此类制剂即使在给药周期短的情况下也仅推荐用于表面或局部应用(例如皮肤、粘膜、皮下肌肉***以及应用部位附近)。
挥发性有机硅很少用于半固体药物制剂。欧洲专利No.410099公开了用于表面应用的无水的抗菌凝胶,其中活性成分是四环素抗生素并且媒介物由有机硅组分或选自八甲基环四硅氧烷、十甲基环五硅氧烷(decamethylcyclopentasiloxane)或六甲基二硅氧烷或其混合物的混合物、作为凝胶和膜-形成剂的选自丙烯酸酯、乙酸乙烯酯或聚乙烯均聚物的聚合物以及酯类软化剂组成。
欧洲专利No.980885公开了含有分散在含有挥发性有机硅分散剂、非挥发性石蜡、水和羟丙基甲基纤维素的凝胶中的化妆品成分的化妆品制剂。
欧洲专利No.998943公开了一种由八甲基环四硅氧烷、十甲基环五硅氧烷或六甲基二硅氧烷或其混合物、维生素E和氢化蓖麻油组成的基本上无水的凝胶制剂。
美国专利No.US4,355,046和US5,336,692公开了使用六甲基二硅氧烷、八甲环三硅氧烷和十甲基五硅氧烷来使化妆品制剂在皮肤表面均匀分布。
已公布的国际专利申请No.WO2009007764公开了一种具有改进的吸收和生物利用度的透皮制剂,含有阿昔洛韦、吡罗昔康、美洛昔康、布洛芬、双氯芬酸钠或钾、克霉唑、联苯苄唑、甲硝唑、硝苯地平、***或西替利嗪作为活性成分,含有在挥发性有机硅中的活性成分的颗粒的悬浮液,所述悬浮液分散在凝胶或乳膏基质中。
需要非侵入性的、可以在摄入片剂困难的情况下,例如老年人或婴儿的情况下给予药物活性成分的方法。对于那些在肠道***中吸收部位易于代谢或经历广泛首过代谢的药物活性成分而言,还需要绕过肠道途径的给药方法。
根据现有技术,不存在已知含有提供活性成分全身效应的挥发性有机硅或此类化合物的混合物的以透皮乳膏或凝胶形式存在的药物制剂。
透皮应用途径对于达到全身效应的优势在于活性成分在血浆中的浓度曲线是稳定的事实。此外,透皮应用方法适合将从肠道吸收差、有刺激性、消除迅速或在代谢过程立即失活的活性成分引入机体。透皮应用方法的主要缺点在于贴剂或乳膏可能引起刺激、皮肤改变,和在某些情况下它们的移除可能有困难或无法完全从应用区域移除的事实。
现有技术中已知亲脂性乳膏的缺点在于活性成分的吸收差且缓慢的事实,因为由于亲脂性媒介物和外层皮肤的分布,大部分活性成分保留在常量媒介物中。
现有技术中已知含有悬浮状态的活性成分的亲水性凝胶制剂。尽管多数情况下从此类制剂的吸收是充分的,但这些制剂在储存过程中易于发生物理-化学改变,包括活性成分分解、制剂的胶体结构降解,并且经常出现微生物污染。该过程降低了制剂稳定性和贮存期限。
对包括半固体凝胶和乳膏在内的透皮药物制剂的主要要求是稳定性、足够长的贮存期限、治疗应用时吸收充分的活性药物成分以及在应用环境下适当的物理状态。
发明内容
本发明提供凝胶或乳膏形式的半固体透皮药物制剂,其中充当媒介物的凝胶或乳膏基质含有被高挥发性硅油或其混合物包被的活性成分的分散颗粒。在根据本发明的制剂中,最优选地,可以使用六甲基二硅氧烷、八甲三硅氧烷或十甲基五硅氧烷。根据本发明的透皮半固体制剂适合任选地以剂量单位(dosage unit)的形式应用于皮肤或粘膜,并且取决于组合物,可以以允许形成表面、局部或全身效应的形式生产本发明的透皮组合物。根据本发明的组合物具有优异的物理-化学和微生物学稳定性。
发明详述
我们的研究目的是开发透皮半固体药物剂型,所述透皮半固体药物剂型适用于具有良好吸收、渗透和生物利用度,同时表现出适当的物理化学稳定性、无微生物污染或降解并具有适宜长的贮存期限的药物活性成分、化妆品成分或营养成分的制剂。此外,我们旨在开发一种媒介物***,所述媒介物***可以被配制成实现将制剂的所需组分可重复靶向递送至所需产生治疗效果的位置,包括获得表面、局部或全身效应的可能性。
根据本发明实现了上述目的。
令人惊讶地,我们已经发现通过使用挥发性有机硅作为助剂可以生产出满足上述需求的半固体透皮制剂。乳膏和凝胶的稳定性、吸收、渗透性受到挥发性有机硅或其混合物的质量和比例的控制。
术语“有机硅”、“甲硅烷”和“硅氧烷”在本说明书中可替换使用,代表元素硅的化合物,其中聚硅氧烷O-[SiR1R2-O]n-Si链中的硅原子被R1、R2烷基基团取代。
在本说明书中,术语“透皮制剂”代表任何应用于皮肤的药物制剂,其与在制剂的应用区域,在位于其邻近处的组织中或遍及包括远离应用位置的器官和组织在内的全身所表现的药理学效应无关。
因此,术语“表面效应”是指药理学效应仅在根据本发明的透皮制剂应用的区域出现。
术语“局部效应”的意思是指药理学效应在根据本发明的透皮制剂应用的区域邻近的组织中出现。例如,应用于皮肤的表面制剂可能在皮肤下的肌肉***发挥效应但活性成分在血浆中检测不到或其浓度远低于治疗作用所需的浓度。
术语“全身效应”代表药理学效应遍及全身或生物体各处出现,即使在位于远离根据本发明的透皮制剂应用区域的组织或器官内也出现。此类制剂的活性成分通常从应用区域吸收进入血流。
根据本发明的第一个方面,提供了透皮药物制剂,其含有与一种或多种挥发性有机硅混合或被其包被的分散在乳膏或凝胶基质中的活性成分的颗粒。
出乎意料地认识到,根据本发明的透皮半固体制剂即使以剂量单位的形式也适合应用于皮肤或粘膜,并且取决于组合物,可以以允许形成表面、局部或全身效应的形式生产本发明的透皮组合物。该效应非常令人惊讶,因为根据现有技术迄今为止还不能通过半固体透皮制剂实现全身效应。
根据本发明的第二个方面,提供了适合表面使用的透皮药物制剂,其含有与一种或多种挥发性有机硅混合或被其包被的分散在乳膏或凝胶基质中的活性成分的颗粒。在本申请的上下文中,术语“表面效应”是指药理学效应仅在根据本发明的透皮制剂应用的皮肤区域出现。
根据本发明的第三个方面,提供了适合实现局部效应的透皮药物制剂,其含有与一种或多种挥发性有机硅混合或被其包被的分散在乳膏、软膏或凝胶基质中的活性成分的颗粒。术语“局部效应”是指药理学效应在根据本发明的透皮制剂应用的区域邻近的组织中出现。
根据本发明的第四个方面,提供了适合获得全身效应的透皮药物制剂,其含有与一种或多种挥发性有机硅混合或被其包被的分散在乳膏、软膏或凝胶基质中的活性成分的颗粒。术语“全身效应”是指药理学效应遍及全身或生物体各处出现,即使在位于远离根据本发明的透皮制剂应用区域的那些组织或器官中也出现。根据本发明该方面的制剂的活性成分通常可以在血浆中检测到。
然而本领域技术人员理解不可能根据治疗效果的主要部位将三个种类明显地分离开。已知即使在表面制剂的情况下也出现药物活性成分的轻度吸收,尽管通常这是不被期望或预期的。此外,可能出现预期局部效应的制剂的活性成分进入血液循环并且出现些许程度的全身效应的情况,尽管这不是预期的。因此可能根据本发明设计制剂,根据作用部位所述制剂是居间的(intermediary),即它们在表面或局部起作用,或在局部或全身起作用。然而该多重作用有时候是有利的,因为其可以增强治疗效果。例如,在抗真菌药的情况中,在皮肤表面并且在一定程度上在皮肤和皮肤附件的深层治疗中(等于局部效应)治疗真菌感染是有利的。因此,可以实现靶向药物递送。
本发明特别有利和令人惊讶的效果,即适合通过皮肤给药的透皮制剂可以制备成允许活性成分从皮肤中以能够渗透进入循环的高的程度吸收,从而提供了全身效应。此类制剂的吸收速率可以比得上通过口服给药达到的吸收速率而不存在可能的摄入片剂的困难。可以将相当于常用口服剂量(或通过给予常规口服剂量达到的血浆水平)的透皮制剂的剂量单位递送至皮肤。
在根据本发明的制剂中,挥发性甲硅烷组分优选自六甲基二硅氧烷、八甲三硅氧烷或十甲基环五硅氧烷(decamethylpentacyclosiloxane)或其混合物。然而,也可以使用其它挥发性有机硅。作为基质媒介物,可以使用优选形成凝胶的聚合物(gel-forming polymer),诸如可以使用羧乙烯聚合物(carboxyvinylpolymer)、羟丙基甲基纤维素、甲基纤维素或类似物或其混合物。
根据本发明的组合物可以含有一种或多种活性成分。活性成分的范围不特别限于药物活性成分和化妆品成分,而可以包括其它应用于人类或动物皮肤的其它化学制品(例如杀虫药)。活性成分可以在表面、局部或全身发挥其效应。应理解一些活性成分仅发现外部使用并通常配制成用于表面给药的制剂。取决于治疗目的,那些可以在外部或内部使用的活性成分可以配制用于表面、局部或全身治疗效果。
然而,活性成分的物理-化学性质也影响其在根据本发明的制剂中的适用性。已发现那些主要以解离形式存在于水溶液中,显著溶胀或属于强碱或酸的活性成分不容易根据本发明配制。
可以用于本发明透皮制剂的药物活性成分没有明确限制。例如,活性成分可以用于治疗或预防传染病,癌或血液学疾病,属于内分泌、营养或代谢障碍的组的疾病,中枢神经***疾病,由于营养不良造成的疾病,精神病,行为障碍,强迫性障碍,性或性传播疾病,精神和认知功能的疾病和病症,神经疾病,中风,眼科疾病,耳鼻喉科疾病,心血管或脑血管疾病,呼吸器官疾病,肺部疾病,牙科疾病,属于胃肠病学或肝脏病学的疾病或障碍。通常应用于皮肤病学、免疫学、男性学、妇科学和产科学,用于治疗骨-关节炎和肌肉***疾病的活性成分可以根据本发明配制。根据本发明的制剂可以非常有利地用于制备抗外部物理作用(physical effect)的药物或生物制剂,包括但不限于烧伤、冻伤、微生物、抗动物或草药毒物和毒素、内部或外部寄生虫或微生物引起的感染,或用于加速伤口愈合并减轻变应性反应的药物。根据本发明其还可以配制诊断剂或消毒剂。
本发明的药物活性成分可以选自那些适于治疗神经***的物质,包括镇痛药、***、解热药、抗偏头痛药、催眠药、镇静药、抗抑郁药、抗焦虑药、抗精神病药物、抗震颤麻痹药、抗癫痫药、安神剂或抗惊厥成分,例如利多卡因、丁卡因、普鲁卡因、苯佐卡因、***、硫喷妥钠、海索比妥、属于天然或合成阿片样物质衍生物的化合物、氨基比林(amidazophen)、安乃近(novamidazophen)、对乙酰氨基酚、阿司匹林、茶碱(theophilline)、咖啡因、阿普***、oxazepinetiazepine或二氮杂衍生物、***、phentiazine或吲哚衍生物、oxypropaneamine衍生物、二苯胺衍生物、唑吡坦、利培酮、阿立哌唑、奥氮平、昂丹司琼、多奈哌齐、格拉司琼、安乃近、氨基比林、非那西丁、麦角胺、那拉曲坦或其它选择性5-羟色胺激动剂、单胺或5-羟色胺再摄取抑制剂、胆碱酯酶抑制剂或刺激剂。
根据本发明配制的活性成分还可以选择有效抗心血管或血液***疾病的那些。例如,制剂可以含有抗凝血剂,抗高血压药,抗血脂药,α或β肾上腺素能受体拮抗剂,血小板聚集抑制剂,抗硬化剂(antisclerotic),离子通道阻滞剂,抗关节炎药,血管扩张或血栓溶解剂,例如强心苷、曲克芦丁、***、戊四硝酯、硝酸异山梨醇、硝苯地平、氨氯地平、非洛地平、维拉帕米、地尔硫卓,ACE-抑制剂,包括卡托普利、培哚普利、依那普利、雷米普利或赖诺普利,血管紧张素II-抑制剂,包括缬沙坦、氯沙坦、依贝沙坦、奥美沙坦或替米沙坦,香豆素衍生物,肝素衍生物,凝血细胞聚集抑制剂(trombociteaggregation inhibitor),包括氯吡格雷、噻氯匹定、普拉格雷和乙酰水杨酸或布洛芬,凝血酶抑制剂,止血-收敛剂,甲基多巴,哌唑嗪,多沙唑嗪,特拉唑嗪,肼屈嗪,阿普洛尔,***,美托洛尔,比索洛尔,阿替洛尔,奈必洛尔,卡维地洛,烟酸,己酮可可碱,麦角生物碱或苄环烷。
作为有效抗炎症并适合作用于免疫***的活性成分,可以使用抗炎药、抗组胺剂、免疫抑制剂、免疫刺激剂、抗变应性剂、抗风湿剂、免疫调节剂、抗关节炎药、白细胞三烯拮抗化合物或适于诱导免疫反应的抗原。此类化合物为例如苄达明、水杨酸衍生物、肝素衍生物、生物类黄酮、非甾类抗炎药,包括双氯芬酸及其盐、布洛芬、酮洛芬、氟比洛芬和***素衍生物。
在适合抗感染的药物活性成分中,可以使用通用消毒剂、抗生素、化学治疗剂、抗微生物剂、抗菌剂、抗真菌剂或抗病毒化合物或适于诱导抗感染剂免疫反应的抗原。适于抗感染的活性成分的实例为甲氧苄啶(trimethoprim)、磺胺二甲嘧啶、磺胺甲唑、益康唑、咪康唑、克霉唑、酮康唑、特比萘芬、托萘酯、阿昔洛韦、利巴韦林、更昔洛韦、伐昔洛韦、拉米夫定、依培夫定、新霉素和其它氨基糖苷类抗生素;大环抗生素,克拉霉素、红霉素、泰洛菌素;四环素或氟喹诺酮类抗生素。通用消毒剂的例子为过氧化氢或其复合物、过氧苯甲酰、西吡铵(cetylpyridinium)、西曲铵(cetrimonium)或四烷基铵衍生物、三氯生、苯并三甲基铵衍生物、乳酸衍生物和氯己定。根据本发明的组合物可以含有有效抗外部或内部寄生虫的活性成分以及杀虫药。
在根据本发明的制剂中,有利地可以使用非甾类或甾类抗炎化合物,例如氢化可的松、***龙、甲泼尼龙、曲安西龙、倍他米松、布***、***、氟轻松、双氯芬酸、布洛芬、氟比洛芬和酮洛芬。
适于治疗消化和分泌***的活性成分的实例为利尿剂、利胆剂、抗溃疡剂、抗酸剂、止吐剂、降低食欲剂、收敛剂或缓泻剂化合物,例如西咪替丁、雷尼替丁、法莫替丁、西沙必利、奥美拉唑、泮托拉唑、兰索拉唑、雷贝拉唑、艾美拉唑、鞣酸蛋白、胰酶、胰蛋白酶、菠萝蛋白酶、罂粟碱、屈他维林、阿托品、莨菪碱、颠茄生物碱及其衍生物、脱氧胆酸衍生物、水飞蓟素衍生物、酚酞、***、利莫那班、氢***、***、可可碱(teobromine)、呋塞米、螺内酯、阿米洛利和氨苯蝶啶。
根据本发明的透皮制剂可以含有影响代谢的活性成分,诸如抗糖尿病剂、利尿剂、降血脂剂、糖皮质激素类或蛋白同化剂,诸如胰岛素、二甲双胍、氨苯磺胺抗糖尿病剂、格列美脲、吡格列酮、罗格列酮、曲格列酮、维格列汀、西他列汀、瑞格列奈、那格列奈、水或脂溶性维生素及其衍生物、其它营养素和基本元素、司坦唑醇、诺龙、依泽替米贝、他汀类或贝特类,例如辛伐他汀、洛伐他汀、阿伐他汀、普伐他汀、氟伐他汀、罗苏伐他汀、氯贝丁酯、非诺贝特。
根据本发明的组合物可以含有适于治疗呼吸器官疾病的活性成分,诸如抗组胺剂、抗变应性剂、止喘药、支气管扩张药、拟交感神经药、止咳药或祛痰药,例如麻黄碱、去氧肾上腺素、羟甲唑啉(oxymethazoline)、赛洛唑啉(xylomethazoline)、萘甲唑林、chromoglycic acid、选择性β2-肾上腺素能受体拮抗剂、白细胞三烯受体拮抗剂、西替利嗪、左西替利嗪、氯苄吡二胺、氯雷他定、地氯雷他定、非索非那定。
根据本发明的透皮组合物的活性成分可以选自适于治疗肌肉***、骨-关节炎***和运动***的药物化合物,诸如抗风湿剂、解痉剂、抗炎剂或肌肉松弛剂化合物以及有效抗骨质疏松症的化合物,例如罂粟碱、屈他维林、阿托品、保泰松、吲哚美辛、双氯芬酸、布洛芬、酮洛芬、萘普生、氟比洛芬、塞来考昔、尼氟酸、尼美舒利和甲苯哌丙酮;阿伦膦酸、zolendronate或伊班膦酸盐。外用有用的抗组胺剂和伤口愈合剂也可以用作本发明的活性成分,例如二甲茚定、苯海拉明、甘菊环、右泛醇。
根据本发明的组合物可以含有适于治疗癌症的活性成分,例如抗肿瘤剂、生物烷化剂(例如氮芥类似物)、烷基磺酸酯、细胞毒性抗生素、抗代谢物、草药生物碱或抗肿瘤细胞蛋白抗体。
在根据本发明的制剂中可以使用用于治疗性器官、性或性传播疾病的活性成分。此类活性成分包括性激素、激素拮抗剂、子宫刺激剂;例如孕酮、麦角生物碱、***素、***、雌三醇、雌酮及其衍生物、炔诺酮、替勃龙、氯米芬;避孕药,例如孕激素、***、诺孕酯、炔诺醇、去氧孕烯、左炔诺孕酮、甲羟孕酮;男性学活性成分,包括4-氧代雄甾衍生物和5-雄甾烷二酮(androstanon)衍生物,例如***(methyltestosteron)、美睾酮(mesterolon)、环丙孕酮、阿扑***、前列地尔、昔多芬、阿夫唑嗪、坦洛新、特拉唑嗪、非那雄胺。
根据本发明的更进一步的方面,提供一种制备透皮半固体药物制剂的方法,包括将活性成分或其混合物与一种或多种挥发性有机硅混合并使由此得到的混合物分散在乳膏或凝胶基质中,其中被挥发性有机硅或其混合物包被的活性成分的颗粒在凝胶、乳膏或软膏基质中形成分离的相,而挥发性有机硅或其混合物的包衣在将活性成分分散在基质中后也保留。
本发明是基于活性成分的固体颗粒被一层挥发性硅油包被,而其在应用过程中大部分蒸发的现象。具有剩余的制剂组分的剩余的活性成分由于皮肤的天然转运现象(扩散、穿透、渗透)而被迅速吸收。吸收的程度取决于制剂的组成。可以用活性成分能够在皮肤上提供其治疗效果的方式配制根据本发明的透皮制剂。然而还可以选择组分和特别是它们的相对比例以提供主题活性成分的全身效应。
已发现根据本发明的含有挥发性有机硅的制剂的物理-化学和微生物学稳定性与那些根据现有技术已知的制剂(溶液、乳液或悬浮液的形式)相比得以改进。该增强的稳定性是由活性成分和媒介物基质之间有机硅包衣的疏水性物理-化学屏障效应造成的,该效应使空气和水从活性成分中排除。通过该分离效应,活性成分变得对引起分解的机制(例如,水解、电离、催化和自身催化分解)无效。
硅油层即使在媒介物是含水的并含有有利于分解的试剂的情况下也能防止活性成分免受化学和微生物攻击。过量的挥发性有机硅阻断了引起分解的微生物试剂(例如细菌、真菌、霉菌等)接近活性成分颗粒。因此没有必要在根据本发明的透皮制剂中使用任何保存剂(conservant)。
在制药工业中常用的稳定性试验条件下已经测定了透皮制剂的稳定性,其在五年贮存期后没有显示出任何可检测到的变化。
在应用于皮肤的过程中,挥发性有机硅蒸发无残留,并且不与身体相互作用。从使用者的观点来看该产品基本上不含保存剂。应用于皮肤后,有机硅化合物蒸发并且活性成分和其它制剂组分保留在皮肤表面上。之后这些物质从皮肤吸收。有机硅基质蒸发后,活性成分的颗粒保留在包埋于凝胶中的皮肤表面上,其增强并加速了向皮肤深层中的吸收。
在根据本发明的透皮制剂中,可以使用任何类型的挥发性有机硅包被颗粒。最适合的硅氧烷是六甲基二硅氧烷、八甲三硅氧烷和十甲基环五硅氧烷。作为媒介物凝胶或乳膏基质,可以使用本领域已知的组合物。优选地,使用亲水性凝胶组合物。
已经在体外膜渗透试验中研究了根据本发明的制剂令人惊讶的有利的性质。
用于测试膜渗透性的装置包括具有准确已知表面积和体积的带开放样品隔室的渗透池(penetration cell)、适合控制环境因素(气流、温度、空气湿度、曝光)的***、适合维持受体相(acceptor phase)流动的递送***、取样和分析单元。术语“开放样品隔室池”是指位于表面的样品不是分离的而是直接与周围环境接触。本申请公开的试验在无气流和曝光情况下于自然日光32℃的温度下进行。在膜表面的池的横截面精确地为10,00cm2,池的体积为3,00cm3。在试验过程中,使用膜厚度为30μm的池。受试样品由约0.5g部分的根据本发明的透皮制剂组成,其被转移至位于池上部的膜上。膜用于模拟受试的生物屏障,在这种情况下是皮肤。
在试验过程中的受体相由0.9重量%的氯化钠溶液组成。受体相以1ml/min的恒定流速递送通过渗透池。在流出物中,测定受试制剂特征性组分(一般是药物活性成分)的浓度。在本试验过程中,使用配置有流动池的分光光度计通过紫外分光法进行测定。测定持续6小时。使用外部校准,确定作为洗脱体积(与样品应用至膜经过的时间成比例)函数的浓度曲线,从这些数据可以计算出在试验期间渗透过膜的特征性组分,例如活性成分的量。吸收速率通过相对于应用至膜的样品中存在的受试制剂的特征性组分的总量而言在试验期间渗透过膜的量来模拟。在那些特征性组分(例如药物活性成分)不具有对于紫外检测而言足够的吸收系数或存在干扰的情况下,可以使用其它分析方法,例如经典分析或电分析法,例如碘量法、离子选择电极等。
在根据本发明为表面应用而配制的透皮制剂的试验过程中,我们已经发现渗透过膜的活性成分的量不超过0.1%,因此可以得出结论认为活性成分实际上保留在皮肤表面。已发现根据本发明的制剂在当渗透过膜的活性成分的量在1-20%,优选7-20%,最优选12-20%的范围内时表现出表面效应。在那些根据本发明的透皮制剂与实现全身效应的组合物制备的情况下,渗透过膜的活性成分的量超过20%。然而在多数情况下,该数值在66-95%之间。表1公开了多种活性成分已经渗透过膜的活性成分的量以及在实施例中公开的两种组合物。然而,本领域技术人员还考虑活性成分的性质,这是现有技术已知的。
表1
*-样品中存在的活性成分的量的百分比(ca.0.5g)
根据本发明的半固体透皮组合物优选以适合递送制剂的剂量单位的形式提供。在这种情况下,以使得通过分配器的一次操作递送相当于一个剂量单位的活性成分的体积的方式来选择活性成分的浓度。配置有适合重复递送定量剂量的分配器的瓶子是现有技术中已知的并且可以商购获得。这种分配方法可以很好地与现有技术中已知的含有相应量的活性成分的剂型中存在的剂量相关联。可以通过将标有刻度的量筒或量勺封入制剂的包装中进行制剂的定量。此类给药方法是现有技术中已知的。
根据本发明的透皮制剂特别适合制备具有高稳定性、良好生物利用度的剂型,并且适合含有利多卡因碱、***、益康唑碱、磺胺二甲嘧啶、鞣酸蛋白、罂粟碱、屈他维林、苄达明、阿托品碱、微粉化硫磺、多硫酸戊聚糖、曲克芦丁、胰酶、新霉素、氢化可的松、磺胺甲唑、甲氧苄啶、氨基比林、安乃近、对乙酰氨基酚、阿普***、茶碱或咖啡因作为活性成分的方便给药。可以非常容易地从表1的数据看出同样的活性成分可以如体外膜渗透实验所模拟的以获得表面效应(磺胺二甲嘧啶,制剂2,0.01%的量的活性成分渗透过膜)或获得高吸收和渗透率、良好生物利用度从而产生全身效应(磺胺二甲嘧啶,制剂1,72.4%的活性成分渗透过膜)的方式配制。
在下述实施例中,在不限制公开的组合物和方法的保护范围的情况下例证了根据本发明的透皮制剂的组成和制备方法。
在实施例中以“有机硅流体”提及的助剂是甲基硅氧烷(六甲基二硅氧烷和/或八甲三硅氧烷或其混合物)。实施例中提及的硅氧烷溶液的粘度为0.65cSt、100cSt或200cSt。这些试剂可以商购获得。
实施例1
适于全身效应的透皮凝胶
根据所需的制剂规格或根据调配的体积和单位剂量选择活性成分的量。
实施例2
用于表面应用的透皮半固体制剂
根据所需的制剂规格或根据调配的体积和单位剂量选择活性成分的量。
实施例3
制备方法
按照下述方法制备根据实施例1或2的组合物以及具有相似定性组成的组合物。
3.1.活性成分悬浮液的制备
将任选地微粉化的活性成分与硅油混合。随后用适合的实验室混合器,例如实验室规模的混合器,使用Ultra-Turrax混合装置将混合物均匀化(4000min-1,5min)。
3.2.凝胶基质的制备
于25℃的温度分小部分将羟丙基纤维素加入水中并搅拌至完全溶解。随后向溶液中加入卡波普980NF并搅拌至溶解。之后用10重量%的氢氧化钾溶液中和溶液。持续搅拌直到获得光滑的凝胶状态。
3.3.含药凝胶的制备
分小部分向根据3.2制备的凝胶基质中加入活性成分的悬浮液并均匀化。
本申请涉及下述具体实施方案:
1.用于透皮应用的半固体药物制剂,含有至少一种被挥发性硅油或该油类混合物包被的分散在凝胶或乳膏基质媒介物中的活性成分的颗粒。
2.根据具体实施方案1所述的药物制剂,其特征在于挥发性硅油组分选自六甲基二硅氧烷、八甲三硅氧烷、十甲基环五硅氧烷或其混合物。
3.根据具体实施方案1或2所述的药物制剂,其特征在于活性成分选自适合治疗或预防传染病,癌或血液学疾病,内分泌、代谢或营养疾病,中枢神经***疾病,精神病,行为和强迫性(vislkedési)障碍,强迫性障碍,性和性传播疾病,与精神或认知功能有关的障碍或病症,神经障碍,中风,眼科疾病,牙科疾病,耳鼻喉科疾病,心血管或脑血管疾病,肺部疾病,胃肠道或肝脏疾病,骨-关节炎和肌肉***疾病,免疫疾病,产科或妇科或男性疾病的药物活性化合物,或对治疗外部物理作用引起的损伤有效的药物活性化合物,或抗外部或内部寄生虫、昆虫或微生物的药物活性化合物,或适用作诊断或消毒剂成分的药物活性化合物。
4.根据具体实施方案1-3中任一项所述的药物制剂,其中所述媒介物是含有一种或多种形成凝胶的聚合物、水以及任选的其它助剂的亲水性凝胶基质。
5.根据具体实施方案1-4中任一项所述的药物制剂,其特征在于所述媒介物中的形成凝胶的聚合物是羧乙烯聚合物、羟丙基甲基纤维素或其混合物。
6.用于透皮应用的半固体药物制剂,含有被0.5-10.0重量%的挥发性硅油包被的分散在硅胶基质中的0.05-5.00重量%的药物活性成分,所述挥发性硅油选自六甲基二硅氧烷、八甲三硅氧烷、十甲基环五硅氧烷或其混合物,所述凝胶基质含有0.5-5.0重量%的亲水性聚合物,优选羧乙烯聚合物、羟丙基甲基纤维素或其混合物。
7.根据具体实施方案3所述的药物制剂,其特征在于所述活性成分不同于阿昔洛韦、吡罗昔康、美洛昔康、布洛芬、双氯芬酸钠及钾盐、克霉唑、联苯苄唑、甲硝唑、硝苯地平、***和西替利嗪。
8.根据具体实施方案1-6中任一项所述的药物制剂,含有利多卡因碱、***、益康唑碱、磺胺二甲嘧啶、鞣酸蛋白、罂粟碱、屈他维林、苄达明、阿托品碱、微粉化硫磺、多硫酸戊聚糖、曲克芦丁、胰酶、新霉素碱、氢化可的松、磺胺甲唑、甲氧苄啶、氨基比林、安乃近、对乙酰氨基酚、阿普***、茶碱或咖啡因。
9.根据具体实施方案1-8中任一项所述的药物制剂,预包装在适合定量递送的容器中。
10.根据具体实施方案1-9中任一项所述的药物制剂,适合产生表面治疗效果。
11.根据具体实施方案1-9中任一项所述的药物制剂,适合产生局部治疗效果。
12.根据具体实施方案1-9中任一项所述的药物制剂,适合产生全身治疗效果。
13.制备根据具体实施方案1-7中任一项所述的药物制剂的方法,包括将任选地以微粉化形式存在的活性成分与挥发性硅油或该油类的混合物混合,并且使由此得到的悬浮液以有机硅包衣在凝胶媒介物中的固体颗粒周围形成连续相的方式分散在凝胶或乳膏基质中。
14.一种制备透皮软膏或凝胶组合物的方法,其中将药物活性成分的颗粒用挥发性有机硅包围由此防止所述活性成分颗粒与凝胶或软膏基质接触,其包括将活性成分的颗粒用高挥发性有机硅或其混合物包被和分布,由此获得在水性凝胶或软膏基质中的混合物。
Claims (1)
1.一种制备透皮软膏或凝胶组合物的方法,其中将药物活性成分的颗粒用挥发性有机硅包围由此防止所述活性成分颗粒与凝胶或软膏基质接触,其包括将活性成分的颗粒用高挥发性有机硅或其混合物包被和分布,由此获得在水性凝胶或软膏基质中的混合物。
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CN2010800111061A Pending CN102573793A (zh) | 2009-02-06 | 2010-02-05 | 透皮药物制剂 |
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US (1) | US20120024743A1 (zh) |
EP (1) | EP2393479A2 (zh) |
JP (1) | JP2012517414A (zh) |
KR (1) | KR20110120304A (zh) |
CN (2) | CN102573793A (zh) |
AU (1) | AU2010212158A1 (zh) |
BR (1) | BRPI1005433A2 (zh) |
CA (1) | CA2751633A1 (zh) |
CL (1) | CL2011001875A1 (zh) |
EA (1) | EA023502B1 (zh) |
HU (1) | HUP0900072A2 (zh) |
IL (1) | IL214402A0 (zh) |
MX (1) | MX2011008213A (zh) |
NZ (1) | NZ594618A (zh) |
PE (1) | PE20120584A1 (zh) |
UA (1) | UA107563C2 (zh) |
WO (1) | WO2010089617A2 (zh) |
ZA (1) | ZA201105662B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022007917A1 (zh) * | 2020-07-10 | 2022-01-13 | 江苏恒瑞医药股份有限公司 | 一种含***物活性成分的透皮制剂及其制备方法 |
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US20170065533A1 (en) * | 2011-01-24 | 2017-03-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Nanoparticles for dermal and systemic delivery of drugs |
US11154535B2 (en) | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
US10045935B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
JP5630679B1 (ja) * | 2013-09-08 | 2014-11-26 | 株式会社E・テック | 揮発性消毒剤、揮発性消毒剤の製造方法 |
WO2015127416A1 (en) * | 2014-02-24 | 2015-08-27 | Urigen Pharmaceuticals, Inc. | Compositions of pentosan polysulfate salts for oral administration and methods of use |
SG11202001824RA (en) | 2016-08-31 | 2020-04-29 | Oji Holdings Corp | Production method for acidic xylooligosaccharide, and acidic xylooligosaccharide |
JP6225321B1 (ja) | 2016-08-31 | 2017-11-08 | 王子ホールディングス株式会社 | ポリ硫酸ペントサンの製造方法 |
JP6281659B1 (ja) | 2017-02-28 | 2018-02-21 | 王子ホールディングス株式会社 | ポリ硫酸ペントサン、医薬組成物及び抗凝固剤 |
MX2019014445A (es) * | 2017-05-31 | 2020-02-10 | Oji Holdings Corp | Preparacion hidratante topica. |
US11390693B2 (en) | 2017-09-12 | 2022-07-19 | Oji Holdings Corporation | Pentosan polysulfate and method for producing pentosan polysulfate |
US11344570B2 (en) | 2017-12-20 | 2022-05-31 | Oji Holdings Corporation | Pentosan polysulfate and medicine containing pentosan polysulfate |
RU2704623C1 (ru) * | 2018-12-07 | 2019-10-30 | Общество с ограниченной ответственностью "Научно-производственное объединение "Ликом" | Перевязочное средство на биополимерной основе |
CN115475224B (zh) * | 2022-08-31 | 2023-11-28 | 中国人民解放军空军特色医学中心 | 一种用于治疗冻疮的药膏及其制备方法 |
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-
2009
- 2009-02-06 HU HU0900072A patent/HUP0900072A2/hu not_active Application Discontinuation
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2010
- 2010-02-05 JP JP2011548789A patent/JP2012517414A/ja active Pending
- 2010-02-05 NZ NZ594618A patent/NZ594618A/en not_active IP Right Cessation
- 2010-02-05 CA CA2751633A patent/CA2751633A1/en not_active Abandoned
- 2010-02-05 CN CN2010800111061A patent/CN102573793A/zh active Pending
- 2010-02-05 KR KR1020117020176A patent/KR20110120304A/ko not_active Application Discontinuation
- 2010-02-05 BR BRPI1005433A patent/BRPI1005433A2/pt not_active IP Right Cessation
- 2010-02-05 AU AU2010212158A patent/AU2010212158A1/en not_active Abandoned
- 2010-02-05 EA EA201190134A patent/EA023502B1/ru not_active IP Right Cessation
- 2010-02-05 PE PE2011001443A patent/PE20120584A1/es not_active Application Discontinuation
- 2010-02-05 UA UAA201110091A patent/UA107563C2/uk unknown
- 2010-02-05 EP EP10707660A patent/EP2393479A2/en not_active Ceased
- 2010-02-05 CN CN2013102181280A patent/CN103349643A/zh active Pending
- 2010-02-05 US US13/148,219 patent/US20120024743A1/en not_active Abandoned
- 2010-02-05 WO PCT/HU2010/000015 patent/WO2010089617A2/en active Application Filing
- 2010-02-05 MX MX2011008213A patent/MX2011008213A/es not_active Application Discontinuation
-
2011
- 2011-08-01 ZA ZA2011/05662A patent/ZA201105662B/en unknown
- 2011-08-02 IL IL214402A patent/IL214402A0/en unknown
- 2011-08-04 CL CL2011001875A patent/CL2011001875A1/es unknown
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EP0639372A1 (fr) * | 1993-08-18 | 1995-02-22 | Laboratoires Cilag | Dispositif de distribution d'une substance thérapeutique ou cosmétique dont le véhicule inerte est un polydiorganosiloxane volatil, et composition destinée à être utilisée dans le dispositif |
WO2006138035A1 (en) * | 2005-06-13 | 2006-12-28 | Dow Corning Corporation | Vehicle for the delivery of topical lipid soluble pharmaceutical agents |
WO2009007764A2 (en) * | 2007-07-10 | 2009-01-15 | Egis Gyógyszergyár Nyilvánosan Müködö | Pharmaceutical preparations containing highly volatile silicones |
Cited By (1)
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WO2022007917A1 (zh) * | 2020-07-10 | 2022-01-13 | 江苏恒瑞医药股份有限公司 | 一种含***物活性成分的透皮制剂及其制备方法 |
Also Published As
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WO2010089617A3 (en) | 2011-06-16 |
ZA201105662B (en) | 2012-10-31 |
NZ594618A (en) | 2014-01-31 |
CA2751633A1 (en) | 2010-08-12 |
CL2011001875A1 (es) | 2012-07-13 |
EA201190134A1 (ru) | 2012-02-28 |
WO2010089617A2 (en) | 2010-08-12 |
US20120024743A1 (en) | 2012-02-02 |
MX2011008213A (es) | 2011-09-28 |
KR20110120304A (ko) | 2011-11-03 |
IL214402A0 (en) | 2011-09-27 |
EA023502B1 (ru) | 2016-06-30 |
HUP0900072A2 (hu) | 2010-09-28 |
EP2393479A2 (en) | 2011-12-14 |
PE20120584A1 (es) | 2012-05-23 |
BRPI1005433A2 (pt) | 2019-09-24 |
CN102573793A (zh) | 2012-07-11 |
JP2012517414A (ja) | 2012-08-02 |
HU0900072D0 (en) | 2009-03-30 |
AU2010212158A1 (en) | 2011-09-08 |
UA107563C2 (uk) | 2015-01-26 |
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