CN1336823A - 活性成分具有更高输送性的组合物 - Google Patents
活性成分具有更高输送性的组合物 Download PDFInfo
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- CN1336823A CN1336823A CN00802692A CN00802692A CN1336823A CN 1336823 A CN1336823 A CN 1336823A CN 00802692 A CN00802692 A CN 00802692A CN 00802692 A CN00802692 A CN 00802692A CN 1336823 A CN1336823 A CN 1336823A
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Abstract
本发明涉及药物活性成分的输送性改善的组合物。这些组合物包含位于无水溶剂中的药物活性成分。这些组合物可以采用置于口中并最终吞服的液态酏剂形式,或者通过注液体的锭剂、和口香糖、量液给药装置、雾化器和释放液体的可食胶囊等方式给药。
Description
技术领域
本发明涉及药物活性成分的输送性改善的组合物。这些组合物包含位于无水的亲水溶剂中的药物活性成分。这些组合物可以采用置于口中并最终吞服的液态酏剂形式,或者通过注液体的锭剂、和口香糖(gums)、量液给药装置(metered liquiddosing devices)、雾化器和释放液体的可食胶囊等方式给药。这些组合物特别适用于治疗与呼吸疾病有关的症状。
背景技术
输送药物活性成分的途径包括鼻内、肺部、颊部、舌下、经皮和直肠给药。为了避免吞服的药物发生首过代谢,倾向于使用这些途径。“首过代谢”指相对于因吞服而进入胃肠道并被吸收进入全身血循环系统的物质所经过路径而言,在人体内的各种代谢酶的分布情况和次序。人所吞服的物品,包括食物、饮料和药物,进入胃然后从胃进入肠。与食物、饮料和药物有关的许多化学物质通过胃肠道的粘膜,进入肠的肠系膜静脉中的血液。血液从肠系膜静脉流入肝脏。在肠粘膜和肝脏中的代谢酶,可化学改变来自肠道,通过肝脏并进入身体共同的血液循环中的物质的性质。因为所有吞服的药物在进入身体的全身血液循环系统之前都受到肠粘膜和肝脏的代谢作用,因此通常仅一小部分物质能够未被代谢并到达全身血液循环系统。
避免首过代谢,可以提高生物可利用性或者给药化合物的血液浓度。然而,给药化合物在代谢中形成的代谢产物会同时下降。在需要首过代谢形成代谢产物时,避免首过代谢不是优选的,因为从逻辑上说这导致血液中代谢产物的数量更低。此外,可增加活性物质的血液浓度,从而导致活性成分本身造成的潜在毒性或副作用。减少活性成分在药剂中的数量以避免毒性,会伴随着减少活性代谢产物在循环血液中的浓度。这导致失去了治疗作用以及对病人的最终益处。为了提供有效且可避免不利副作用的药物,必需改进组合物及其输送方式。
呼吸疾病包括了大量的疾病,包括病毒感染和对吸入的变应原的过敏反应。在人上呼吸道中的病毒感染导致通常称为感冒、或流感的疾病。这种疾病在整个人群中是相当普遍的,并且是严重不适和疼痛的原因。吸入变应原对人群中相当数量的人所造成的负面影响,相当于或甚至大于那些患病毒感染的人。
对于防止病毒感染或过敏,没有公认的有效而方便的方法。对于病毒感染,身体的自然防御机制会与感染斗争一段时间,通常为3天-2周。通常就是这种情况,即用最常用的药物来治疗这些呼吸系统疾病的不适的、有问题的症状。这些症状包括鼻塞和流鼻涕,鼻子和咽喉的疼痛和炎症、持续咳嗽、全身疼痛、发热、和头痛。在这些症状中,无法控制地咳嗽发作被许多人认为是最成问题和最不适的。咳嗽破坏正常的呼吸,导致头痛和咽喉肿痛的加剧以及患者和与患者一起生活的其他人的睡眠减少。
用于治疗上述症状的组合物通常落入下列药理分类之一:抗组胺剂;减充血剂;镇咳药;祛痰剂;粘液溶解药;镇痛剂,解热药和消炎剂。这些组合物被制成多种产品形式,最常见的是用于吞服的糖浆和酏剂,口服滴剂和锭剂以及吸入剂和局部用药膏或洗液(它们释放挥发性物质,通过鼻子而吸入呼吸道)。这些组合物通常是立刻吞服或缓慢地溶解在口中。它们通常含有活性成分,例如愈创甘油醚(协助祛除过多的呼吸道粘液或粘痰),苯海拉明(缓解因对病毒感染作出反应过程中身体内产生的组胺所造成的负面作用,包括咳嗽和其他症状),以及右美沙芬(它在控制咳嗽反射的人脑部分中起作用)。在这些活性成分中,右美沙芬是世界上缓解咳嗽最常用的活性成分。
因为其物理化学性、吸收性和生物可利用性,右美沙芬是可通过除吞服之外的给药方式来提高生物可利用性的非常好的候选物质。例如,已经在专利和药物文献中报道过,使用鼻内制剂可大大提高其生物利用性。参见H Char等人,NasalDelivery of 14-C Dextromethorphanin Rats,Journal of Pharmaceutical Sciences81:750,1992。
迄今尚未认识到的是,通过仔细和勤奋研究活性化合物的药物的、治疗的和副作用方面的性质,可以使组合物的治疗效果得以改善且不增加副作用或毒性。
发明内容
因此,本发明的一个目的是提供治疗与呼吸系统疾病相关的症状,尤其是用于减少咳嗽发作次数的改善的组合物。该组合物是药物活性成分在小体积无水的亲水液体中的溶液,它可快速地输送药物活性成分,其中包括:镇咳药;抗组胺剂(包括非镇静性抗组胺剂);减充血剂;祛痰剂;粘液溶解药;镇痛剂,解热药和消炎剂;以及用于治疗呼吸系统疾病症状的局部麻醉药。该组合物的剂型可以用各种不同产品形式和/或一揽子输送方式。本发明组合物可提供更高的活性,同时减少药物活性成分的副作用。本发明的另一目的是提供实现上述组合物快速的透粘膜(transmucosal)输送的方法。
定义和术语
下列是在本说明书中出现的术语的定义
1.透粘膜输送:
指将药物施用于口腔的粘膜,包括颊、唇、牙龈、腭和舌,以便使药物通过覆盖着这些部位的皮肤并进入血流。
2.治疗剂量
指当以适当形式施用于人时,会在身体中产生所需效果且副作用最小的药物数量。
3.药物活性成分/活性成分
指以合适数量和形式施用时,对身体产生所需效果的化学分子。
4.活性代谢产物
指在活性成分发生代谢后的药物活性成分的化学种类。
5.单分子分散体
指这样的事实,即活性成分分子经扩散变为游离和不受晶体或无定形固体形式中的缔合,或多分子缔合的束缚。
6.百分比溶解度值
指在正常室温的溶剂中分子的平衡溶解度极限或最大溶解度,以分子在组合物中的重量百分比表示。
发明详述
本发明的组合物含有用于治疗疾病(尤其是与呼吸系统疾病如感冒、流感和过敏等有关的症状)的本文称为“活性成分”的药物活性成分。这些活性成分是最常见用于治疗最成问题症状的成分,这些症状包括鼻塞和流鼻涕,鼻子和咽喉的疼痛和炎症、持续咳嗽、全身疼痛、发热、和头痛。在本发明中,当活性成分与小体积无水溶剂混合时,活性成分获得更高的透粘膜输送进入血液的能力。在活性代谢产物导致所需治疗效果时,这种增强的输送性是在不显著降低相应活性代谢产物的水平的情况下实现的。此外,血液中活性成分的浓度维持在某一水平,在该水平下可避免因血液中活性成分过高浓度而造成不利副作用。
药物组合物含有处于亲水的、与水可混合的无水溶剂中的药物活性成分,其中处于非离子化形式的药物活性成分在室温下溶剂中的百分比溶解度值等于或大于0.075%,并且药物活性成分是作为溶剂中单分子分散体处于游离的非离子化形式。
本发明的药物活性成分的分子量小于500克/摩尔,能够在水性溶剂中被离子化,并且在非离子化形式下的辛醇-水分配系数至少100。辛醇-水分配系数在A.Martin,P.Bustamante,和A.H.C.Chun,Physical Pharmacy,第4版,Lea and Febiger出版社,Philadelphia,1993,第237页中有公开;该文献在此引用作为参考。
构成本发明组合物的活性成分通常落入至少一种下列药理分类:镇咳药;抗组胺剂;非镇静性抗组胺剂;减充血剂;祛痰剂;粘液溶解药;镇痛剂,解热药、消炎剂、局部麻醉药以及它们的混合物。描述这些活性成分用途的的文献包括J.G.Hardman,The Pharmacologic Basis of Therapeutics,第9版,McGraw-Hill,NewYork,1995。可用于本发明的镇咳药包括(但并不限于):可待因、右美沙芬、右啡烷、苯海拉明、氢可酮、那可丁(noscapine)、氧可酮、喷托维林、及其混合物。可用于本发明的抗组胺剂包括(但并不限于):阿伐斯汀、阿扎他定、溴苯那敏、氯苯那敏、氯马斯丁、赛庚啶、右溴苯那敏、茶苯海明、苯海拉明、多西拉敏、羟嗪、氯苯甲嗪、苯茚胺、苯托沙敏、异丙嗪、美吡拉敏、曲吡那敏、曲普利啶、及其混合物。可用于本发明的非镇静性抗组胺剂包括(但并不限于):阿司咪唑、西替利嗪、依巴斯汀、非索那汀(fexofenadine)、氯雷他定、特非那定、及其混合物。可用于本发明的减充血剂包括(但并不限于):苯丙醇胺、伪麻黄碱、麻黄碱、苯福林、羟甲唑啉、及其混合物。可用于本发明的祛痰剂包括(但并不限于):氯化铵、愈创木酚甘油醚、吐根流体提取物、碘化钾及其混合物。用于本发明的粘液溶解剂包括(但并不限于):乙酰半胱氨酸、氨溴索、溴己新、和它们的混合物。可用于本发明的镇痛剂、退热剂和消炎剂包括(但并不限于):乙酰氨基酚、阿斯匹林、二氯芬酸、二氟尼柳、依托度酸、非诺洛芬、氟比洛尔、布洛芬、酮洛芬、酮咯酸、萘丁美酮、萘普生、吡罗昔康、咖啡因、和它们的混合物。可用于本发明的局部麻醉剂包括(但并不限于):利多卡因、苯佐卡因、苯酚、达克罗宁、苯佐那酯(benzonotate)和它们的混合物。
本发明组合物中的活性成分可溶于无水溶剂中。活性成分在溶剂中的浓度宜小于或等于百分比溶解度值的125%,较佳地小于或等于药物活性成分的百分比溶解度值。为了使本发明组合物的益处最大化,活性成分宜以单分子分散体处于溶液中。用于本发明中的活性成分在溶剂系统中的水平为组合物重量的约0.075%-25.0%,较佳地约为0.28-10.0%。
较佳地,活性成分为游离形式,然而活性成分的盐也可用于本发明。无论其形式如何,活性成分在该溶剂系统中以单分子分散体处于非离子化状态。
特别有用的活性成分是那些可阻止不受控制的阵咳的种类。在可利用的镇咳药中,右美沙芬是优选的。已知右美沙芬具有作为镇咳药的药理活性,这在美国专利5,196,436中有描述,该文献在此引用作为参考。如本文所用,“右美沙芬”指消旋甲啡烷,3-甲氧基-17-甲基吗啡喃(dl-顺-1,3,4,9,10,10a-六氢-6-甲氧基-11-甲基-2H-10,4a-亚氨基桥亚乙基菲)(iminoethanophenanthrene)及其药学上可接受的盐。含右美沙芬的组合物宜含有约0.1%至9.3%,较佳地约0.26-6.2%,最佳地约1.16-4.6%右美沙芬。在这种含右美沙芬的组合物中可以包含其他安全有效量的其他咳嗽/感冒药活性成分。
在本发明给予用户的组合物中,给予消费者的右美沙芬的剂量水平约为6.85-30.83毫克/剂。在组合物中是右美沙芬的氢溴酸盐一水合物时,给予消费者的氢溴酸右美沙芬盐一水合物的剂量水平约为10.0-45毫克/剂。
非离子化形式的药物活性成分用无水溶剂维持。“无水”指溶剂含有小于约5%水。本发明的无水溶剂占组合物重量的约60-99.975%,较佳地约70-99%,最佳地约85-98%。
本发明的无水溶剂通常在室温下为液态。它是水溶性的或可与水混合。溶剂选自下组:丙二醇、乙醇、聚乙二醇即PEG、碳酸异丙烯酯、二乙二醇一乙基醚、泊洛沙姆(poloxamer)、甘糠醛(glycofuro1)、甘油、及其混合物。有一些这些溶剂的混合物是特别优选用于本发明的某些产品形式的。例如,如果产品形式是酏剂、液态胶囊或含液体的锭剂,那么溶剂是丙二醇、乙醇和PEG的混合物。如果产品形式是喷雾剂,那么溶剂是丙二醇、乙醇、PEG和(通常)碳酸异丙烯酯的混合物。构成这些混合物的各溶剂的水平,部分依赖于配制者所希望的感觉(aesthetic)利益。
任选成分
通常与感冒和流感治疗药物一起使用的成分,可以与此处公开的药物活性成分一起使用。这样的成分在美国专利5,196,436中有公开,该文献在此引用作为参考。此外,在本发明中可以使用下列成分。
缓冲剂和缓冲剂混合物(包括作为pKa 8-11的单组份形式的碱性缓冲液),包括三乙醇胺、氨基酸盐(包括甘氨酸、甘氨酰甘氨酸、谷氨酰胺或其他氨基酸的碱性盐)、碱性磷酸盐、碳酸盐以及它们的混合物。在用唾液稀释组合物时,缓冲液使组合物能够抵抗pH变化,并在7-10,较佳地8-10范围内变化。
甜味剂,包括天冬糖素、糖精及其盐,SucraloseTM(McNeil Specialty ProductsCo.,New Brunswick,NJ出售);ProsweetTM(Virginia Dare Extract Co.,New York,NY出售);MagnasweetTM(MAFCO Worldwide Corp.,Licorice Division,Camden,NJ出售);甘草酸铵,其盐,TalinTM(Thaumatin)及其稀释产品例如Talin GA90(TalinFood Company,Birkenhead,England出售);和乙酰舒泛K,以及它们的混合物。
香料包括茴香、薄荷油、丁香油、桉树油、柠檬、酸柠檬、甜柠檬、红果(redfruit)、薄荷、葡萄柚、橙、樱桃可乐(cherry cola)及其混合物。
感觉剂(sensory agents)。可用于本发明有用的感觉剂选自清凉剂、促唾液分泌剂、温热剂。这些药剂在组合物中的存在量宜占组合物的约0.001-10%重量,优选的是约0.1-1%重量。
合适的清凉剂包括羧酰胺类(carboxamides)、薄荷醇、麝香草酚、樟脑、辣椒、酚、桉树油、苯甲醇、水杨醇、乙醇、丁香芽油和己雷琐辛、缩酮类、二醇类和它们的混合物。优选的清凉剂是对烷羧酰胺类,如N-乙基-对-烷-3-羧酰胺(Sterling Organics提供的WS-3),这在美国专利4,136,163(1979年1月23日授予Watson等人)中讲授到,该文献在此引用作为参考。另一个优选的对烷羧酰胺类药剂是N,2,3-三甲基-2-异丙基丁酰胺,称为“WS-23”,以及WS-3和WS-23的混合物。
其它优选的清凉剂选自薄荷醇、3-1-氧基丙-1,2-二醇(称为TK-10,由Takasago Perfumery Co.,Ltd.(日本东京)提供)、薄荷酮甘油缩醛(称为MGA,由Haarmann and Reimer制造)、乳酸酯(称为Frescolat,由Haarmann andReimer制造),以及它们的混合物。
其它的清凉剂包括环状砜和亚砜和其它物质,所有这些都描述于1977年6月28日授予Rowsell等人的美国专利4,032,661中,该文献在此引用作为参考。
如本文所用,术语“薄荷醇”和“基”包括这些化合物的右旋和左旋异构体,以及它们的消旋混合物。
1984年7月10日授予Amano等人的美国专利4,459,425(该文献在此引用作为参考)详细描述了TK-10。
本发明的促唾液分泌剂包括Jambu。它是Takasago Perfumery Co.,Ltd(日本东京)制造的。
温热剂包括红辣椒和烟酸酯,如烟酸苄酯。
使用方法
对于输送活性成分的方法,通常认为在口内进行的口腔粘膜输送必须定向于舌下区域,以便非常快速地实现治疗效果。参见D.Harris和J.R.Robinson,DrugDelivery via the Mucus Membranes of the Oral Cavity,Journal of PharmaceuticalSciences 81:1,1992。这些剂型被设计成置于舌下且位于口腔底部之上,并保持一段时间。然而,本发明人发现,当有关组合物被置于任何口腔粘膜,甚至在舌上并吞服时,可以使生物利用性大幅增加并吸收非常快速。本发明的形式是液态酏剂溶液。可以被施用于口中任何的粘膜。这可用滴药器通过将酏剂喷在舌头上然后吞服而实现,其中该滴药器经校正以显示施用的合适数量。酏剂可以喷雾在口和咽喉中,然后被吞服。可以封装在某种形式的外壳中,使其便于携带并可方便地运输和施用而不必测量液态酏剂的数量。封装外壳的例子包括用于锭剂的硬糖、咀嚼口香糖、凝胶或非凝胶(如基于淀粉的)外壳。酏剂可以被包装入小的一次性小瓶中,该小瓶易于开启和喷射入口中,整个小瓶正好含有一个治疗剂量。本发明典型的组合物剂型含有不超过3毫升,较佳地约0.2-3毫升。
一种优选形式是将液体封装入硬糖或凝胶外壳中。外壳含有用于预处理粘膜从而提高从液态中心吸收活性成分的物质。预处理是通过吮吸或咀嚼外壳材料而发生的,而这种优点是通过将粘膜处理(首先发生)与提供待吸收的活性成分在时间上相分离而获得的。用于预处理粘膜的物质的例子是本领域已知的透膜增强剂,其例子包括薄荷脑和薄荷油,表面活性剂如聚山梨酯80或泊洛沙姆。另一种粘膜预处理的例子是上面列出的缓冲液,它们可以将唾液微环境的pH值预调节在8-10范围内。
实施例
实施例1液态酏剂
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 2.055 |
2 | 乙醇(100%) | 10.000 |
3 | 聚乙二醇600 | 81.88 |
4 | 丙二醇 | 5.000 |
5 | 糖精钠 | 0.300 |
6 | ProSweet液体K | 0.700 |
7 | 甘草酸一铵 | 0.050 |
8 | 茴香脑 | 0.0075 |
9 | 绿影色素(Green Shade) | 0.003 |
总计 | 100.000 |
将一部分乙醇加至活性成分(右美沙芬基本成分)和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(丙二醇、聚乙二醇600)和液态甜味剂(ProSweet液体K)。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100网眼的筛网进行过滤(产品密度=1.07克/毫升)。注入琥珀玻璃瓶中,用一体化的瓶盖/量药滴器组件进行封盖。
将约1.0毫升酏剂滴在舌头上然后吞服。右美沙芬被快速地吸收入血液。
实施例2液态酏剂
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 2.055 |
2 | 乙醇(100%) | 10.000 |
3 | 聚乙二醇600 | 78.285 |
4 | 丙二醇 | 5.000 |
5 | 三乙醇胺 | 3.740 |
6 | Sucralose | 0.150 |
7 | ProSweet液体K | 0.700 |
8 | 甘草酸一铵 | 0.050 |
9 | 香料 | 0.015 |
10 | 色素 | 0.005 |
总计 | 100.000 |
将一部分乙醇加至活性成分(右美沙芬基本成分)和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(丙二醇、聚乙二醇600)、液态甜味剂(ProSweet液体K)和缓冲剂(三乙醇胺,液态)。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100网眼的筛网进行过滤(产品密度=1.07克/毫升)。注入琥珀玻璃瓶中,用一体化的瓶盖/量药滴器组件进行封盖。将约1.0毫升酏剂滴在舌头上然后吞服。右美沙芬被快速地吸收入血液。
实施例3液态喷雾剂
*从Warner Jenkins Co.,St.Louis,MO,USA获得
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 3.425 |
2 | 乙醇(100%) | 5.350 |
3 | 聚乙二醇400 | 50.155 |
4 | 碳酸异丙烯酯 | 40.000 |
5 | Sucralose | 0.300 |
6 | ProSweet液体K | 0.700 |
7 | 甘草酸一铵 | 0.050 |
8 | 香料 | 0.015 |
9 | 绿影色素CSL-15689* | 0.005 |
总计 | 100.000 |
将一部分乙醇加至活性成分(右美沙芬基本成分)和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(碳酸异丙烯酯、聚乙二醇400)和液态甜味剂(ProSweet液体K)。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100网眼的筛网进行过滤(产品密度=1.075克/毫升)。注入手工操作的喷雾泵和瓶。一种例子是Calmar-Albert GmbH公司制造的Mistette MarkII,它配有16mm高粘度喷头组件,每次喷射可输送0.2毫升。
向口内喷3次。右美沙芬被快速地吸收入血液,并且在喷射过程中,一部分喷射的液体与喉咙区域接触,这提供了额外的好处例如使此处受刺激的咳嗽受体变得麻木。实施例4液态喷雾剂
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 3.425 |
2 | 乙醇(100%) | 5.350 |
3 | 聚乙二醇400 | 46.415 |
4 | 碳酸异丙烯酯 | 40.000 |
5 | 三乙醇胺 | 3.740 |
6 | Sucralose | 0.300 |
7 | ProSweet液体K | 0.700 |
8 | 甘草酸一铵 | 0.050 |
9 | 香料 | 0.015 |
10 | 色素 | 0.005 |
总计 | 100.000 |
将一部分乙醇加至活性成分(右美沙芬基本成分)和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(碳酸异丙烯酯、聚乙二醇400)、液态甜味剂(ProSweet液体K)和缓冲剂(三乙醇胺,液体)。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100网眼的筛网进行过滤(产品密度=1.075克/毫升)。注入手工操作的喷雾泵和瓶。一种例子是Calmar-Albert GmbH公司制造的MistetteMarkII,它配有16mm高粘度喷头组件。
向口内喷3次。右美沙芬被快速地吸收入血液,并且在喷射过程中,一部分喷射的液体与喉咙区域接触,这提供了额外的好处例如使此处受刺激的咳嗽受体变得麻木。实施例5中心为液体的锭剂
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 2.055 |
2 | 乙醇(100%) | 2.000 |
3 | 纯水 | 5.000 |
4 | 聚乙二醇600 | 84.875 |
5 | 丙二醇 | 5.000 |
6 | Sucralose | 0.300 |
7 | ProSweet液体K | 0.700 |
8 | 甘草酸一铵 | 0.050 |
9 | 香料 | 0.015 |
10 | 色素 | 0.005 |
总计 | 100.000 |
将一部分乙醇加至活性成分(右美沙芬基本成分)和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(丙二醇、聚乙二醇600)和液态甜味剂(ProSweet液体K)。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇和水中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100网眼的筛网进行过滤(产品密度=1.07克/毫升)。通过常用的方法(如挤出法),制造各填塞的锭剂,每个锭剂含约1.0毫升液体。
一个人将填有液体的锭剂置于口中,然后吮吸锭剂直至液体填料被释放出。通过对锭剂外壳的吮吸作用,获得了一定程度的咳嗽缓解。当中心液体被释放时,右美沙芬被快速地吸收入血液。实施例6中心为液体的锭剂
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 2.055 |
2 | 乙醇(100%) | 2.000 |
3 | 纯水 | 5.000 |
4 | 聚乙二醇600 | 79.875 |
5 | 丙二醇 | 5.000 |
6 | 甘氨酸钠 | 5.000 |
7 | Sucralose | 0.300 |
8 | ProSweet液体K | 0.700 |
9 | 甘草酸一铵 | 0.050 |
10 | 香料 | 0.015 |
11 | 色素 | 0.005 |
总计 | 100.000 |
将一部分乙醇加至活性成分(右美沙芬基本成分)和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(丙二醇、聚乙二醇600)和液态甜味剂(ProSweet液体K)和缓冲剂(三乙醇胺,液体)。制备缓冲剂(甘氨酸钠)的水性预混合物,并加至容器中。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100网眼的筛网进行过滤(产品密度=1.07克/毫升)。通过常用的方法(如挤出法),制造各填塞的锭剂,每个锭剂含约1.0毫升液体。
一个人将填有液体的锭剂置于口中,然后吮吸锭剂直至液体填料被释放出。通过对锭剂外壳的吮吸作用,获得了一定程度的咳嗽缓解。当中心液体被释放时,右美沙芬被快速地吸收入血液,并在10分钟时间内缓解了咳嗽。实施例7液态酏剂
该组合物根据实施例1和2的方法制造。实施例8液态酏剂
该组合物根据实施例1和2的方法制造。实施例9液态酏剂
项目# | 材料 | 组合物%(w/w) |
1 | 右美沙芬基本成分 | 2.055 |
2 | 伪麻黄碱基本成分 | 4.593 |
3 | 乙醇(100%) | 10.000 |
4 | 聚乙二醇600 | 73.689 |
5 | 丙二醇 | 5.000 |
6 | 三乙醇胺 | 3.740 |
7 | Sucralose | 0.150 |
8 | ProSweet液体K | 0.700 |
9 | 甘草酸一铵 | 0.050 |
10 | 香料 | 0.015 |
11 | 色素 | 0.005 |
总计 | 100.000 |
项目# | 材料 | 组合物%(w/w) |
1 | 氯苯那敏基本成分 | 0.263 |
2 | 伪麻黄碱基本成分 | 4.593 |
3 | 乙醇(100%) | 10.000 |
4 | 聚乙二醇600 | 79.224 |
5 | 丙二醇 | 5.000 |
6 | Sucralose | 0.150 |
7 | ProSweet液体K | 0.700 |
8 | 甘草酸一铵 | 0.050 |
9 | 香料 | 0.015 |
10 | 色素 | 0.005 |
总计 | 100.000 |
项目# | 材料 | 组合物%(w/w) |
1 | 乙酰氨基酚 | 27.169 |
2 | 右美沙芬基本成分 | 1.195 |
2 | 伪麻黄碱基本成分 | 2.671 |
3 | 乙醇(100%) | 10.000 |
4 | 聚乙二醇1000和PEG 600 | 25.019 |
5 | 聚乙二醇600 | 22.765 |
6 | 丙二醇 | 4.350 |
7 | 聚乙烯基吡咯烷酮K-17PF | 2.170 |
8 | 三乙醇胺 | 3.740 |
9 | Sucralose | 0.150 |
10 | ProSweet液体K | 0.700 |
11 | 甘草酸一铵 | 0.050 |
12 | 香料 | 0.015 |
13 | 色素 | 0.005 |
总计 | 100 |
程序:将右美沙芬基本成分和伪麻黄碱基本成分溶解在部分醇中,以制得预混合物。在单独容器中,在加热PEG1000、PEG 600、PVP-K17PF和丙二醇至70℃。一旦所有的材料都熔化并处于澄清液体形式,加入乙酰氨基酚,继续加热至110-120℃并继续混合。一旦液体澄清就停止加热。冷却至室温。将混合物加至右美沙芬和伪麻黄碱预混合物中。还加入液态甜味剂(ProSweet液体K)和缓冲剂(三乙醇胺)。
混合直至所有的材料溶在溶液中。在余下部分的醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合至均匀,然后通过US#100网眼的筛网进行过滤。注入琥珀玻璃瓶中,用一体化的瓶盖/量药滴器组件进行封盖。将约1.84克酏剂滴在舌头上然后吞服。这是在外壳中有粘膜预处理剂的中心为液体锭剂。
实施例10中心为液体的锭剂
项目# | 材料 | 组合物%(w/w) |
1 | 氢溴酸右美沙芬一水合物 | 0.690 |
2 | 乙醇(100%) | 10.0 |
3 | 纯水 | 5.0 |
4 | 聚乙二醇600 | 74.16 |
5 | 丙二醇 | 5.00 |
6 | 甘油 | 5.00 |
7 | Sucralose | 0.10 |
8 | ProSweet液体K | 0.03 |
9 | 甘草酸一铵 | 0.025 |
10 | 香料 | 0.015 |
11 | 色素 | 0.005 |
总计 | 100.000 |
将一部分乙醇加至氢溴酸右美沙芬和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(丙二醇、聚乙二醇600,甘油)和液态甜味剂(ProSweet液体K)。混合直至所有的材料溶在溶液中,时间约为2小时。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100筛网进行过滤。通过常用的方法(如挤出法),将液体溶液注入各填充式咳嗽糖球(drop)中,每个糖球含约1.5毫升液体。制造的咳嗽糖球的糖果质量为每个糖球含5毫克薄荷油、2.5毫克薄荷醇、0.50毫克聚山梨酯80和5毫克甘氨酸钠。
一个人将填有液体的锭剂置于口中并吮吸。口腔粘膜组织被糖球外壳中的薄荷油、薄荷醇、聚山梨酯80和甘氨酸盐预处理,使得一旦将液体填料释放入口中,右美沙芬更易于吸收。通过对锭剂外壳的吮吸作用,获得了一定程度的咳嗽缓解。当中心液体被释放时,右美沙芬被快速地吸收入血液,并在10分钟时间内缓解了咳嗽。
实施例11液态酏剂
项目# | 材料 | 组合物%(w/w) |
1 | 氢溴酸右美沙芬一水合物 | 0.80 |
2 | 乙醇(100%) | 10.00 |
3 | 聚乙二醇600 | 78.64 |
4 | 丙二醇 | 5.00 |
5 | 纯水 | 5.00 |
6 | Sucralose | 0.15 |
7 | ProSweet液体K | 0.35 |
8 | 甘草酸一铵 | 0.04 |
9 | 香料 | 0.015 |
10 | 色素 | 0.005 |
总计 | 100.000 |
将一部分乙醇加至氢溴酸右美沙芬和固体甜味剂(Sucralose,甘草酸一铵),然后在低热(30℃)下持续混合。向容器中加入其他溶剂(丙二醇、聚乙二醇600)和液态甜味剂(ProSweet液体K)。混合直至所有的材料溶在溶液中,时间约为2小时。加入水并简单混合。在余下部分的乙醇中制备香料和色素的预混合物,然后将其加至含有几乎全部溶液的容器中。混合直至获得均匀溶液,然后通过US#100筛网进行过滤。注入琥珀玻璃瓶中并封盖。
取半调羹(2.5毫升)放入口中并吞服。右美沙芬被快速地吸收入血液。
Claims (17)
1.一种组合物,其特征在于,含有在亲水的、与水可混合的无水溶剂中的药物活性成分,其中处于非离子化形式的药物活性成分在室温下溶剂中的百分比溶解度值等于或大于0.075%,并且药物活性成分是作为溶剂中单分子分散体处于游离的非离子化形式。
2.如权利要求1所述的组合物,其特征在于,药物活性成分的分子量小于500克/摩尔,能够在水性溶剂中被离子化,并且在非离子化形式下的辛醇-水分配系数至少100。
3.如权利要求1或2所述的组合物,其特征在于,药物活性成分选自下组:镇咳药、抗组胺剂、非镇静性抗组胺剂、减充血剂、祛痰剂、镇痛剂、粘液溶解药、解热药、消炎剂、局部麻醉药以及它们的混合物。
4.如权利要求1-3中任一所述的组合物,其特征在于,药物活性成分在溶剂中的浓度小于或等于该活性成分百分比溶解度值的125%。
5.如权利要求1-4中任一所述的组合物,其特征在于,药物活性成分在溶剂中的水平为组合物重量的0.075%-25.0%,较佳地为0.28-10.0%。
6.如权利要求1-5中任一所述的组合物,其特征在于,药物活性成分是右美沙芬,浓度为组合物重量的0.1-9.3%,较佳地0.26-6.2%,最佳地1.16-4.6%。
7.如权利要求1-6中任一所述的组合物,其特征在于,亲水的、与水可混合的无水溶剂占组合物重量的60-99.975%,较佳地70-99%,最佳地85-98%。
8.如权利要求1-7中任一所述的组合物,其特征在于,亲水的、与水可混合的无水溶剂选自下组:丙二醇、乙醇、聚乙二醇即PEG、碳酸异丙烯酯、二乙二醇一乙基醚、泊洛沙姆、甘糠醛、甘油、及其混合物。
9.如权利要求1-8中任一所述的组合物,其特征在于,除了药物活性成分,宜为右美沙芬之外,其他药物活性成分选自下组:镇咳药、抗组胺剂、非镇静性抗组胺剂、减充血剂、祛痰剂、镇痛剂、粘液溶解药、解热药、消炎剂、局部麻醉药以及它们的混合物。
10.如权利要求1-9中任一所述的组合物,其特征在于,右美沙芬和其他药物活性成分在溶剂中的水平为组合物重量的0.075%-25.0%,较佳地为0.28-10.0%。
11.如权利要求1-10中任一所述的组合物,其特征在于,其他药物活性成分选自下组:伪麻黄碱、苯丙胺、乙酰氨基酚、氯苯那敏、多西拉敏、苯茚胺、曲普利啶、它们的盐、及其混合物。
12.如权利要求1-11中任一所述的组合物,其特征在于,产品形式是下组中的任何形式:可咀嚼胶囊、填有液体的口香糖、酏剂、喷雾剂和锭剂。
13.如权利要求1-12中任一所述的组合物,其特征在于,该产品是可咀嚼胶囊、填有液体的口香糖、或锭剂,它们具有含粘膜组织预处理组合物的外壳。
14.一种制备权利要求6-13中任一所述组合物的方法,其特征在于,该组合物用于将该组合物中足量体积药物活性成分进行口服给药,其中输送给消费者的右美沙芬水平为6.85-30.83毫克/剂组合物。
15.一种制备权利要求6-13中任一所述组合物的方法,其特征在于,该组合物用于将该组合物中足量体积药物活性成分进行口服给药,其中输送消费者一种制备权利要求6-13中任一所述组合物的方法,其特征在于,该组合物用于将该组合物中足量体积药物活性成分进行口服给药,其中输送消费者的来自氢溴酸右美沙芬盐一水合物的的右美沙芬水平约为10.0-45毫克/剂组合物。
16.如权利要求14或15所述的方法,其特征在于,该组合物被置于口中任何口腔粘膜组织。
17.一种制备权利要求1-13中任一所述组合物的方法,其特征在于,该组合物用于将该药物活性成分进行口服给药,总剂量体积不超过3.0毫升。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US11537899P | 1999-01-11 | 1999-01-11 | |
US60/115,378 | 1999-01-11 |
Publications (2)
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CN1336823A true CN1336823A (zh) | 2002-02-20 |
CN1203854C CN1203854C (zh) | 2005-06-01 |
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US (1) | US6846495B2 (zh) |
EP (1) | EP1140093A2 (zh) |
JP (1) | JP2002534463A (zh) |
KR (1) | KR100511730B1 (zh) |
CN (1) | CN1203854C (zh) |
AU (1) | AU762366B2 (zh) |
BR (1) | BR0007445A (zh) |
CA (1) | CA2356881C (zh) |
CO (1) | CO5270007A1 (zh) |
CZ (1) | CZ20012491A3 (zh) |
HU (1) | HUP0105021A3 (zh) |
NO (1) | NO20013442L (zh) |
PE (1) | PE20001415A1 (zh) |
TR (1) | TR200101927T2 (zh) |
WO (1) | WO2000041693A2 (zh) |
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CN1203854C (zh) | 2005-06-01 |
CA2356881C (en) | 2012-02-28 |
CO5270007A1 (es) | 2003-04-30 |
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AU2962700A (en) | 2000-08-01 |
KR20010093255A (ko) | 2001-10-27 |
WO2000041693A3 (en) | 2000-11-30 |
NO20013442L (no) | 2001-09-11 |
KR100511730B1 (ko) | 2005-08-31 |
NO20013442D0 (no) | 2001-07-11 |
PE20001415A1 (es) | 2001-01-05 |
CZ20012491A3 (cs) | 2001-12-12 |
US6846495B2 (en) | 2005-01-25 |
EP1140093A2 (en) | 2001-10-10 |
TR200101927T2 (tr) | 2001-11-21 |
HUP0105021A2 (hu) | 2002-05-29 |
WO2000041693A2 (en) | 2000-07-20 |
US20030139437A1 (en) | 2003-07-24 |
JP2002534463A (ja) | 2002-10-15 |
CA2356881A1 (en) | 2000-07-20 |
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