CN102612372A - 用于快速治疗外耳炎的方法和组合物 - Google Patents
用于快速治疗外耳炎的方法和组合物 Download PDFInfo
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- CN102612372A CN102612372A CN2010800512457A CN201080051245A CN102612372A CN 102612372 A CN102612372 A CN 102612372A CN 2010800512457 A CN2010800512457 A CN 2010800512457A CN 201080051245 A CN201080051245 A CN 201080051245A CN 102612372 A CN102612372 A CN 102612372A
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Abstract
提供经少到单剂量构成的疗程治疗和预防外耳炎的方法。该方法通过对外耳道局部施用具有脂质载体如脂质体和非囊泡脂质的组合物进行实施。这样的组合物没有增强粘度的纤维素或粘合剂，且优选地不以凝胶的形式。对于治疗外耳中的疼痛、炎症、真菌或寄生物侵扰和/或感染有用的活性剂在该组合物内共同施用或与该组合物一起共同施用。
Description
发明领域
本发明涉及不使用增强粘度的纤维素成分、凝胶或者基于粘合剂的制剂的治疗外耳炎(otits externa)(外耳感染或侵扰并发炎)的非创伤性方法和组合物。
发明背景
每年有数以百万的动物和人，特别是儿童，患上外耳炎，即外耳的感染和/或侵扰，通常伴随患病组织的疼痛性炎症。有耳瓣(ear flap)的动物，比如许多品种的犬，特别容易被感染。它们被遮盖的外耳道为微生物的滋生和炎症的形成提供了环境，但看管者可能不会像在耳朵隆起的动物中那样容易注意到病况。
各种细菌、病毒和真菌可以是造成外耳炎的原因。通常一线(first-line)治疗限于口服或局部的抗生素。口服药物的效用可能由于药物的全身分布而被削弱，并且会使患者处于与全身输送有关的副作用的风险中(例如，雌性中酵母感染)。另外，只通过用于细菌感染的局部抗生素治疗的患者耳道内真菌过度生长的风险加强了对所有与外耳炎及其后遗症(sequalae)有关的病原体仔细诊断和治疗的需要(Schraederand Issacson,Pediatrics,111(5):1123,2003)。因此，优先选择多试剂局部治疗外耳炎，特别是对可能难以获得长期口服给药方案依从性的儿童和动物。
当局部应用一种或多种活性剂治疗外耳炎时，功效通常取决于可以保持药物接触患病组织多久，特别是当出现真菌或寄生虫侵扰(例如，耳螨)时。传统的滴耳剂是有问题的，因为其接触的组织直接受到患者头部姿态的影响，并且随着运动滴剂可轻易地流出耳朵。增加局部药物在外耳道内的停留时间的方法包括应用用纤维素(例如羟丙甲基纤维素)、胶塞、奶油冻、泡沫、或者其它具有粘性的制剂使得更粘的可流动凝胶。
然而对使用此类制剂的用药方案的依从性同样是一个问题，因为它们在耳内厚和/或粘的感觉可能是失败的根源，特别是对动物和年纪小的孩子。如果接受能保持的局部制剂不可能，则剩下的选择通常是更频繁且较不方便地给予粘性较低的溶液，比如传统的滴耳剂。因此，对局部治疗外耳炎以改善(显著减少症状)或消退病状的方法存在需要，其不依赖于使用凝胶、基于纤维素或粘合剂的组合物，并且其可不频繁应用(即，作为整个疗程，一次或两次)。
发明概述
本发明提供了治疗抗生素或寄生虫感染、真菌侵扰和炎症的多试剂组合物(multiple agent composition)，其不使用凝胶、纤维素或者其它粘性制剂，可以足够长的时间置于并保持在耳内以治疗外耳炎。令人惊讶地，发现本发明的制剂可以如一次不频繁地应用，任选补充给药，以完全消退治疗的病况。
根据本发明输送的优选药物是那些对治疗或预防外耳炎及其后遗症(比如瘙痒症)有用的药物。本发明特别适合输送药物如抗生素或抗病毒剂(取决于存在感染的根源)、抗真菌剂、以及抗炎药或其它止痛药。为了预防慢性复发的外耳感染，也可将本发明的方法用于活性感染(active infection)之间以输送预防剂到外耳道。
上述的发明概述不是限制性的，本发明的其它特征和优点将由于下面优选实施方式的详述以及权利要求书而显而易见。
发明详述
A.用于局部治疗外耳炎的方法
本发明提供了用于局部治疗和预防外耳炎的方法，其通过施用多种活性剂，优选地至少两种，最优选地至少三种活性剂，其对于预防或治疗外耳感染、侵扰和炎症是有用的。局部施用(topicaladministration)”是指将本发明的组合物应用于外耳道；即，在鼓膜(耳膜)的外耳一侧。本发明的组合物不包括胶凝剂、甲基纤维素或其它粘性成分，但通过单剂量疗程足以有效改善或消退外耳炎。
完成对外耳道的局部施用是经由，例如，通过任何医学上可接受的装置将本发明的组合物引入外耳道；例如，通过将无针注射器、滴管或拭子插入耳道(auditory canal)将载体组合物施加到膜上。在需要时重复施用以使给定的抗生素化合物达到治疗上有效的剂量水平。然而，本发明提供的特别优点是它能够实现经少到一个剂量构成的疗程改善(基本上减少症状)或消退(消除症状)外耳炎。
如果外耳炎证明是不寻常地难以治疗的，但该病情的临床症状在施用第一剂量后就得到改善，在医学上合适的时间段后可输送后续剂量。例如，如实施例1所示，可一次输送10至20滴的局部载体组合物，如果对患者状况的临床观察显示施用的第一剂量没有完全消除病情，在治疗后的第14天，症状严重的情况在第7天输送后续剂量。本领域普通技术人员将熟悉并能够容易选择适于后续治疗具体感染的给药方案。
B.本发明中所用的基于脂质的载体
根据本发明采用的活性剂的目前优选的局部载体是基于脂质的那些，比如脂质乳剂(包括微乳剂和水包油乳液)，以及脂囊泡，比如脂质体、微脂囊(liosome)、胶粒和输送体(transfersome)(超柔性脂囊泡)。基于磷脂的制剂是目前优选的，尤其是对于在本发明中有用的非囊泡制剂。
最优选地，根据本发明输送的药物优选地在脂质相(例如，在脂质体的脂双层内)而不是在水相(例如，在脂质体的核内)中运载。因此，对于在本发明中应用，尽管不是必须的，但是可溶于脂质的药物(其一般可以在囊泡的脂质层中以比扩散在水相中的水溶性药物更高的浓度提供)是优选的。
关于在本发明中应用的局部载体组合物的目前最优选实施方式、不需要空间稳定剂(steric stabilizer)和不需要粘度增强、胶凝剂和/或粘合剂而制备的脂质体，用于制备脂质乳液和囊泡的方法是本领域众所周知的，因此这里只简要概述。
“脂质体(liposome)”是指以有序的脂双层为边界并包封水相的球形脂囊泡。脂质体的脂双层通常由天然或合成磷脂制成，但也可由非磷脂制成。脂质体的脂双层是有序的双分子层，意思是脂质的分子“头(head)”和“尾(tail)”结构相互连接排列。
本发明利用的脂质体可以是单层的(具有一个脂双层)，或者更优选是多层的。“多层的(multilamellar)”脂质体具有多个层或膜。这类脂质体具有多个层的脂双层，在脂双层之间以水性流体隔开。多层的脂质体具有至少两层脂质。
优选的脂质体是本文以及共同拥有的2003年2月12日申请的美国专利申请系列号10/366,584中描述的那些脂质体，该申请的公开内容通过引用以其全部并入本文。然而，本领域普通技术人员将认识到可应用脂质体的其它制剂，包括磷脂酰化合物，比如磷脂酰甘油、磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、鞘脂、脑苷脂和神经节甘脂。尤其有用的是二酰基磷脂酰甘油，其中脂质部分包含14-18个碳原子，特别是16-18个碳原子而且是饱和的。例证性的磷酯包括蛋黄磷脂酰胆碱(egg phosphatidylcholine)、二软脂酰卵磷脂和二硬脂酰卵磷脂。这样的脂质在本发明的非囊泡局部载体组合物中也将是有用的。
若有的话，本发明中使用的脂质体和脂囊泡的尺寸可以是可变的，但是在每批制剂中这种囊泡优选地具有一致尺寸。脂质体可达到20μm、25μm、或甚至30μm。但是在优选的实施方式中大约95%的脂质体的直径将从大约0.5μm到大约10μm。在一个实施方式中，根据本文所述方法制造的优选组合物中至少80%的脂质体是大约0.5μm到大约5μm。在这方面，术语“大约(about)”包含从所述值上浮或下降5%的范围。脂质体的实际直径将是遵循的冷却曲线以及搅拌或涡动水合(vortex hydration)的长度和效力的函数——当那些方法用于制造脂质体时。在还有其它实施方式中，脂质体可以是多层脂质体，其中一个较大脂质体包封一个或多个较小脂质体。
根据本领域众所周知的装置制造的传统脂质体可用在本发明中，但是本发明优选的脂质体不包含可溶于脂质的防腐剂，如现有技术中出现的(参见，例如Mezei的美国专利号4,761,288和4,897,269，都通过引用以其全部内容并入本文)。实际上，尽管本发明的组合物将优选地不含防腐剂，但如果储存条件必要的话，可使用水溶性防腐剂，比如苯甲酸或者苯乙铵盐(benzethonium salt)(例如，苯索氯铵)，或者，最优选地，不溶于油的产品，比如DOWCILTM 200(不溶于油的96%顺1-(3-氯烯丙基)-3,5,7-三氮杂-1-氮
金刚烷氯化物，Dow Biocides)或者本领域已知的相似产品，包括其它DOWCILTM品牌的产品。
然而制备的本发明的组合物不包括任何甲基纤维素或者任何其它粘度增强剂或胶凝剂。所谓“粘度增强剂或胶凝剂”是指加入到组合物中以提高粘度的试剂。粘度增强剂在25℃将提高组合物的粘度至少10000厘泊。粘度增强剂包括但不限于甲基纤维素、羟丙甲基纤维素(HPMC)、藻酸、明胶、合金欢(阿拉伯树胶)卡波姆(carbomer)和鲸蜡硬脂醇(cetostearyl alcohol)。在此定义内，磷脂不被认为是粘度增强剂。
如果脂质体是基于磷脂的囊泡，优选的脂质将是从大豆卵磷脂获取和提纯的phospholipon 90H，化学名称为(1,2-二酰基-5N-甘油基-3-磷脂酰胆碱)。其最少90%的磷脂酰胆碱并且完全氢化。然而普通技术人员将意识到其它脂质也可用在本发明中。例如，磷脂酰胆碱可具有低纯度，或者可包含其它脂质或载体材料，比如，例如，丙二醇/乙醇、中链甘油三酯、油/乙醇、磷脂酸、胆固醇和磷脂酰肌醇。该磷脂可以是天然或合成磷脂，例如磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、磷脂酸、溶血磷脂、蛋或大豆磷脂或者其组合物。该磷脂可以是含盐的或脱盐的，氢化的或部分氢化的，天然的、合成的或半合成的。商业可得的磷脂的例子包括但不限于卵磷脂P123(eggphospholipids P123)(Pfanstiehl,Waukegen,Ill.)、脂质E80(LipoidE80)(Lipoid,Ludwigshafen,德国)；以及氢化大豆磷脂Phospholipon
和
)(Nattermann,Munich,德国)以及99%纯大豆磷脂酰胆碱(Avanti Polar Lipids,Alabaster,Ala.)。
任选地，无水醇和丙二醇可用作脂质相的共溶剂，并可包括作为抗氧化剂的维生素E醋酸酯。在各种实施方式中，其它脂质或者类脂质物质用于本发明，比如神经酰胺、卵磷脂、磷脂酰乙醇胺、磷脂酰丝氨酸、心磷脂、三亚精油和类似化合物。非磷脂也可用于本发明。例如可能有用的非磷脂物质包括形成脂囊泡的聚氧化乙烯脂肪酯、聚氧化乙烯脂肪酸醚、二乙醇胺、长链酰基酰胺、长链酰基氨基酸酰胺、长链酰基酰胺、聚氧化乙烯失水山梨糖醇油酸酯、聚氧化乙烯甘油单硬脂酸酯、单硬脂酸甘油酯及其混合物、类似物和衍生物。囊泡也可包括甾族化合物和电荷产生剂。优选的甾族化合物包括胆固醇、皮质醇，以及其类似物、衍生物和混合物。优选的负电荷产生材料是油酸、磷酸二鲸蜡酯、棕榈酸、硫酸鲸蜡酯、视黄酸、磷脂酸、磷脂酰丝氨酸，及其混合物。为了在需要时为囊泡提供净正电荷，可使用长链胺类，例如硬脂胺或者油胺，长链吡啶
化合物，例如氯化十六烷基吡啶季胺化合物，或它们的混合物，只要脂囊泡可携带足够数量的水相。
其它脂质体制剂，包括非磷脂脂质体，可用在本发明中。作为一般参考，Mezei的1998年8月2日授权的美国专利号4,761,288(其公开的内容并入本文以便于参考)公开的多相脂质体药物输送系统是可用在本发明中的脂质体组合物的典型代表。对于用作局部载体，对脂质体(或者用于本发明的其它脂质载体)改性以便空间上稳固囊泡，或者提供用于靶向，或者提供具有缓释性能的囊泡(或者所用的其他基于脂质的载体)，可能干扰组合物的局部活性，因此不是优选的。
可并入用于本发明中的基于脂质的载体的化合物的数量没有理论上的限制。然而，据本领域普通技术人员了解，包封率(encapsulationefficiency)一般在具有脂质与水含量比值相对较高的脂质体组合物中更大，并且脂质相运载的溶于脂质的药物通常可以以比水相运载的水溶性药物更高的浓度提供。
例如，两种或更多种成分可被包封在同一个囊泡内，或者假如活性化合物是不相容的，则化合物可被分别包封，并且合并局部载体组合物以提供组合物两种或更多种适应症，或者提供用多种活性化合物治疗单个适应症的化合物。
通过施用包括包封在囊泡里的用于治疗外耳道的一种或多种活性化合物以及第二组以不包封的形式在周围水相中扩散的用于治疗耳道的一种或多种活性化合物的局部载体组合物，同时治疗外耳道也是可能的。或者，可选地，非囊泡脂质可存在，并且所有的活性物都不包封。
优选地，以缓释的形式提供本发明的组合物，比如在制造以抵抗降解的脂质体中。本领域普通技术人员熟悉完成这一目标的制造方法，其包括但不限于向脂质相添加胆固醇(参见，例如美国专利号6,352,716，其通过引用并入本文以说明为此目的将胆固醇合并于脂质体的方法)。
预期这种相对不溶的脂囊泡可保持在输送的地方，以缓慢释放一种或多种活性剂。这种囊泡也可具有杀菌剂或者其它对治疗或控制外耳感染率有用的性质；例如，如果溴化十六烷基三甲铵——一种有效的消毒剂——用作囊泡内的正电荷产生材料，则提供第二种优势。在这样的实施方式中，囊泡随着它们各自退化而作为持续释放制剂。
C.治疗和预防外耳炎的有用的活性剂
“活性剂”是指任何对于治疗和/或预防外耳炎及其后遗症以及相关的疼痛和炎症有用的生物活性化合物。因此在这方面，特别优选的药物是对治疗或预防哺乳动物，特别是人的外耳炎有用的抗生素。根据病状和病因的严重程度，这样的抗生素包括但不限于阿莫西林(和其它青霉素)、环丙沙星(和其它喹诺酮抗生素，比如氧氟沙星)、克拉维酸(和其它β-内酰胺酶抑制剂)、头孢克洛(和其它头孢菌素，比如头孢克肟)、阿奇霉素(和其它大环内脂类抗生素，比如克拉霉素)，以及磺胺二甲基异
唑(以及其他磺胺类药，比如磺胺甲基异
唑)。在本发明中有用的抗生素中，具有高的脂质可溶性、可不溶于水的那些是优选的，特别优选的是甲砜氯霉素及其类似物(例如氯霉素)。
优选地，本发明的组合物将包括对治疗外耳炎有用的多种试剂，包括但不限于抗真菌的和抗炎的化合物。用于共同施用或者独立于抗生素疗法使用的有用的抗炎化合物包括有时口服效果较低或充分耐受的那些；例如，非甾体抗炎药(NSAID)，比如双氯芬酸、萘普生、酮洛芬、塞来昔布(celecoxib)、消炎痛、以及其药学上可接受的衍生物。甾族化合物当临床需要时可用作NSAID的替代物或添加剂(例如在伴随瘙痒的外耳炎的慢性情况)，但不要求在本发明中使用。在存在的情况，甾族化合物可以是倍他米松、二丙酸倍他米松、醋酸氟新诺龙酯、氟轻松、皮质醇、甲泼尼龙、氯倍他索、倍氟米松、磷酸钠地赛米松、曲安西龙及其药学上可接受的衍生物。
在优选的实施方式中，提供的药学活性剂将包括抗真菌剂。合适的抗真菌剂主要包括作用于真菌的细胞壁或者膜的那些，尽管临床需要时其他(例如，细胞内作用剂)也可适用。一般而言，细胞壁/膜活性抗真菌药包括烯丙胺、唑类、多烯抗有丝分裂剂(polyene antimicotic)和棘白霉素。非限性的具体实例包括特比萘芬、双氯苯咪唑、酮康唑、两性霉素、氟康唑、氟胞嘧啶、游霉素、两性霉素B、制霉菌素、色甘酸、洛度沙胺、左卡巴斯汀、萘唑啉、安他唑啉、非尼拉敏(pheniramimane)及其药学上可接受的衍生物。特比萘芬是目前优选的用于本发明中的抗真菌剂，除非其使用是禁忌的（例如，对于某些狼疮患者）。
在一些实施方式中，药学活性剂也可包括局部麻醉剂或止痛剂。合适剂的实例包括苯佐卡因、苯甲酸苄酯、布比卡因、炉甘石、氯普鲁卡因、氯二甲苯酚、辛可卡因、可卡因、地昔卡因、二胺卡因、二丁卡因、达克罗宁、依替卡因、海克卡因、氯胺酮、左布比卡因、利多卡因、薄荷醇、甲哌卡因、奥昔卡因、苯酚、普莫卡因、丙胺卡因、阿美索卡因、地卡因、丙美卡因、丙氧卡因、吡咯卡因、间苯二酚、利索卡因、罗多卡因、罗哌卡因、地卡因及其药学上可接受的衍生物。由于本发明的组合物在消退治疗的外耳炎方面的快速作用，使用这样的麻醉剂或止痛剂可能是不必要的。
特别是在动物中，外耳炎通常与寄生物侵扰有关，最通常是耳螨病(otocariosis)或者耳痒螨病(Otodectes cynotis)(耳螨)侵扰。局部治疗耳螨通常用相对长期的局部杀虫疗程来完成；例如，用含除虫菊酯的组合物。然而，更近期以来，例如通过注射或在皮肤上视觉地(otically)施用霉素(mectin)和霉菌素(mycin)化合物；例如阿凡曼菌素(比如伊维菌素和塞拉菌素)和美倍霉素，获得较短的疗程。如果临床需要，这类抗寄生物的化合物可以在本发明的组合物内共同施用，或者作为本发明组合物的单独辅助剂共同施用。此外，临床需要的情况下，抗病毒的化合物，比如阿昔洛韦，可代替抗生素化合物或作为其辅助剂施用。
下面的实施例阐明了治疗狗的外耳炎的本发明的优选组合物的制备和使用。如所示的，大部分动物的病状通过一个剂量疗程得以消退。对治疗后第14天继续显现病状体征的动物给予另一剂量，并且消退了病状。
当然，应理解，本发明可用于治疗任何哺乳动物的外耳炎，将本发明药学上可接受的无纤维素的、非胶凝组合物以足够临床上改善(显著地减少症状至容易通过复治(re-treatment)消退，优选地为单剂量复治)或消退所治疗病状的剂量局部应用于所述哺乳动物的外耳道。虽然医生和兽医当然熟悉给予单个活性剂的适合浓度，但该浓度和剂量范围预期在大多数临床状况下有效，并且种类(species)为0.1%到2.0%活性物w/w，以最多大约1毫升或者10-20滴的单位剂量输送，这取决于临床医生对适当疗程和输送的剂量强度的判断。
本发明已经进行了充分地描述，下面的实施例意欲阐明但不限制由所附权利要求限定的本发明范围。
实施例1
本发明的含抗生素、抗真菌剂、NSAID的组合物
脂质载体用phospholipon 90H制备，并且列出的活性/非活性成分与之混合至100g的量，如下。
为了制备水相，将水加入不锈钢夹套涡流水合室混合容器中。盖住容器的室以防止水蒸发，并且容器的室配置有底口和阀门以调节材料流出容器的流量。对于制剂1B，将DOWCILTM 200加入并溶解于水中。对于两种制剂，将一半的甲砜霉素加入并溶解于水中并将混合物加热到50℃±2℃。以低速进行混合以避免形成泡沫。随着混合物加热，加入双氯芬酸并混合直至溶解。一旦混合物达到50℃±2℃的温度，随着继续混合，将黄原胶缓慢加入漩涡，直至所有成分都溶解或(就胶而言)完全水合。升高温度，当混合物达到55℃与60℃之间的温度时混合完成。
为了制备脂质相，非常靠近第一个，使用第二个不锈钢夹套混合容器。在该第二个容器内，丙二醇、乙醇、胆固醇、维生素E醋酸酯、特比萘芬以及剩下一半甲砜霉素与phospholipon90H的混合首先缓慢进行，以避免形成泡沫或者表面起泡。启动顶部混合器并加热以升高混合物的温度至55℃到60℃之间，直到所有都溶解。在室上用一个盖子防止整个过程中乙醇蒸发。
在中等混合速度下迅速地将脂质相加入水相。具体而言，将室底口上的阀门打开，调节来自两个容器的流动。水相和油相流动并且汇合于在线的调节用T形管，分散泵(dispersing pump)将两相抽到一起。将混合物循环通过60网目的分散屏，以优化脂质相的水合。之后将混合物引向室顶，整个过程用10分钟循环通过泵，返回室。
在循环之后，将室夹套冷却，以伴随持续缓慢的混合冷却，直至产品的温度为40℃，完成这一过程。优选地，材料的结合足够迅速以彻底混合而不造成表面泡沫的形成或起泡。优选地，通过利用底口和T形管将前者倾倒或快速泵入后者以使它们混合，冷却过程是缓慢的，最优选以每小时大约6℃冷却。不对混合物加热。制备的制剂如下所示。
制剂1A
下面的包含防腐剂和较低浓度的特比萘芬的组合物的效果略差，表明可使用较低浓度的抗真菌剂，仍允许一个剂量消退治疗的耳朵。
制剂1B
实施例2
犬齿类动物(canines)的外耳炎的治疗
用一个剂量的实施例1的组合物，通过滴管方式对每只耳朵施用20滴，治疗26只确诊患外耳炎的不同品种的狗，包括细菌感染、真菌侵扰和炎症。对狗1-16给予制剂1B，对狗17-26给予制剂1A。在用药后第7天和第14天对治疗的耳朵评估外耳炎的体征。
双耳的最终效果是临床得分改善到2或更低，允许动物进入研究的条件是每只耳朵具有的得分至少是6。临床得分由临床医生基于以下每项外耳炎体征的标准评分系统客观地分配得分并进行评估：疼痛、红斑、渗出物、肿胀、气味和溃疡。得分可如下分配：疼痛：0=无，1=轻度/中度——心悸疼痛，2=重度——抬起耳廓疼痛。红斑：0=无，1=轻度/中度——耳镜检查时从几乎察觉不到至明显红色，2=重度——检查时呈甜菜红或亮红色和/或红斑蔓延到耳廓组织。渗出物：0=无，1=轻度/中度——在耳道内少量可见，2=重度——蔓延到耳道外并可能成壳。肿胀：0=无，1＝轻度/中度——耳道有些堵塞，2=重度——耳道完全堵塞。气味：0=无，1=轻度/中度——抬起耳廓时检测到恶臭，2=重度——不用抬起耳廓就检测到恶臭。溃疡：0=无，1=轻度/中度——轻度可见的破损，2=重度——大量的破损和/或可能出血。
1只用制剂1B治疗的动物在第7天呈现特别显著感染的体征，并被复治。2只用制剂1B治疗的动物在第14天注意到酵母过度生长，因此它们也进行了复治。接受制剂1A的动物都不需要复治，尽管对一只这样的动物的治疗被认为失败(没有显著改善或完全康复)。
总的来说，到第14天4只动物的治疗响应在统计上不显著。治疗失败可能的原因包括存在不易受到所涉及活性剂或其它因素影响的细菌和真菌。所有4只动物中，外耳炎都呈现非常严重，为12刻度中的12(12 out of a scale of 12)。
然而，19只动物中，外耳炎在单剂量施药后第14天彻底消退。所有的这些动物到第7天显现了所治疗病状改善的显著体征，包括出现的病状在12刻度上评级为12的动物。
本文说明性描述的发明可以在不存在本文没有具体公开的任何要素或多个要素、限制或多个限制的情况下实施。已经使用的术语和表达被用作描述性术语而非限制性术语，并且不意欲在这些术语和表达的使用中排除所显示和表述特征的任何等同物或其部分，但应认识到在要求保护的发明范围内各种修改是可能的。因此，应该理解，尽管本发明通过优选的实施方式和任选的特征已经被具体地公开，但是本文公开概念的修改和改变可以由本领域技术人员进行，并且这些修改和改变被认为在所附权利要求限定的本发明的范围内。
本文提到或引用的文章、专利和专利申请以及所有其它文件和电子可得信息的内容通过引用以其全部内容并入本文至这样的程度，如同每一单独的出版物被具体且单独地表明通过引用并入。申请人保留将任何和所有的来自任何这些文章、专利、专利申请或其它文件的物质和信息物理上并入本申请的权利。
本文说明性描述的发明可以在不存在本文没有具体公开的任何要素或多个要素、限制或多个限制的情况下合适地实施。因此，例如术语“包括(comprising)”、“包括(including)”、“包含(containing)”等应当广义且非限制性地理解。此外，本文所用的术语和表达已经作为描述性术语而非限制性术语，并且不意欲在这些术语和表达的使用中排除所显示和表述特征的任何等同物或其部分，但应认识到在要求保护的发明范围内各种修改是可能的。因此，应该理解，尽管本发明通过优选的实施方式和任选的特征已经被具体地公开，但是本文公开的在其中具体体现的发明的修改和改变可以由本领域技术人员进行，并且这些修改和改变被认为在本发明的范围内。
本发明在本文中已经作了广泛且一般性的描述。落入上位公开内容中的每一个较窄类别和亚组也构成发明的部分。这包括本发明带条件或者否定性限制的一般描述——其从种类中去除了任一主题，而无论排除的物质是否在本文中具体描述。其它实施方式在所附权利要求之内提出。
此外，在本发明的特征或方面按照马库什组进行描述的情况下，本领域普通技术人员应认识到本发明也因此按照马库什组的任何单个成员或成员的亚组进行描述。
我们发明的范围由所附权利要求限定。
Claims (15)
1.一种通过对外耳道局部施用药学上可接受的组合物治疗或预防外耳炎感染及其后遗症的方法，其中所述组合物不包括增强粘度的纤维素或者粘合剂成分，且不以凝胶的形式，并且其中所述组合物包括脂质载体以及从抗生素、抗真菌药、抗寄生物药、抗病毒药、非甾体抗炎药、止痛药、麻醉剂和甾族化合物选取的至少两种活性剂，所述方法包括以足以临床上改善或消退所治疗病状的单剂量对外耳道应用所述组合物。
2.根据权利要求1所述的方法，其中所述脂质载体是脂囊泡。
3.根据权利要求1所述的方法，其中所述组合物中的一种活性剂是抗生素。
4.根据权利要求1所述的方法，其中所述组合物中的一种活性剂是抗真菌药。
5.根据权利要求1所述的方法，其中所述组合物中的一种活性剂是非甾体抗炎药(NSAID)。
6.根据权利要求3所述的方法，其中所述抗生素选自喹诺酮抗生素、青霉素抗生素、大环内脂类抗生素、头孢菌素抗生素、磺胺抗生素和β-内酰胺酶抑制剂。
7.根据权利要求6所述的方法，其中所述抗生素包括甲砜霉素。
8.根据权利要求4所述的方法，其中所述抗真菌药是烯丙胺抗真菌剂。
9.根据权利要求8所述的方法，其中所述烯丙胺是特比萘芬。
10.根据权利要求5所述的方法，其中所述NSAID是双氯芬酸。
11.根据权利要求1所述的方法，其中所述活性剂是抗生素、抗真菌药和NSAID。
12.根据权利要求1所述的方法，其中所述抗生素是甲砜霉素，所述抗真菌药是特比萘芬，并且所述NSAID是双氯芬酸。
13.根据权利要求12所述的方法，其中所述特比萘芬以所述组合物的1%到1.5%w/w的浓度提供。
14.根据权利要求12所述的方法，其中所述双氯芬酸以所述组合物的0.5%w/w的浓度提供。
15.根据权利要求12所述的方法，其中所述组合物进一步包括不溶于油的防腐剂。
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