CN103561724B - 给药给甲的药物组合物 - Google Patents
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- CN103561724B CN103561724B CN201280025400.7A CN201280025400A CN103561724B CN 103561724 B CN103561724 B CN 103561724B CN 201280025400 A CN201280025400 A CN 201280025400A CN 103561724 B CN103561724 B CN 103561724B
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Abstract
本发明提供了用于局部给药给人的手指甲或脚趾甲的半固态或液态的药物组合物。该组合物对活性成分深入所述甲的递送是有用的。各种活性成分可被加入，比如抗真菌剂、抗感染剂、抗炎剂、免疫抑制剂、局部麻醉剂和类维生素A可被加入。
Description
技术领域
本发明属于药疗领域。更具体地，其涉及侵袭人类和其它哺乳动物的甲（nail）的疾病和病症的处理。
背景技术
当许多皮肤疾病侵袭皮肤本身时，也存在涉及皮肤附器（尤其是甲）的疾病与病症。这些往往因厚密甲板主要由角蛋白组成及其对治疗剂的摄取不良而难以治疗。
甲是表皮的角质区的硬化物。它们表现为覆盖手指和脚趾的末端指骨的背侧上的皮肤的片状附器。甲的角质区由硬α-角蛋白组成且具有远端、裸露部分或者本体，以及近端、隐藏部分或者根部。根部被皮肤的角质层的远端延伸部覆盖。这种狭窄的皱襞由软性角蛋白组成且被称为甲上皮。甲上皮的远端是“半月”或甲半月，是相对于底层毛细血管不透明的角质区的一部分。
在甲的远端或独立缘下面，指尖的角质区被增厚，通常称为甲床。甲的角质区附着于底层甲床。基体（matrix）或者甲床的近端部分产生硬性角蛋白。然而，在更远端，甲床也可产生甲物质。此外，甲的最表层可通过贴近根部背侧和甲上皮近端的上皮产生。甲的生长受营养、荷尔蒙和疾病的影响。甲生长牵涉相当多的蛋白质合成，其结果是非特异性变化响应于各种局部和全身的失调而发生在甲中。
甲在胎儿时发育，作为表皮增厚物，其底切皮肤以形成皱襞，甲的角质从该皱襞向远端生长。就成人而言，手指甲要用大约6个月形成，对应于每个月约2-3mm的生长速度。脚趾甲往往比手指甲生长得更慢。
甲比皮肤的角质层厚大约两个量级。硬α-角蛋白（角质区的主要成分）是纤维结构的蛋白质，其特征在于高含量的半胱氨酸，半胱氨酸容易通过硫化物桥接形成热稳定的交联。甲的含水量相当低，通常范围在约10%至30%。一般而言，甲非常耐分子（如原料药）的渗透。
甲的主要功能是保护手指和脚趾的敏感末梢。另外，手指甲用于抓刨（scratching）。脚趾甲对平衡而言也很重要。
侵袭甲器官的最常见的疾病之一是真菌感染，也被称为甲癣，一种侵袭约20%的美国成年人口的病症。该发病率正在世界范围内上升。事实上，所有浅部真菌感染中约30%会侵袭甲。感染可因皮肤癣菌（癣，甲癣）、酵母菌、或者其它非皮肤癣菌（霉菌）种类而起。在甲沟炎中，甲襞的慢性感染最常由念珠菌属引起，但革兰氏阴性菌种（如假单胞菌）的细菌感染也可共存。还可发生因葡萄球菌感染而起的急性甲沟炎（化脓性指头炎），且这些细菌感染的存在会影响治疗。在存在甲沟炎、免疫缺陷状态（包括慢性皮肤粘膜念珠菌病）、雷诺氏病、或内分泌失调的情况下，可发生甲板被念珠菌属侵入。
另一种常见病症是甲银屑病，银屑病的可能的临床表现之一，其在手指甲和脚趾甲的外表上产生各种变化。这些变化包括甲板下面的变色、甲的凹点（pitting）、横贯甲的线、甲下面皮肤的增厚、以及甲的松动（甲松离）和粉碎。
大多数有甲银屑病的人也有皮肤银屑病（皮肤牛皮癣）。只有5%有甲银屑病的人没有皮肤银屑病。在有皮肤银屑病的人中，10%-55%有甲银屑病（也称银屑病甲病）。约10%-20%有皮肤银屑病的人也有银屑病关节炎，一种特殊的病症，有银屑病关节炎的人具有关节炎和银屑病两种症状。53%-86%有银屑病关节炎的人具有受侵袭的甲，常常有凹点。
甲的另一病症是甲床炎，这是围绕甲板组织的甲襞的一种炎症，伴随形成甲的脓和脱落。甲床炎的起因之一是创伤后细菌感染。
甲松离指的是甲的裸露部分从甲床松动，通常开始于甲前缘并延续到甲半月。这可与多种可能的原因有关，包括与感染和过敏反应有关。
许多其它的甲病症（如甲营养不良、甲脱落、甲下垂）往往表明对药物（例如，抗生素或抗癌剂）的不良反应。
有意思的是，甲的病症常常要全身治疗，这本身表明了通过局部给药在甲中达到治疗药物的浓度是如何之难。举例来说，甲癣用口服特比萘芬每日250mg持续3-6个月或者依曲康唑每日200mg持续3-6个月进行治疗。甚至用口服灰黄霉素10mg/kg/日（500mg，每日两次）持续6-18个月的相当常规的疗法在现下仍受推荐。尤其是近端甲疾或严重的甲床损害被视为全身治疗而非局部治疗的适应症。
存在一些用于甲癣治疗的已知抗真菌剂的局部用制剂，比如包含环吡酮、阿莫罗芬或布替萘芬的甲油（nail lacquer）。虽然有一些疗效证据，但相信成功的局部抗真菌疗法需要很长时间的治疗，比如一年甚或更长。一些专家推荐结合局部治疗和全身治疗以获得更好的疗效。没有充分的治疗和病人依从性，感染不会消失。
此外，对甲银屑病而言，最有效的治疗选择看来是全身性的而非局部性的。最近的报告表明一些注射性生物药品（如英夫利昔和依那西普）会是非常有效的。但是，这些治疗伴有相当大的不良反应风险，且它们都非常昂贵。
用它们当前可用剂型的局部治疗的疗效被认为小得多。可以每日对甲襞施用两次含有维生素D衍生物（比如钙泊三醇）的溶液。其它选择有局部高效皮质类固醇溶液或软膏。一些专家还推荐将5-氟尿嘧啶乳膏施用到基体持续6个月以改善凹点和甲下角化过度。每当继发性真菌感染出现（其在甲银屑病情况下非常频繁），即表示有抗真菌治疗。
为使甲疾的局部治疗更为成功，已付出种种努力，主要集中在改善原料药到甲基体的渗透性。通常推荐使用尿素霜的联合治疗以便软化甲的角蛋白并使其更易渗透。虽然存在一些证据表明结合尿素的抗真菌疗法有所改进，但全身疗法在考虑其所有风险和不良反应的情况下仍然显得更有效得多。
其它渗透促进剂已被建议用于增强抗真菌剂贯穿甲的递送，比如在US6,042,845，US6,159,977，US6,224,887和US6,391,879中。然而，大多数所建议的化合物未获批准用于药剂且存在未知的健康风险。
美国专利No.5,326,566记载了药理剂结合己二酸二丁酯、或者己二酸二丁酯和十四烷酸异丙酯的混合物的组合物，其可增强穿过角蛋白的渗透。但是，当渗透促进剂与特定原料药不相容时，会出现大量问题，导致药物的不稳定性并降解成潜在有害的降解产物。
US2005/0079210A1提出了使用脂质体、药物和美容用剂的经皮给药。但是，脂质体难以符合成本效益地并难以以可再生的方式制造。
其它用于局部药物治疗的递送策略需要在给药之后包藏甲，但许多病人感到这不方便。
显然，仍需要允许通过局部给药有效治疗甲患的药物剂型和辅料。因此，本发明的目的是提供这样的改进的组合物，其克服了已知组合物的一或多个缺点。特别地，本发明的目的是提供局部活性原料药的组合物，其可有效地穿透致密甲板且其便于使用。基于下面的本发明的包括实施例的说明书以及基于权利要求书，本发明进一步的目的会变得清晰。
发明内容
本发明提供了一种给药给甲的新的药物组合物。该组合物包括有效量的活性成分和根据式RFRH或RFRHRF的半氟化烷烃（SFA），其中RF是具有20个或更少碳原子的全氟化烃段且RH是具有3至20个碳原子的非氟化烃段。在优选的实施方式中，SFA选自F4H5、F4H6、F4H8、F6H6和F6H8。
本发明人已出人意料地发现，SFA类能够将活性药物成分有效地递送至手指甲和脚趾甲的角蛋白基体以比如甚至在所述基体的较深区域中产生治疗相关的药物浓度。
该组合物可例如为溶液、凝胶、甲油、乳剂、悬浮液、喷雾或者贴剂的形式。这对给药在各种甲疾病和病症中需要的范围广泛的局部药剂是有用的。
附图说明
图1示出了他克莫司在作为基于SFA的制剂给药给人的甲1000分钟之后的渗透轮廓，分别示为沿着深度的他克莫司摩尔浓度。进一步细节请参见实施例1。
图2示出了他克莫司在作为基于SFA的制剂给药给人的甲1000分钟之后的渗透轮廓，分别示为每层的他克莫司量（相对于给药剂量）。进一步细节请参见实施例1。
图3示出了环吡酮胺在作为基于SFA的制剂给药给人的甲1000分钟之后的渗透轮廓，分别示为沿着深度的环吡酮胺量（相对于给药剂量）。进一步细节请参见实施例2。
具体实施方式
本发明提供了用作给药给甲的局部制剂的新的药物组合物。该组合物包括有效量的活性成分和根据式RFRH或RFRHRF的半氟化烷烃，其中RF是具有20个或更少碳原子的全氟化烃段且RH是具有3至20个碳原子的非氟化烃段。
本发明基于意想不到的发现：如上面所定义的半氟化烷烃类（SFAs）是高度适合的用于局部给药药物的载体且能够递送活性成分深入所述甲。这是Hardung（博士论文，阿尔伯特-路德维希-弗莱堡大学，德国，2008年）特别意想不到的，他使用例如睾酮作为模型药物研究了SFAs作为用于局部药物治疗的载体的适用性，且他得出结论：诸如F6H8等SFA（参见下面对术语SFAs的说明）不影响改进的渗透，也不与角质层（其屏障功能也依赖于角蛋白）相互影响，也不表现出任何增渗作用（第103页，第1段整段）。然而，尽管现有技术中有这样令人沮丧的陈述，但本发明人利用离体的人甲进一步研究了SFAs和基于SFA的载体对药物到甲的角蛋白基体中的递送的影响（与利用猪的皮肤作为模型的Hardung形成对照），且现已出人意料地发现：SFAs的确能够增强药物到甲中的渗透，如下面将更详细示出的。
本文所使用的药物组合物是包含用于疾病、症状或健康状况的诊断、预防、治疗或疗法的有效成分以及至少一种载体或赋形剂的任何组合物。局部剂型是以适于局部给药的形式的组合物。在本发明中，所述组合物适于给药给受药者的皮肤附器，所述受药者可以是人或动物。所述皮肤附器（如手指甲或脚趾甲）可以是完好的或者受伤的、擦伤的、受损的或以其它方式受到侵袭的。
半氟化烷烃类是直链烷烃或支链烷烃，其氢原子中的一些已被氟取代。在优选实施方式中，本发明中所使用的半氟化烷烃类（SFA's）由至少一个非氟化烃段和至少一个全氟化烃段构成。特别有用的是根据通式F(CF2)n(CH2)mH的将一个非氟化烃段连接到一个全氟化烃段的SFA's、或者根据通式F(CF2)n(CH2)m(CF2)oF的由一个非氟化烃段分隔两个全氟化烃段的SFA's。
本文所使用的另一命名系统是指上面提到的根据RFRH和RFRHRF分别具有两或三个分段的SFA's，其中RF指全氟化烃段，RH指非氟化段。作为选择，所述化合物可分别被称为FnHm和FnHmFo，其中F表示全氟化烃段，H表示非氟化段，而n、m和o是各分段的碳原子数。例如，F3H3被用于全氟化丙基丙烷。此外，这种类型的命名系统通常被用于具有直链分段的化合物。因此，除非另有说明，否则，应假定F3H3表示1-全氟化丙基丙烷，而不是2-全氟化丙基丙烷、1-全氟化异丙基丙烷或2-全氟化异丙基丙烷。
优选地，根据通式F(CF2)n(CH2)mH和F(CF2)n(CH2)m(CF2)oF的半氟化烷烃具有3至20个碳原子范围内的分段大小，即n、m和o独立地从3至20的范围内进行选择。在本发明的语境中有用的SFAs也在EP-A965334、EP-A965329和EP-A2110126中进行了描述，这些文本的公开内容被并入本文。
在另一实施方式中，半氟化烷烃是根据式RFRH的化合物，其分段RF和RH是直链的且每一个（但彼此独立地）具有3至20个碳原子。在另一具体实施方式中，全氟化分段是直链的且包括4至12个碳原子，和/或非氟化分段是直链的且包括4至8个碳原子。优选的SFA's具体包括化合物F4H5、F4H6、F4H8、F6H4、F6H6、F6H8和F6H10。目前最优选的用于实施本发明的是F4H5、F4H6、F4H8、F6H6和F6H8。
任选地，该组合物可包括多于一种的SFA。这对组合SFA's会是有益的，例如，以便实现特定的目标属性，比如用于特定活性成分的某个密度、粘度、或增溶能力。如果使用SFA's的混合物，则进一步优选的是，该混合物包括F4H5、F4H6、F4H8、F6H4、F6H6、F6H8和F6H10中的至少一者，特别是F4H5、F4H6、F4H8、F6H6和F6H8中的一者。在另一实施方式中，该混合物包括选自F4H5、F4H6、F4H8、F6H4、F6H6、F6H8和F6H10中的至少两个成员，特别是选自F4H5、F6H6、F4H8和F6H8中的至少两个成员。此外，也可考虑半氟化烷烃（例如F4H5）与全氟化合物（如全氟辛基溴化物或全氟萘烷）、或者与其它油性物质的混合物。其它油性物质可例如包括硅油类、甘油三酸酯类（例如，天然的或者合成的中链甘油三酸酯类）、或者诸如肉豆蔻酸异丙酯等化合物。然而，在一些优选的实施方式中，全氟化合物不存在。
液态SFA在化学和生理学上是惰性的、无色的和稳定的。其典型的密度范围从1.1至1.7g/cm3，且其表面张力可低至19mN/m。RFRH类型的SFA's不溶于水，但也有些两亲性，具有与增加的非氟化分段的大小相关联的增加的亲脂性。再次地，为了实施本发明，应选择具有至少1.2g/cm3的密度的SFA。
RFRH类型的液态SFA's在商业上被用于展开和重新应用视网膜，作为玻璃体液替代物用于长期填塞（H.Meinert等人，EuropeanJournal of Ophthalmology（欧洲眼科杂志），第10卷（3），第189-197页，2000年），以及作为在玻璃体-视网膜手术之后用于残余硅油的冲洗溶液。在实验上，它们也被用作血液代用品（H.Meinert等人，Biomaterials,Artificial Cells,and Immobilization Biotechnology（生物材料、人造细胞和固定化生物技术），第21卷（5），第583-95页，1993年）。这些应用已将SFA's确立为生理耐受性良好的化合物。另一方面，SFA's迄今还没有在已批准的药品中用作赋形剂。
为了方便给药给甲，所述组合物优选液态或半固态。本文所使用的半固态是指物质在被施加低剪切力时表现得像固体，但在超过特定力阈值（所谓的“屈服点”）时，它表现得像粘性流体。
无论是液态或半固态，该组合物可表现为单相（即溶液），或者由两或更多相组成。溶液可被原样施用，优选地利用刷子状施药器，或者在分配器适于发射作为气雾剂或喷雾剂的剂型时，其可被喷涂。任选地，所述剂型可包含成膜赋形剂，比如改性纤维素（如硝化纤维素）、丙烯酸或甲基丙烯酸的聚合物或共聚物、聚酯、聚（丁基氢-马来酸-共-甲氧基乙烯）或其它合适的树脂，以比如表现为作为溶液施用并接着干燥从而在甲上形成固体膜的甲油。除了成膜树脂之外，这种组合物还可包含用于改善成膜物质在甲上的粘附性的赋形剂，比如甲苯磺酰胺-甲醛树脂。此外，它还可包含增塑剂，比如甘油三乙酸酯、莰酮、邻苯二甲酸酯、柠檬酸三乙酯或者类似物，以提高膜的挠性并降低其脆性。此外，也可能有利的是加入挥发性助溶剂，比如乙酸乙酯、乙醇、1-丙醇、2-丙醇或丙酮。
在进一步的实施方式中，该组合物是以乳剂的形式。本文所使用的乳剂是在连续的（或外部的，或连贯的）液相或半固态相内包括分散的（或内部的，或乳化的、或不连续的）液相的系统。该两种液相是不混溶的。在O/W型乳剂（也被称为水包油型乳剂）中，并不必须是任何具体定义的“油”的与水不混溶的有机液相被分散在可能是或可能不是基本上由水本身组成的与水混溶的连续相中。
在另一实施方式中，该组合物是微型乳剂的形式。微型乳剂是亲脂性组分、亲水性组分和两亲性组分的透明的、热力学稳定的、光学各向同性的混合物。通常，当所述组分彼此结合或混合时，微型乳剂自发地形成，不需要高能量输入，而形成“普通”乳剂通常需要高能量输入。微型乳剂可具有分散在亲水相中的胶质亲脂相、或者胶质地分散在亲脂相中的亲水相。分散相的大小通常在从约5nm至约400nm的范围内，且大多数往往低于约200nm。在本发明的优选实施方式之一中，粒径从约5nm至约100nm。根据其流变性质，微型乳剂可以为液体或凝胶的形式，即液态或半固态的形式。在优选实施方式中，微型乳剂为液体形式。
对于根据本发明的微型乳剂而言，优选的是使用油相，所述油相包括从约5至约95wt.-%的SFA且更优选地从约10至约80wt.-%的SFA，所述油相的剩余部分是另一种油，比如肉豆蔻酸异丙酯。就加入水性组分、表面活性剂和任选助表面活性剂而言，公知成分的微型乳剂可被用于配制该组合物。
要指出的是，乳剂和微型乳剂可尤其适于治疗甲在其与皮肤交界处的近端区域，特别是涉及给药给甲上皮，甲上皮是从后段甲壁延伸到所述甲的基部上的狭小的上皮组织带。甲上皮是近端皱襞的末端，近端皱襞折叠回到其自身上以使皮肤的表皮层溢出（shed）到新形成的甲板上，因此，这对活性成分的递送而言是重要的目标位点，以在甲被形成时改善甲的健康。
可选地，该组合物可被设计成作为甲贴剂进行给药。为此，可将液态或半固态剂型纳入非织造材料，其通过粘合贴片被覆盖并保持在适当位置。替代地，所述活性成分和SFA可被纳入粘合基质层（粘合剂包药物型的设计）。另一选择是将液态的、基于SFA的药物剂型填充在袋（pouch）中，其通过粘合贴片被覆盖并施加给甲（贮液器设计）。在这种情况下，该袋在与甲的交界处具有（半）渗透膜，所述活性成分和SFA通过该（半）渗透膜释放给甲。
无论是配制成溶液、微型乳剂或常规乳剂、悬浮液、或者贴剂，该组合物可包含任何进一步的在药学上可接受的鉴于预期应用所需要的或者有用的成分。如上所述，可加入额外的溶剂或助溶剂，例如以便就特定的活性成分达到较高的溶解度，从而修改剂型的粘度或稳定性，或者从而进一步增强活性成分的渗入。当然，这样的助溶剂应当选择类型、质量和数量，比如以维持剂型的生理耐受性。潜在合适的助溶剂包括乙醇、丙酮、乙酸乙酯、异丙醇、丙三醇、丙二醇、戊二醇、聚乙二醇、液体石蜡、甘油三酸酯油、诸如HFA134a和/或HFA227之类的氢氟碳化合物、以及液态的甘油单酯或甘油二酯。其中，乙醇、异丙醇和戊二醇属于特别优选的溶剂。已经发现的是，相对少量的乙醇可大大改变SFAs的增溶性质且允许一些活性成分以较高浓度混入。例如，该组合物可包括上至约25wt.-%、或者上至10wt.-%的乙醇、或者上至5wt.-%的乙醇。即使在上至约3wt.-%的低浓度，乙醇在该组合物中也会是非常有用的添加剂，具体取决于待递送的具体的原料药。一般而言，戊二醇作为助溶剂也是非常有用的，且特别是已经发现，它的加入对配制微型乳剂是有利的。
此外，该组合物可包括一或多种稳定剂、表面活性剂（特别是当该组合物是以乳剂或微型乳剂的形式时）、助表面活性剂（特别是当它是微型乳剂的形式时）、着色剂、抗氧化剂（例如，α-生育酚）、增稠剂（粘度增加剂，比如膨润土）、以及芳香剂。
如果存在表面活性剂，则它可例如选自生理上可接受的磷脂类（如磷脂酰胆碱类）；非离子型表面活性剂，比如脂肪醇类、聚乙二醇化的甘油酯类、聚乙二醇化的脂肪酸类、聚乙二醇化的脂肪醇类、聚乙二醇化的山梨糖醇酐脂肪酸酯类以及泊洛沙姆类；阴离子表面活性剂，比如月桂基硫酸钠、多库酯钠以及脱氧胆酸钠。
该组合物可通过用于制造药物的溶液、乳剂、悬浮液、凝胶、喷雾和微型乳剂的公知技术进行制备。根据它们的稠度和具体用途，它们可呈现在瓶、喷雾瓶、管状物中，有或没有施药器均可。
原则上，加入该组合物的活性成分可选自对与甲有关的疾病或病症的预防、治疗或疗法有用的原料药。
在具体实施方式之一中，该活性成分是水难溶性的。尤其是，其水溶度不大于约1mg/ml。在其它优选实施方式中，水溶度分别不高于约0.1mg/ml，或者不大于约10μg/ml。本发明对递送这样的活性成分特别有用，因为它允许相对较小体积的有效剂量的给药，这至少部分是由于半氟化烷烃类对于许多水难溶性原料药具有高得惊人的溶解能力。
为免生疑问，肯定的是，本发明并不局限于水难溶性的原料药。已经发现某些生物活性剂具有大的水溶度，但也可有利地配制在基于SFA的载体中。
所述活性成分可选自对任何甲疾病或病症或任何与此相关的症状，包括甲银屑病、甲癣、甲床炎、甲内生（onychocryptosis）、甲松离（onycholysis）、甲脱落（onychomadesis）、甲下垂（onychoptosis）、甲沟炎、甲基体无知觉（onychomatricoma）、无甲症、白甲症、软甲症、红甲症、甲营养不良、甲髌骨综合征，以及疼痛、瘙痒和悸动的预防尤其是治疗和疗法有用的原料药。
在具体实施方式之一中，该组合物被用在甲银屑病的疗法中，且加入可用于控制银屑病或其症状的活性成分。这样的活性成分可例如是免疫抑制药，比如大环内酯免疫抑制剂。潜在合适的大环内酯免疫抑制剂的示例包括他克莫司、西罗莫司、依维莫司、吡美莫司、雷帕霉素（ridaforolimus）、西罗莫司脂化物、佐他莫司和环孢菌素A。他克莫司在这个组中是特别优选的药物之一。本发明人已发现他克莫司可被非常有效地（即比使用常规剂型快且深入）递送给甲基体。该化合物渗入甲至少到400μm的深度（参见实施例1）。
本发明的组合物可使通常难渗入甲的活性成分能够将疗效显著的剂量渗入甲基体中，所述通常难渗入甲的活性成分比如诸如他克莫司等大环内酯免疫抑制剂。例如，在将该组合物局部施用到甲之后1000分钟内，活性剂的给药剂量的至少约8%可渗入甲基体。在另一实施方式中，在将该组合物局部施用到甲1000分钟内，在至少150μm的深度可找到至少约20μM的活性成分。在进一步的实施方式中，在将该组合物局部施用到甲之后1000分钟内，在至少250μm的深度可找到至少约10μM的活性成分。
此外，在甲银屑病的治疗中潜在有用的是加入来自类维生素A之类的活性成分。这样的局部活性类维生素A的示例包括视黄醇、视黄醛、维A酸、异维A酸、阿利维A酸（alitretinoin）、依曲替酯、阿曲汀、他扎罗汀、蓓萨罗丁和阿达帕林。
另外，对甲银屑病而言，选自维生素D类似物之类的活性成分（特别是维生素D3类似物）的加入是进一步的治疗方案。其示例包括钙泊三醇、骨化三醇和他卡西醇。
甲银屑病以及甲的其它病症可涉及大的炎症反应，这可通过皮质类固醇或非甾体类抗炎剂（NSAID）的加入而解决。可被加入基于SFA的组合物的合适的皮质类固醇包括安西奈德、二丙酸倍他米松、丙酸氯倍他索、地奈德、去羟米松、醋酸双氟拉松、氟轻松、醋酸氟轻松、氟氢缩松、丙酸氟替卡松、哈西奈德、卤贝他索丙酸酯（halobetasol proprionate）、氢化可的松、氢化可的松丁酸酯、氢化可的松戊酸酯、糠酸莫米松、泼尼卡酯、以及曲安奈德。合适的NSAID包括双氯芬酸、布洛芬、酮洛芬、吲哚美辛、吡罗昔康、氟芬那酸、依托芬那酯、以及氟比洛芬。
另一治疗适应症是甲癣，甲的一种真菌感染，其中治疗剂渗透受侵袭的甲的较深层是非常重要的。在具体实施方式中，本发明的组合物用在甲癣的治疗中且包括在治疗上有效的量或浓度的抗真菌剂。出于该目的可被加入的抗真菌剂包括选自唑类抗真菌剂、烯丙胺类抗真菌剂的化合物及其它。建议用于实施本发明的特别是克霉唑、酮康唑、咪康唑、特比萘芬、萘替芬、布替萘芬、环吡酮胺和阿莫罗芬。
本发明的组合物可实现疗效显著剂量的活性剂的快速渗透，比如抗真菌剂（例如，环吡酮胺）。举例来说，在将该组合物局部施用到甲之后1000分钟内，活性剂的给药剂量的至少约15%可已渗入甲基体。在其它实施方式中，在将该组合物局部施用到甲之后1000分钟内，活性剂的给药剂量的至少约25%或至少约40%可渗入甲基体。
此外，特别地，本发明的组合物可使活性剂能够渗入甲的较深层。例如，在将该组合物局部施用到甲之后1000分钟内，活性剂的给药剂量的至少约8%可渗透到至少约100μm的深度。在其它实施方式中，在将该组合物局部施用到甲之后1000分钟内，活性剂的给药剂量的至少约3%可渗透到至少约200μm的深度，或者活性剂的给药剂量的至少1%可渗透到至少约400μm的深度。
在进一步的实施方式中，本发明的组合物包括局部麻醉剂，比如苯佐卡因、氨苯丁酯、二丁卡因、利多卡因、奥布卡因、布比卡因、丙吗卡因、丙美卡因、丙氧间卡因和丁卡因。这样的组合物可被用于缓解可能由各种甲疾病和病症直接或间接引起的或者由其治疗导致的疼痛或瘙痒。此外，它们可被用在小手术的准备程序中。
另外，该组合物可包括用在细菌感染的预防和治疗中的抗生素。合适的局部活性抗生素的示例包括诸如新霉素或庆大霉素等氨基糖甙类；诸如红霉素和阿奇霉素等大环内酯类；诸如氯四环素、土霉素、甲氯环素或四环霉素等四环素类；以及诸如瑞他帕林、克林霉素、夫西地酸、莫匹罗星、氯碘羟喹、那氟沙星或短杆菌素等其它抗生素。
通过下面的实施例进一步阐述本发明。
实施例
实施例1
将他克莫司溶解在包括F6H8和3.8wt.-%的乙醇的液体载体中以获得具有1mg/mL的他克莫司浓度的清液。该组合物被用于评估他克莫司从基于SFA的载体到人甲中的渗透。
获取并在等渗氯化钠溶液中清洗离体的人脚趾甲。对于每一个甲，直径为16mm（2.01cm2）的过滤器膜被加载30μL的测试溶液，被置于所述甲上且被培养1000分钟。在该期间的最后，收集所述过滤器中和所述甲上的测试溶液的剩余量。从每一个甲获取直径为5mm（0.1963cm2）的钻取活组织切片（punch biopsy）。该钻取活组织切片被冷冻并在-40℃被显微切片（microtomise）成40μm厚度的20个水平切片。如同所收集的未渗入剂型量，通过HPLC-MS，每一个切片被提取并对他克莫司进行分析。
结果发现在测试期间，他克莫司被甲很好地摄取。鉴于通常认为甲非常难渗透且他克莫司因其分子大小不是一种特别好渗透的原料药等事实，这是非常出人意料的。所述甲中找到的他克莫司的总量是给药剂量的大约9%。在甲表面下深至400μm处发现显著的他克莫司浓度（参见图1）。图2中示出了该药在每一层中的各自的量。
实施例2
重做实施例1的试验，但用环吡酮胺溶液替代他克莫司溶液。该测试组合物含有1%（w/v）的环吡酮胺，溶解在辅料F6H8和乙醇中（85/15wt.-%）。
结果，在甲基体中找到环吡酮胺的给药量的49.5%。即使该化合物具有比他克莫司低的分子量，这种非常高的药物渗透量也是显著的且远超预期。显著的药量被发现遍及甲基体的深度（参见图3），表明对于环吡酮胺至甲中的递送而言，SFAs是非常有前景的辅料。
Claims (6)
1.一种包括有效量的活性成分和根据式RFRH的半氟化烷烃的局部药物组合物在制备用于预防或治疗侵袭甲的疾病或病症的药物中的用途，
其中：RF是具有4-12个碳原子的全氟化烃段，且
RH是具有4至8个碳原子的非氟化烃段，
其中所述活性成分是大环内酯免疫抑制剂或抗真菌剂，所述大环内酯免疫抑制剂选自他克莫司、西罗莫司、依维莫司、吡美莫司、雷帕霉素、西罗莫司脂化物、佐他莫司和环孢菌素A，所述抗真菌剂选自克霉唑、酮康唑、或咪康唑、特比萘芬、萘替芬或布替萘芬、环吡酮胺或阿莫罗芬，
其中所述组合物要被给药给所述甲。
2.如权利要求1所述的组合物的用途，其中所述半氟化烷烃选自F4H5、F4H6、F4H8、F6H6和F6H8。
3.如权利要求1所述的组合物的用途，其中所述组合物呈液态溶液剂或半固态溶液剂、凝胶、喷雾、乳剂、悬浮液、微型乳剂、甲油、或者贴剂的形式。
4.如权利要求1所述的组合物的用途，其中所述组合物包括生理上能够接受的助溶剂，所述助溶剂选自乙醇、丙酮、乙酸乙酯、异丙醇、丙三醇、丙二醇、戊二醇、聚乙二醇、液体石蜡、甘油三酸酯油、氢氟碳化合物、以及液态的甘油单酯或甘油二酯。
5.如权利要求1所述的组合物的用途，其中所述甲受到甲银屑病的侵袭，以及其中所述药物组合物包含如权利要求1中所定义的大环内酯免疫抑制剂。
6.如权利要求1至5中任一项所述的组合物的用途，其中所述甲受到甲癣的侵袭，以及其中所述药物组合物包含如权利要求1中所定义的抗真菌剂。
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| AU (1) | AU2012260788B2 (zh) |
| CA (1) | CA2834862C (zh) |
| DK (1) | DK2714008T3 (zh) |
| ES (1) | ES2617968T3 (zh) |
| WO (1) | WO2012160180A2 (zh) |
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| EP2462921A1 (en) | 2010-11-11 | 2012-06-13 | Novaliq GmbH | Liquid pharmaceutical compositions for the treatment of a posterior eye disease |
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| EP3488847B1 (en) | 2012-09-12 | 2023-11-08 | Novaliq GmbH | Semifluorinated alkane compositions |
| CN106511322B (zh) | 2012-09-12 | 2021-09-17 | 诺瓦利克有限责任公司 | 包含半氟化烷烃的混合物的组合物 |
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| JP6642935B2 (ja) | 2015-09-30 | 2020-02-12 | ノバリック ゲーエムベーハー | 眼投与用の半フッ素化化合物 |
| PL3355990T3 (pl) | 2015-09-30 | 2019-11-29 | Novaliq Gmbh | Semifluorowane związki oraz ich kompozycje |
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| KR20200059272A (ko) | 2017-09-27 | 2020-05-28 | 노바리크 게엠베하 | 안구 질환의 치료에서의 사용을 위한 라타노프로스트를 포함하는 안과적 조성물 |
| WO2019068763A1 (en) | 2017-10-04 | 2019-04-11 | Novaliq Gmbh | OPHTHALMIC COMPOSITIONS COMPRISING F6H8 |
| CA3091308A1 (en) | 2018-03-02 | 2019-09-06 | Novaliq Gmbh | Pharmaceutical compositions comprising nebivolol |
| US11000513B2 (en) | 2018-07-02 | 2021-05-11 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
| PL3856128T3 (pl) | 2018-09-27 | 2023-10-16 | Dermaliq Therapeutics, Inc. | Formulacja filtra przeciwsłonecznego do stosowania miejscowego |
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Also Published As
| Publication number | Publication date |
|---|---|
| DK2714008T3 (en) | 2017-03-13 |
| ES2617968T3 (es) | 2017-06-20 |
| CN103561724A (zh) | 2014-02-05 |
| JP6023181B2 (ja) | 2016-11-09 |
| US9308262B2 (en) | 2016-04-12 |
| KR20140035419A (ko) | 2014-03-21 |
| CA2834862A1 (en) | 2012-11-29 |
| WO2012160180A3 (en) | 2013-01-17 |
| EP2714008A2 (en) | 2014-04-09 |
| US20140140942A1 (en) | 2014-05-22 |
| WO2012160180A2 (en) | 2012-11-29 |
| EP2714008B1 (en) | 2016-12-14 |
| AU2012260788A1 (en) | 2013-12-12 |
| JP2014515366A (ja) | 2014-06-30 |
| KR101773648B1 (ko) | 2017-08-31 |
| CA2834862C (en) | 2019-12-17 |
| AU2012260788B2 (en) | 2017-01-19 |
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