CN104302281A - 包含特比萘芬与尿素的局部药物组合物 - Google Patents
包含特比萘芬与尿素的局部药物组合物 Download PDFInfo
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- CN104302281A CN104302281A CN201380025181.7A CN201380025181A CN104302281A CN 104302281 A CN104302281 A CN 104302281A CN 201380025181 A CN201380025181 A CN 201380025181A CN 104302281 A CN104302281 A CN 104302281A
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- alcohol
- acid
- terbinafine
- acceptable salt
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Abstract
本发明涉及一种局部药物组合物,以该组合物的总重量为基准,其包含:a)1.5wt.%至5wt.%的特比萘芬,或其任何药学可接受的盐;b)15wt.%至35wt.%的尿素;和c)超过25wt.%的水。
Description
发明领域
本发明涉及包含特比萘芬与尿素的局部药物组合物,及这些组合物在治疗局部真菌疾病、诸如甲真菌病(onychomycosis)中的用途。该所提供的组合物稳定,且显示强烈的指甲水化与穿透。
发明背景
甲真菌病,也称为甲癣(tinea unguium),是指甲的一种真菌感染,在一般群体中具有约2-8%的患病率,且在60岁以上的成年人中14-28%提高的患病率(Finch和Warshaw,Dermatol.Ther.,2007,20,31-46)。
指甲的真菌感染包括皮癣菌(dermatophytes)、真菌和酵母菌(主要来自念珠菌属的种)。在超过90%的病例中,皮癣菌(尤其是红色发癣菌(Trichophyton rubrum))为感染的原因。存在不同类型的脚趾甲甲真菌病(Seebacher等人Mycoses,2007,50(4),321-327):
-远端侧缘甲下型甲真菌病(DLSO):最常见的指甲真菌感染形式。在此种病例中,真菌经由甲床(hyponychium)侵入指甲板底面并逐渐蔓延到基质。甲下角化过度(hyperkeratosis)和甲剥离症(oncholysis)发展,导致变黄和凸起的指甲板。
-近端甲下型甲真菌病(PSO):在其他健康的人中最不常见的形式,但在免疫功能低下的病人中较为普遍。在此种病例中,真菌在该指甲板内在该基质开始远侧增殖。
-白色浅表型甲真菌病(SWO):仅占10%的病例。此形式的特征在于该指甲板表面上的垩白斑点。
在身体活动和社交尴尬方面,指甲感染影响患者的生活品质。特别是在厚脚趾甲的病例中,压力可能会造成刺激与疼痛。甲真菌病不会自发地消退;它可能会恶化,蔓延至其他未受感染的位置(其他指甲或周围的皮肤)或感染其他人。另外,其可能支持额外的细菌感染。所以,对此疾病找到有效的治疗是重要的。
作为一般规则,如果小于50%的指甲感染且不涉及基质,建议局部治疗。在所有其他病例中,尤其是如果指甲基质被侵袭,全身性治疗(有时与局部治疗相结合)是目前推荐的(Lecha等人J.Eur.Acad.Dermatol.Venereol.,2005,19(1),25-33)。
指甲疾病的局部治疗具有明显优势,诸如消除全身性不良事件与药物相互作用并降低治疗成本。然而,一般情况下,用于处理脚趾甲感染的局部治疗的证据较少。可用的局部甲真菌病治疗包括环吡酮胺(ciclopirox olamine)指甲漆(8%)与阿莫罗芬指甲漆(5%)。
也许是这些产品通过指甲的不良药物穿透的结果,治疗时间长(至少一年),且治愈率低(在48周环吡酮后6.5%至12%治愈率(例如,Baran R.等人JEADV 2009)。
因此,正在寻求替代制剂,其改良药物到指甲的递送(指甲递送),并导致相比可用的局部治疗选择较短的治疗时间和较高的治愈率。
特比萘芬是用于口服治疗甲真菌病的一种领先抗真菌剂。在一些国家已经批准以霜剂、凝胶、溶液和喷雾剂型给药,用于局部治疗真菌感染,但是,不是用于治疗甲真菌病。
由于人类指甲的物理结构,药物递送到指甲是复杂的。指甲板相比角质层更厚、更硬且更致密得多,表明对药物递送而言为长得多的扩散途径。这可能导致不足的指甲板穿透和渗透,这解释了目前市场上局部指甲抗真菌制剂的低功效。
目前已批准且实验的指甲漆基于有机溶剂,未能提供指甲水化。它们甚至从该角蛋白基质中除去水,且因此,使指甲干燥。再进一步,归因于这些漆类的主要溶剂为乙醇和/或乙酸乙酯这样的事实,其非常迅速地蒸发,该制剂往往在数分钟内干燥。这仅提供非常短的时间用于该活性物质从溶解状态穿透。此外,漆类典型地在指甲板上形成薄膜,且不协助除去病变的指甲物质,病变的指甲物质常常作为孢子储库且造成甲真菌病的复发。
霜剂也被用于治疗皮肤真菌的感染。然而,对阿莫罗芬与特比萘芬而言,批准的霜剂是具有低药物负载(分别为0.25%和1%)的制剂,其指甲水化仅为中度的,且不会导致病变指甲物质的除去。
WO2011/079234描述了用于治疗甲真菌病的局部水醇制剂,其包含特比萘芬或其盐,优选10wt.%的特比萘芬或其盐;两性离子表面活性剂或其带电衍生物;羧酸;低级醇和水。根据WO 2011/079234,该低级醇(优选乙醇)的浓度可以为20-50wt.%,在大多数情况下,35wt.%以上。然而,低级醇如乙醇在如此高的浓度下可能会提高皮肤或指甲中的潜在刺激性。
US 6,281,239 B1描述了用于治疗甲真菌病的局部抗真菌组合物,其基本上由高达5wt.%的抗真菌剂(优选硝酸咪康唑(miconazolenitrate))与组织软化组合物混合组成,该组织软化组合物包含40wt.%的尿素和其它赋形剂。然而,具有如此高尿素浓度的组合物可能会造成过度角质层分离(keratolysis)。此外,随着时间的推移,在低温下贮存后尿素可能发生沉淀。
所以,对具有高药物负载的新的制剂是有需要的,所述制剂提供强烈的指甲水化作用、持久的穿透时间,且使得病变指甲与孢子的除去,从而导致优异的临床疗效。
具有高量水的制剂是优选的,因为水似乎促进某些分子的指甲渗透。然而,对此种制剂开发的一个特别挑战是在高量水的存在下实现高浓度的抗真菌剂,由于这些药物已知具有低的水溶解度。
我们已经开发出具有高含量的水和高浓度特比萘芬的制剂。这些制剂显示提高的指甲渗透且允许对指甲板精确的定量给药和出色的黏附性。
发明概述
已经开发了新的局部药物组合物,以该组合物的总重量为基准,其包含:
a)1.5wt.%至5wt.%的特比萘芬,或其任何药学可接受的盐;
b)15wt.%至35wt.%的尿素;和
c)超过25wt.%的水。
本发明进一步涉及如上文定义的组合物,用于在局部真菌感染、优选甲真菌病的治疗或预防。
优选实施方式的详细说明
特比萘芬是烯丙胺类抗真菌药物,其通过阻断酶鲨烯环氧酶(squalene epoxidase)(真菌麦角固醇(ergosterol)生合成中的关键酶)来抑制真菌生长。其他烯丙胺类抗真菌剂的实例包括阿莫罗芬、萘替芬(naftifine)和布替萘芬(butenafine)。
在本发明的实施方式中,特比萘芬或其药学可接受的盐的量为2wt.%至4wt.%。在优选的实施方式中,特比萘芬的量为2wt.%至3wt.%。
优选地,特比萘芬为特比萘芬盐酸盐的形式。
在本发明的实施方式中,尿素的量为15wt.%至30wt.%。在优选的实施方式中,尿素的量为15wt.%至25wt.%。
典型地,水的量超过35wt.%,优选超过40wt.%,且更优选超过45wt.%。
在本发明的实施方式中,水的量为25wt.%至65wt.%。在优选的实施方式中,水的量为35wt.%至55wt.%。在更优选的实施方式中,水的量为40wt.%至50wt.%。
在特定的实施方式中,局部的半固体药物组合物以该组合物的总重量为基准,其包含:
a)2wt.%至3wt.%的特比萘芬,或其药学可接受的盐;
b)15wt.%至25wt.%的尿素;和
c)超过40wt.%的水。
在本发明的一个实施方式中,该组合物进一步包含d)载体或媒介物,其选自:C2-5醇、C2-8多元醇、C6-24脂肪酸甘油三酯、C6-24脂肪醇、C6-24烷基硫酸盐、C6-24脂肪酸、非离子型表面活性剂或其混合物。
在本发明的优选实施方式中,载体或媒介物选自:C2-5醇、C2-8多元醇、和非离子型表面活性剂或其混合物。
在本发明的更优选的实施方式中,载体或媒介物选自:乙醇、丙二醇和聚山梨酯80或其混合物。
在特定的实施方式中,局部的半固体药物组合物以该组合物的总重量为基准,其包含:
a)2wt.%至3wt.%的特比萘芬,或其药学可接受的盐;
b)15wt.%至25wt.%的尿素;
c)超过40wt.%的水;和
d)载体或媒介物,其选自:乙醇、丙二醇和聚山梨酯80或其混合物。
在优选的实施方式中,载体或媒介物选自C2-5醇与C2-8多元醇或其混合物。
在优选的实施方式中,载体或媒介物选自C2-5醇与非离子型表面活性剂或其混合物。
在优选的实施方式中,载体或媒介物选自C2-8多元醇与非离子型表面活性剂或其混合物。
在优选的实施方式中,载体或媒介物是C2-5醇,更优选乙醇。
在优选的实施方式中,载体或媒介物是C2-8多元醇,更优选丙二醇。
在优选的实施方式中,载体或媒介物是非离子型表面活性剂,更优选聚山梨酯80。
在本发明的进一步的实施方式中,组合物进一步包含e)胶凝剂。
典型地,胶凝剂选自:胶原蛋白、明胶、琼脂、藻酸钙、藻酸钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、透明质酸或其任何药学可接受的盐、角叉菜胶(carrageenan)、羟乙酸淀粉钠(羧甲基淀粉钠)、角豆胶(ceratonia)、黄蓍胶、黄原胶、聚乙二醇(具有200至10,000,000的标称平均分子量)、卡波姆、泊洛沙姆、聚维酮(聚乙烯吡咯烷酮)和聚季铵盐聚合物。
在特定的实施方式中,胶凝剂选自:羧甲基纤维素钙、羧甲基纤维素钠、透明质酸或其任何药学可接受的盐、羟乙酸淀粉钠(羧甲基淀粉钠)、黄原胶、聚乙二醇(具有200至10,000,000、优选5,000到8,000,000、更优选1,000,000至5,000,000的标称平均分子量)、卡波姆、泊洛沙姆、聚维酮(聚乙烯吡咯烷酮)和聚季铵盐聚合物。
在优选的实施方式中,胶凝剂选自:羟丙基纤维素钠、羧甲基纤维素、透明质酸或其任何药学可接受的盐(优选透明质酸钠)、黄原胶、聚乙二醇(具有范围200至10,000,000、优选5,000到8,000,000、更优选1,000,000至5,000,000的标称平均分子量)、卡波姆、泊洛沙姆、聚维酮(聚乙烯吡咯烷酮)和聚季铵盐聚合物。
在优选的实施方式中,胶凝剂选自透明质酸或其任何药学可接受的盐和聚季铵盐聚合物。在更优选的实施方式中,胶凝剂是透明质酸钠。
在另一优选的实施方式中,胶凝剂选自:羧甲基纤维素钠、黄原胶和聚乙二醇(具有200至10,000,000、优选5,000到8,000,000、更优选1,000,000至5,000,000的标称平均分子量)。在更优选的实施方式中,胶凝剂是黄原胶。
典型地,胶凝剂的量为0.5wt.%至5wt.%,优选1wt.%至3wt.%。
在本发明的另一实施方式中,组合物进一步包含f)缓冲剂。
在特定的实施方式中,局部的半固体药物组合物以该组合物的总重量为基准,其包含:
a)2wt.%至3wt.%的特比萘芬,或其药学可接受的盐;
b)15wt.%至25wt.%的尿素;
c)41至60wt.%的水;和
d)载体或媒介物,其选自:乙醇、丙二醇和聚山梨酯80或其混合物;
e)胶凝剂;和
f)缓冲剂。
在另一特定实施方式中,局部的半固体药物组合物以该组合物的总重量为基准,其包含:
a)2wt.%至3wt.%的特比萘芬,或其药学可接受的盐;
b)15wt.%至25wt.%的尿素;
c)41至60wt.%的水;和
d)10至30wt.%的载体或媒介物,其选自:乙醇、丙二醇和聚山梨酯80或其混合物;
e)0.1至4wt.%的胶凝剂,更优选0.5至4wt.%,还更优选0.5至3wt.%,最优选1至3wt.%的胶凝剂;和
f)缓冲剂。
本发明的实施方式涉及如上文定义的局部药物组合物,用于在局部真菌感染、优选甲真菌病的治疗或预防。
本发明的另一实施方式涉及使用一种如上文定义的局部药物组合物用于制造用于局部真菌感染、优选甲真菌病的治疗或预防的药物的用途。
本发明的另外的实施方式涉及用于治疗患有局部真菌感染的个体的方法,该方法包括施用有效量的如上文定义的组合物至该个体受侵袭的皮肤或指甲区域。
使用本发明的局部药物组合物的方法通过由将其施用以完全覆盖该受侵袭的区域。通常的施用频率为每天一次,虽然对一些患者而言足够的维持治疗可以通过较不频繁的施用而实现。
典型地,治疗应始于向后修剪该受感染的一个或多个指甲越远越好,接着使用指甲锉以修锉该指甲表面尽可能地薄。应采取预防措施,以避免修锉或研磨穿过指甲到皮肤内。
本发明的实施方式涉及试剂盒,其包含如上文描述的组合物、指甲锉与膏药,连同使用说明。
在一个实施方式中,本发明涉及使用尿素用于助溶局部制剂中的抗真菌剂,其中以该组合物的总重量为基准,该制剂包含超过25%的水。
在优选的实施方式中,抗真菌剂具有小于5mg/ml的水中溶解度和2-3.5的log D,在pH4至6时测量。
在优选的实施方式中,抗真菌剂选自特比萘芬、阿莫罗芬和环吡酮或其任何药学可接受的盐。
定义
如本文所使用,术语“C2-5醇”涵盖具有2至5个碳原子的直链或支链烷基,其可以被一个或多个羟基残基取代。
C2-5醇的实例包括乙醇、丙醇、丁醇和戊醇。
如本文所使用,术语C2-8多元醇涵盖具有2至8个碳原子的直链或支链烷基,其可以被至少两个羟基残基取代。C2-8多元醇的实例包括丙二醇、丁二醇、己二醇和甘油。
合适的C6-24脂肪酸甘油三酯正常地在动物与植物组织中发现,包括已经氢化以降低或消除不饱和度的那些,但也可以为甘油与脂肪酸的合成制备的酯。酯化甘油的不同位置的脂肪酸可以为不同的,产生了大量的可能组合,包括位置组合。在天然的甘油三酸酯中该不同脂肪酸的位置不是随机的,而是取决于脂肪的起源。更简单的甘油三酯是那些由唯一脂肪酸构成的。脂肪酸的甘油酯可以有利地选自,例如,合成、半合成和天然油,例如,动物脂肪与油类,诸如牛脂、猪油、骨油、水生动物脂肪与油类(鱼类,诸如鲱鱼、鳕鱼或沙丁鱼;鲸目动物;等等);和植物脂肪与油类,诸如鳄梨油、杏仁油、榛果油、巴巴苏棕榈油、琉璃苣油、花生油、芥子油、大麻油、牛奶蓟油、红花油、荸荠油(chufa oil)、椰子油、油菜籽油、黑色小茴香油(black cumin oil)、小麦芽油、向日葵油、亚麻籽油、夏威夷核油(macadamia nut oil)、玉米油、核桃油、橄榄油及其副产物诸如橄榄油渣油(olive pomace oil)、棕榈油及其级分诸如棕榈油酸(palmolein)与棕榈硬脂酸(palm stearin)、月见草油、玫瑰果油、蓖麻油、稻糠油(rice bran oil)、杏核油(apricot kernel oil)、棉籽油、南瓜籽油、棕榈核油(palm kernel oil)及其级分诸如棕榈核油酸与棕榈核硬脂酸、葡萄籽油、芝麻油、大豆油、可可脂、乳木果油(shea butter)及的类等。
根据本发明适合的C6-C24脂肪醇类源自植物与动物脂肪和油类的C6-C24脂肪醇,诸如2-辛基十二烷醇、2-乙基己醇、花生醇、山嵛醇(behenyl alcohol)、辛醇、己醇、癸醇、蓖麻油醇(castor oilalcohol)、鲸蜡醇、棕榈(鲸蜡基)醇、椰子醇、棉醇、癸醇、反-9-十八烯醇(elaidyl alcohol)、芥子醇(erucyl alcohol)、鳕油醇(gadoleyl alcohol)、异硬脂醇、月桂醇、亚麻醇(linoleylalcohol)、亚麻籽醇、肉豆蔻醇、三油酸甘油酯醇(oleinalcohol)、橄榄油渣醇、油醇、橄榄醇、棕榈醇、棕榈核醇、棕榈酰醇(palmitoyl alcohol)、岩芹醇(petroselinic alcohol)、油菜籽醇、篦麻油醇(ricinoleyl alcohol)、红花醇、大豆醇、硬脂醇、向日葵醇、妥尔油醇、牛油醇、十三烷基醇、或其工业级混合物,诸如鲸蜡硬脂醇。
如本文所使用,术语合适的C6-C24烷基硫酸盐涵盖具有6至24个碳原子的直链或支链烷基,其可以被一个或多个硫酸基取代。
合适的非离子表面活性剂包括,例如,乙氧化聚山梨醇酯、聚乙二醇、环氧乙烷/环氧丙烷共聚物和聚乙氧化蓖麻油。乙氧化聚山梨醇酯包括,例如,聚山梨酯-20(吐温-20)、聚山梨醇酯-40(吐温-40)和聚山梨醇酯-80(吐温-80)。
可以使用任何药学可接受的缓冲剂,以调整根据本发明的该局部药物组合物的pH到用于局部给药的可接受范围内,优选2.0至6.0,更优选2.5至4.5。典型地,该pH调节剂可以为酸、酸性盐或其混合物。合适的酸的实例对于本领域技术人员是公知的,且例示地包括乙酸、柠檬酸、富马酸、盐酸、磷酸、乳酸和硝酸及其混合物。特别优选的缓冲剂是乳酸、乳酸钠及其混合物。
如本文所使用,术语局部真菌感染意指由不同类型真菌造成的指甲或皮肤疾病。这些疾病的实例是甲真菌病;在身体不同部位的癣病,意即体癣(tinea corporis)、足癣(tinea pedis)、股癣(tineacruris)、头癣(tinea capitis)、花斑癣(tinea versicolor)(汗斑);糠秕孢子菌性毛囊炎(pityrosporum folliculitis);和念珠菌感染(念珠菌病(moniliasis))。优选地,术语局部真菌感染意指甲真菌病。
根据本发明的局部药物组合物可以配制成霜剂、凝胶剂、悬浮液、洗液(lotion)、泡沫剂、喷雾剂、气雾剂(aerosol)或溶液的形式,优选为诸如霜剂或凝胶的半固体制剂形式,更优选为凝胶形式。
美国食品和药物管理局(FDA),药品评估和研究(CDER)数据标准手册,剂型(08版)将霜剂定义为“乳液、半固体剂型,通常含有超过20%的水和挥发物,和/或小于50%的烃类、蜡类或多元醇作为该媒介物,一般用于外部施用至皮肤或黏膜”。凝胶在其中定义为“半固体剂型其含有一胶凝剂以提供刚度至溶液或胶体分散液”。
本发明的局部药物组合物的黏度将取决于该组合物的形式。例如,在霜剂的例子中,该黏度典型地为2,000到15,000mPa.s,优选2,500至10,000mPa.s,更优选3,000至7,000mPa.s,在20℃使用DIN旋转流变仪(Paar Physica)测量;测量系统Z 3 DIN;D=571/s。
在凝胶的例子中,该黏度典型地为300到15,000mPa.s,优选500至12,000mPa.s,更优选1,000至10,000mPa.s,在20℃使用DIN旋转流变仪(Paar Physica)测量;测量系统Z 3 DIN;D=57.2/s。
根据本发明的该局部药物组合物可能任选地进一步包含其他众所周知的药学和/或化妆品可接受的添加剂,诸如,例如抗刺激剂、抗氧化剂、螯合剂、软化剂(emollients)、穿透增强剂、防腐剂、增溶剂、增稠剂、润湿剂,或其混合物。
合适的抗刺激剂的实例是芦荟、洋甘菊、α-没药醇(α-bisabolol)、可乐树(cola nitida)萃取物、绿茶萃取物、茶树油、甘草萃取物、鲨肝醇(α-十八基甘油醚)、鲨油醇(α-9-十八烯基甘油醚)、鲛肝醇(chimyl alcohol,α-十六基甘油醚)、维生素原B5(panthenol)、尿囊素(allantoin)、咖啡因或其他黄嘌呤、甘草酸及其衍生物,及其混合物。
该所使用的抗氧化剂可以为任何适合或通常用于化妆品和/或皮肤病应用的抗氧化剂。合适的抗氧化剂有利地选自:氨基酸(例如甘氨酸、组氨酸、酪氨酸、色氨酸)及其衍生物;咪唑类(例如咪唑丙烯酸)及其衍生物;肽诸如D,L-肌肽、D-肌肽、L-肌肽及其衍生物(例如鹅肌肽(anserine));类胡萝卜素、胡萝卜素类(例如,α-胡萝卜素、β-胡萝卜素、茄红素)及其衍生物;硫辛酸及其衍生物(例如二氢硫辛酸);金硫葡萄糖、丙基硫尿嘧啶和其他硫醇(例如,硫氧还蛋白、谷胱甘肽(glutathione)、半胱氨酸、胱氨酸、胱胺(cystamine)、及其糖基、N-乙酰基、甲基、乙基、丙基、戊基、丁基和月桂基、棕榈酰基、油基、γ-亚麻基、胆固基和甘油基酯类)及其盐;硫代二丙酸二月桂酯、硫代二丙酸二硬脂酯、硫代二丙酸及其衍生物(酯、醚、肽、脂质、核苷酸、核苷及盐类);和非常小耐受剂量(例如pmol/kg至μmol/kg)的亚砜亚胺(sulphoximine)化合物(例如丁硫氨酸(buthionine)亚砜亚胺、同半胱氨酸(homocysteine)亚砜亚胺、丁硫氨酸砜、五-、六-、七-硫堇(thionine)亚砜亚胺);还有(金属)螯合剂(例如α-羟基脂肪酸、棕榈酸、植酸、乳铁蛋白);α-羟基酸(例如柠檬酸、乳酸、苹果酸);腐殖酸(humic acid)、胆汁酸、胆汁萃取物、胆红素(bilirubin)、胆绿素(biliverdin)、EDTA、EGTA及其衍生物;不饱和脂肪酸及其衍生物(例如,γ-次亚麻油酸、亚麻油酸、油酸);叶酸及其衍生物;泛醌和泛醇(ubiquinol)及其衍生物;维生素C和衍生物(例如棕榈酸抗坏血酸酯、抗坏血酸磷酸镁、乙酸抗坏血酸酯);生育酚和衍生物(例如维生素E乙酸酯);和安息香的松柏醇苯甲酸酯(coniferylbenzoate);芸香酸(rutinic acid)及其衍生物;阿魏酸(ferulic acid)及其衍生物;丁基化羟基甲苯、丁基化羟基茴香醚、去甲二氢愈创木树脂酸(nordihydroguaiac resin acid)、去甲二氢愈创木酸(nordihydroguaiaretic acid)、三羟基苯丁酮、尿酸及其衍生物;甘露糖及其衍生物;锌及其衍生物(例如ZnO、ZnSO4);硒及其衍生物(例如硒甲硫氨酸);茋(stilbenes)及其衍生物(如氧化茋、反式-氧化茋);和适于本发明的活性成分的衍生物(盐类、酯类、醚类、糖类、核苷酸类、核苷类、肽和脂质)。
可以在本发明的组合物中使用的适合软化剂包括,例如,十二烷、角鲨烷(squalane)、胆固醇、异十六烷、异壬酸异壬酯、PPG醚类、凡士林、羊毛脂、红花油、蓖麻油、椰子油、棉籽油、棕榈核油、棕榈油、花生油、大豆油、多元醇羧酸酯、其衍生物等,及其组合。
适合的穿透增强剂的实例可以包括,例如,二甲基亚砜(DMSO)、N-甲基吡咯烷、二甲基甲酰胺(DMF)、尿囊素、尿唑、N,N-二甲基乙酰胺(DMA)、癸甲基亚砜(decylmethylsulfoxide)、聚乙二醇单月桂酸酯、丙二醇、丙二醇单月桂酸酯、甘油单月桂酸酯、卵磷脂、1-取代的氮杂环庚-2-酮类,尤其1-正-十二基环氮杂环庚-2-酮、醇、甘油、透明质酸、还氧二元醇(transcutol)等、及其组合。某些油组分(例如某些植物油,诸如红花油、棉籽油和玉米油)也可以显示穿透增强性质。
防止微生物污染的适合防腐剂的实例是烷基对羟基苯甲酸酯,尤其甲基对羟基苯甲酸酯、丙基对羟基苯甲酸酯和丁基对羟基苯甲酸酯;苯甲酸钠;丁基化羟基甲苯;丁基化羟基茴香醚;乙二胺四乙酸;氯丁醇;苄醇;苯乙醇;去氢乙酸;山梨酸;山梨酸钾;苯扎氯铵(benzalkonium chloride);苄索氯铵(benzethonium chloride);及其混合物。一般利用的防腐剂的量取决于所选择的防腐剂。
进一步增溶剂的实例是,例如,源自下列中至少一种的非离子型表面活性剂:添加1至30摩尔的环氧乙烷和/或0至5摩尔的环氧丙烷至直链C8-C22脂肪醇、C12-C22脂肪酸及烷基内含有8至15个碳的烷基酚的产物;其烷基内含有8至22个碳的烷基和/或烯基寡糖苷及其乙氧化类似物;1至15摩尔的环氧乙烷与蓖麻油和/或氢化蓖麻油的加成产物;15至60摩尔的环氧乙烷与蓖麻油和/或氢化蓖麻油的加成产物;甘油和/或山梨糖醇酐与含有12至22个碳的不饱和或饱和、直链或支链脂肪酸和/或含有3至18个碳原子的羟基羧酸的部分酯、及其与1至30摩尔的环氧乙烷的加成产物;烷氧化甘油酯和烷氧化甘油的混合物、聚甘油(平均自缩合度为2至8)、聚乙二醇(重均分子量为400至5000)、三羟甲丙烷、季戊四醇、糖醇(例如山梨糖醇)、烷基糖苷(例如甲基糖苷、丁基糖苷、月桂基糖苷)和聚糖苷(例如纤维素)与含有12至22个碳的饱和和/或不饱和、直链或支链脂肪酸和/或含有3至18个碳的羟基羧酸的部分酯、及其与1至30摩尔的环氧乙烷的加成产物;季戊四醇、脂肪酸、柠檬酸与脂肪醇的混合酯类和/或含有6至22个碳的脂肪酸、甲基葡萄糖与多元醇,优选甘油或聚甘油的混合酯类;磷酸单-、二-和三烷基酯和磷酸单-、二-和/或三-PEG-烷基酯及其盐;嵌段共聚物,例如聚乙二醇-30二聚羧基硬脂酸酯;聚合物乳化剂;聚亚烷基二醇和烷基甘油酯。特别优选的增溶剂是添加1至30摩尔的环氧乙烷和/或0至5摩尔的环氧丙烷至直链C8-C22脂肪醇(诸如月桂醇、肉豆蔻醇、鲸蜡醇(棕榈醇)、硬脂醇、油醇、和蓖麻油醇)的产物、或其工业级混合物,诸如鲸蜡硬脂醇或棕榈油醇。
可以包括增稠剂或黏度增强剂,以一般地增稠液体药物组合物。虽然任何适合的增稠剂可以被包括在本发明的组合物中,当使用时,优选的增稠剂包括下列的一种或多种:金合欢胶(acacia)、藻酸、皂土、卡波姆、羧甲基纤维素钙或钠、鲸蜡硬脂醇、甲基纤维素、乙基纤维素、甘油、明胶、瓜耳胶(guar gum)、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、麦芽糊精、聚乙烯醇、聚维酮、碳酸丙烯酯、丙二醇藻酸酯、藻酸钠、羟乙酸淀粉钠、淀粉黄蓍胶、和黄原胶、及其任意组合。更优选的增稠剂是甘油、羟丙基甲基纤维素和黄原胶,及其任意组合。
湿润剂(通过降低其表面张力而提高液体的蔓延和穿透性质的化学物质)的实例包括以下的一种或多种:阳离子表面活性剂,诸如苯扎氯铵;非离子表面活性剂,诸如聚氧乙烯和聚氧丙烯嵌段共聚物;聚氧乙烯脂肪酸甘油酯和油(诸如聚氧乙烯(6)辛酸/癸酸甘油单-和二甘油酯)、聚氧乙烯(40)氢化蓖麻油;聚氧乙烯山梨糖醇酐酯,诸如聚山梨酸酯20和聚山梨酸酯80;丙二醇脂肪酸酯,诸如丙二醇月桂酸酯;甘油脂肪酸酯,诸如甘油单硬脂酸酯;山梨糖醇酐酯,诸如山梨糖酐单月桂酸酯、山梨糖醇酐单油酸酯、山梨糖醇酐单棕榈酸酯和山梨糖醇酐单硬脂酸酯;甘油脂肪酸酯,例如甘油单硬脂酸酯;阴离子表面活性剂,诸如月桂基硫酸钠、月桂醚硫酸钠;或脂肪酸及其盐,诸如油酸、油酸钠和三乙醇胺油酸酯。
给出下列实施例,以向本领域技术人员提供本发明的充分清楚且完全的解释,但不应视为限制如本说明书的上述部分中所公开的其主题的基本观点。
实施例
实施例1-12
如表1中所示制备根据本发明的组合物(wt.%以该组合物的总重量为基准)
表1:
以下列方式制备所述组合物:
1)将尿素、聚山梨酯80、丙二醇、乙醇、水和pH调节剂混合。
2)将这些成分在搅拌下加热至60℃并使溶解,直至获得均匀且透明的溶液。
3)将特比萘芬加入到该混合物中,直至其溶解。
4)在均质作用下,将透明质酸钠转移到该批次。
5)将该批次在温和搅拌下冷却至30℃。
实施例11的物理稳定性在稳定箱中在5℃和环境相对湿度(RH)条件下持续12周的期间进行评估。
实施例11的黏度与pH值显示在5℃和环境相对湿度(RH)下12周后与其初始值无统计学显著的偏差。
实施例13-14
如表2中所示制备根据本发明的组合物(wt.%以该组合物的总重量为基准)。
表2:
以下列方式制备所述组合物:
1)将鲸蜡硬脂醇、硬脂酸、中链甘油三酸酯加入到不锈钢容器中。这些成分在搅拌下加热到70℃并熔融(油相)。
2)将鲸蜡硬脂醇硫酸酯、尿素、聚山梨酯80、丙二醇、水和pH调节剂混合,并加热至70℃。然后加入特比萘芬,直至其完全溶解(水相)。
3)将油相与水相在均质作用中混合。
4)在均质作用时将透明质酸钠/黄原胶转移到该批次。
5)将该批次在温和搅拌下冷却至30℃。
这些制剂显示通过指甲的良好穿透与渗透,且允许到该指甲板的精确定量给药与出色的黏附性。
实施例15-17
如表3中所示制备根据本发明的组合物(wt.%以该组合物的总重量为基准)。
表3:
以下列方式制备组合物:
1)将尿素、聚山梨酯80、丙二醇、乙醇、水和该pH调节剂混合。
2)将这些成分在搅拌下加热至60℃并使溶解,直至获得均匀且透明的溶液。
3)将特比萘芬盐酸盐加入到该混合物中,直至其溶解。
4)在均质作用时将黄原胶/聚乙二醇转移到该批次。
5)将该批次在温和搅拌下冷却至30℃。
实施例15-17的物理稳定性系在稳定箱中在5℃与25℃和60%相对湿度(RH)条件下持续12周的期间进行评估。
实施例15-17的黏度与pH值显示在5℃与25℃和60%相对湿度(RH)下12周后与其初始值无统计学显著的偏差。
不影响、改变、更改或改质本文描述的药物组合物的重要基本方面的修饰包括在本发明的发明范围内。
Claims (19)
1.局部药物组合物,以该组合物的总重量为基准,其包含:
a)1.5wt.%至5wt.%的特比萘芬或其任何药学上可接受的盐;
b)15wt.%至35wt.%的尿素;和
c)超过25wt.%的水。
2.如权利要求1的组合物,其中特比萘芬或其药学上可接受的盐的量为2wt.%至4wt.%,优选为2wt.%至3wt.%。
3.如前述任一项权利要求的组合物,其中尿素的量为15wt.%至30wt.%,优选为15wt.%至25wt.%。
4.如前述任一项权利要求的组合物,其中水的量为超过35wt.%,优选为超过40wt.%。
5.如前述任一项权利要求的组合物:
a)2wt.%至3wt.%的特比萘芬或其药学上可接受的盐;
b)15wt.%至25wt.%的尿素;和
c)超过40wt.%的水。
6.如前述任一项权利要求的组合物,其进一步包含:d)载体或媒介物,选自:C2-5醇、C2-8多元醇、C6-24脂肪酸甘油三酯、C6-24脂肪醇、C6-24烷基硫酸盐、C6-24脂肪酸、非离子型表面活性剂或其混合物。
7.如权利要求6的组合物,其中载体或媒介物选自:C2-5醇、C2-8多元醇、和非离子型表面活性剂或其混合物。
8.如权利要求7的组合物,其中载体或媒介物选自:乙醇、丙二醇和聚山梨酯80或其混合物。
9.如前述任一项权利要求的组合物,其中组合物进一步包含e)胶凝剂。
10.如权利要求9的组合物,其中胶凝剂选自:羧甲基纤维素钙、羧甲基纤维素钠、透明质酸或其任何药学上可接受的盐、羟乙酸淀粉钠(羧甲基淀粉钠)、黄原胶、聚乙二醇(具有200至10,000,000、优选5,000到8,000,000、更优选1,000,000至5,000,000的标称平均分子量)、卡波姆、泊洛沙姆、聚维酮(聚乙烯吡咯烷酮)和聚季铵盐聚合物。
11.如权利要求9或10的组合物,其中胶凝剂选自透明质酸或其任何药学上可接受的盐和聚季铵盐聚合物。
12.如权利要求9至11中任一项的组合物,其中胶凝剂的量为0.5wt.%至4wt.%,优选1wt.%至3wt.%。
13.如前述任一项权利要求的组合物,其进一步包含f)缓冲剂。
14.如权利要求1至13中任一项的组合物,组合物用于局部真菌感染、优选甲真菌病的治疗。
15.如权利要求1至13中任一项的组合物于制造药物的用途,所述药物用于局部治疗真菌感染、优选甲真菌病。
16.用于治疗患有局部真菌感染、优选甲真菌病的个体的方法;所述方法包括施用如权利要求1至13中任一项所定义的组合物的有效量至该个体。
17.试剂盒,其包含如权利要求1的组合物、指甲锉和膏药以及使用说明。
18.尿素的用途,用于溶解抗真菌剂于局部制剂中,所述局部制剂以组合物的总重量为基准包含超过25%的水。
19.如权利要求18的用途,其中抗真菌剂选自特比萘芬、阿莫罗芬和环吡酮、或其任何药学上可接受的盐。
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