CN117482078A - 双醋瑞因或大黄酸局部用制剂及其用途 - Google Patents
双醋瑞因或大黄酸局部用制剂及其用途 Download PDFInfo
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- CN117482078A CN117482078A CN202311670907.4A CN202311670907A CN117482078A CN 117482078 A CN117482078 A CN 117482078A CN 202311670907 A CN202311670907 A CN 202311670907A CN 117482078 A CN117482078 A CN 117482078A
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Abstract
提供了一种含有双醋瑞因和/或其类似物的局部用药物组合物。还提供了使用该局部用药物组合物来治疗多种疾病的方法。
Description
本案是申请日为2016年6月30日、题为《双醋瑞因或大黄酸局部用制剂及其用途》的中国发明专利申请201680050004.8的分案申请。
相关申请的交叉引用
本申请要求于2015年7月1日提交的美国临时申请号62/187,743的优先权,其全部内容通过引用并入本文。
技术领域
本发明涉及含有双醋瑞因(diacerein)和/或其类似物的局部用药物组合物,并且还涉及该局部用药物组合物在治疗多种疾病或病况中的用途。
背景技术
在化学上,大黄酸(rhein)是9,10-二氢-4,5-二羟基-9,10-二氧代-2-蒽甲酸,具有式(I)的结构,其前药之一,双醋瑞因,是4,5-双(乙酰氧基)9,10-二氢-4,5-二羟基-9,10-二氧代-2-蒽甲酸,具有式(II)的结构。双醋瑞因在到达体循环之前完全转化为大黄酸,并在体内以大黄酸的形式发挥其生理功能。
式(I)
式(II)
双醋瑞因是在治疗骨关节炎中广泛使用的一种抗炎剂,其已被证实能抑制白细胞介素-1(IL-1)信号传导。目前,双醋瑞因胶囊有50mg的规格并且在不同国家以多种商品名称销售,包括等。如美国专利号8,536,152和8,865,689中所公开的,双醋瑞因可以用作II型糖尿病的辅助治疗,还被发现能有效降低血尿酸水平,并因此可用于治疗高尿酸血症或与高尿酸血症相关的代谢病症。此外,据报道,双醋瑞因在治疗大疱性表皮松解症(epidermolysis bullosa)中具有潜在的效果(Wally等人,Orphanet Journal ofRare Diseases,2013,第69期,第8卷)。
尽管双醋瑞因可以口服施用,但其不能被消化道完全吸收,而且据估计双醋瑞因的口服生物利用度为约40%至60%。双醋瑞因的不完全吸收可能导致不良副作用如腹泻或软便。体外和体内研究显示,未吸收的双醋瑞因在结肠中被代谢为大黄酸,其然后引起通便效果。
由于这种副作用可能由于口服施用而发生,所以已经提出非口服双醋瑞因组合物来克服这些问题。
PCT国际申请号WO2009/133430公开了含有双醋瑞因或大黄酸的局部用组合物,其可以是多种形式,例如洗剂、乳膏、软膏、糊剂、凝胶等。然而,这些组合物不旨在用于任意具体的疾病,因此不能从该文的上下文中得知哪种形式最适合某种疾病。
Wally等人公开了一种用于大疱性表皮松解症的双醋瑞因乳膏制剂(Wally等人,Orphanet Journal of Rare Diseases,2013,第69期,第8卷)。然而,从该文中不清楚该制剂的性质是否以及如何影响对大疱性表皮松解症的治疗功效。
似乎双醋瑞因制剂的精确性质对于其针对不同疾病的治疗功效是非常重要的。
考虑到文献很少提供关于双醋瑞因/大黄酸局部用制剂的理化性质与其治疗效果之间的关系的信息,因此,本发明提供了适于不同疾病的局部用制剂。
发明内容
本发明提供了一种局部用组合物,其包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂,其中所述组合物是软膏、乳膏或凝胶的形式,并且,至少约90%体积的化合物具有约0.5至35μm的粒度。
本发明还提供了一种局部用组合物,其包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂,其中所述组合物是凝胶的形式,并且,至少约90%体积的化合物具有小于约1μm的粒度。
本发明还提供了治疗炎性和/或过度增殖性和瘙痒性皮肤疾病以及具有上皮屏障功能障碍的疾病包括老化的皮肤和大疱性表皮松解症的方法,所述方法包括向需要其的受试者施用有效量的本发明的组合物。
本发明还提供了治疗高尿酸血症、与高尿酸血症相关的代谢病症、骨关节炎或2型糖尿病的方法,所述方法包括向需要其的受试者施用有效量的本发明的组合物。
在一些实施方案中,本发明的治疗方法明确排除施用任何其他活性剂来治疗可由本发明的组合物治疗的疾病。然而,在一些实施方案中,所述方法允许施用其他活性剂。
优选地,本发明的治疗方法在至少一个所治疗的受试者中,优选地,在相当数量的所治疗的受试者中,更优选地,在大部分所治疗的受试者中产生相关疾病的有效治疗。
为了使本领域的技术人员较好地领会所要求保护的本发明的特征,在下面的段落及附图中描述了用于实施本发明的详细技术和优选实施方案。
附图说明
图1是显示用三种测试的双醋瑞因制剂(G1、C1和O1,n=4)处理8小时后,真皮和表皮中大黄酸浓度的统计柱状图;
图2A和2B是三种测试的双醋瑞因制剂(G1、C1和O1,n=4)从皮肤组织至接收器溶液中的大黄酸累积渗透(ng/cm2)-时间的绘图。
图3是显示用两种测试的双醋瑞因软膏制剂(O2和O3,n=3)处理8小时后,真皮和表皮中大黄酸浓度的统计柱状图;
图4是两种测试的双醋瑞因软膏制剂(O2和O3,n=3)从皮肤组织至接收器溶液中的大黄酸累积渗透(ng/cm2)-时间的绘图。
图5是显示用测试的双醋瑞因软膏制剂(O3,n=3)或对比制剂(n=3)处理8小时后,真皮和表皮中大黄酸浓度的统计柱状图;以及
图6是测试的双醋瑞因软膏制剂(O3,n=3)和对比制剂(n=3)从皮肤组织至接收器溶液中的大黄酸累积渗透(ng/cm2)-时间的绘图。
具体实施方式
如本文所用,术语“治疗有效量”指缓和或减轻疾病的一种或多种症状的量。
如本文所用,术语“双醋瑞因或其类似物”指双醋瑞因、大黄酸、单乙酰大黄酸或其药学上可接受的盐或酯或前药。
除本文另有说明外,本说明书(特别是权利要求书)中使用的术语“一种(a(an))”、“所述(the)”等应理解为包括单数形式和复数形式。
如上所述,局部施用双醋瑞因可以防止口服施用的不期望的副作用,因为与口服施用相比,局部施用绕过了具有耐受性限制的胃肠道途径,并且降低了进入体循环的双醋瑞因的量。此外,当双醋瑞因用于治疗皮肤疾病时,有利的是,双醋瑞因可以很容易地渗透穿过角质层以到达靶部位(例如,可能发生皮肤病症的真皮或表皮)。同时,还期望双醋瑞因尽可能长时间地保留在皮肤中以充分发挥其功能。因此,需要实现一个微妙的平衡,以便一方面使双醋瑞因或大黄酸能够快速渗透至靶部位,另一方面使其保留在靶部位以延长暴露时间。
本发明的发明人发现,双醋瑞因/大黄酸局部用组合物的形式和/或其中含有的活性成分的粒度在渗透性(或扩散性)和在皮肤中的保留率方面起关键作用。
因此,本发明提供了适用于皮肤疾病并满足上述要求的双醋瑞因/大黄酸局部用药物组合物。所述局部用药物组合物包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂,其中所述组合物是软膏、乳膏或凝胶的形式,并且,至少约90%体积的化合物具有约0.5至35μm的粒度。
在本申请的上下文中描述的粒度分布是基于体积D值(即,Dv值,诸如Dv10、Dv50和Dv90)的,其通常用于表示给定样品的粒度范围
优选地,所述组合物作为软膏或乳膏提供,更优选地作为软膏提供。出乎意料地发现,与凝胶制剂相比,软膏或乳膏制剂提供在皮肤中更高的保留率和更长的保留时间。
在一个实施方案中,组合物中,至少约90%体积的化合物具有约1至约15μm,优选约2至约5μm的粒度。优选地,含有具有这种粒度的化合物的组合物是软膏或乳膏形式,并且将其施用于受试者的皮肤时,在施用后大于90%(以数量计)的化合物,优选基本上全部的化合物在皮肤中保留至少约2小时,更优选约4小时,甚至更优选约6小时,最优选约8小时。化合物在皮肤中的保留率和时间可以通过例如扩散池研究来测量。在该研究中,安装了基本上由夹在两个夹具之间的一片皮肤组成的扩散池装置,并且将含有该化合物的制剂应用在皮肤的一侧(顶部),并且在装置的接收器部分(底部)(其可以是填充有与皮肤接触的缓冲液的容器)以一定的时间间隔测量化合物浓度。
此外,当将其施用于受试者的皮肤时,自施用8小时后,化合物的浓度可以为例如约8至约20μg/克表皮组织,和/或约1至约3μg/克真皮组织。
在另一个实施方案中,组合物中,至少约90%体积的化合物具有约10至约30μm,优选约12至约25μm的粒度。优选地含有具有这种粒度的化合物的组合物为软膏或乳膏形式,更优选为软膏形式,并且将其施用于受试者的皮肤时,在施用后大于90%(以数量计)的化合物,优选基本上全部的化合物在皮肤中保留至少优选约4小时,更优选约6小时,最优选约8小时。
此外,当将其施用于受试者的皮肤时,自施用8小时后,化合物的浓度可以为例如约3至约6μg/克表皮组织,和/或约0.2至约2μg/克真皮组织。
具有上述性质的局部用药物组合物提供了渗透和保留之间的良好平衡,因此可用于治疗皮肤疾病,例如炎性和/或过度增殖性和瘙痒性皮肤疾病,所述皮肤疾病选自特应性皮炎、银屑病、脓疱性银屑病、红斑痤疮、瘢痕瘤、增生性疤痕、痤疮、内塞顿综合征(Netherton’s syndrome)或其他瘙痒性皮肤病,包括结节性痒疹、老年人不明确瘙痒以及包括皮肤老化和大疱性表皮松解症在内的具有上皮屏障功能障碍的疾病。优选地,其在治疗大疱性表皮松解症中是有用的。
本发明还涉及治疗炎性和/或过度增殖性和瘙痒性皮肤疾病以及具有上皮屏障功能障碍的疾病包括老化的皮肤和大疱性表皮松解症的方法,所述方法包括向需要其的受试者施用有效量的本发明的组合物。
本发明还提供了可用于治疗高尿酸血症、与高尿酸血症相关的病症(例如,急性痛风、慢性痛风、痛风发作、尿酸肾结石、痛风性肾病等)、骨关节炎和2型糖尿病的双醋瑞因/大黄酸局部用药物组合物。与用于治疗皮肤疾病的那些组合物不同,本文的组合物使活性化合物能够很容易地并相对较快地渗透至皮肤中并进入体内,从而到达体循环并在体内发挥其功能。所述局部用组合物包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂,其中所述组合物是凝胶的形式,并且,至少约90%体积的化合物具有小于约1μm,并优选大于约0.1μm的粒度。
优选地,当将组合物施用于受试者的皮肤时,化合物在施用后约6小时内,更优选约4小时,最优选约2小时内从皮肤释放到体内。
本发明还提供了治疗高尿酸血症、与高尿酸血症相关的病症(例如,急性痛风、慢性痛风、痛风发作、尿酸肾结石、痛风性肾病等)、骨关节炎和2型糖尿病的方法,其包括向需要其的受试者施用有效量的本发明的组合物。
在一些实施方案中,本发明的治疗方法明确排除施用任何其他活性剂以治疗可由本发明的组合物治疗的疾病。然而,在一些实施方案中,所述方法允许施用其他活性剂。
优选地,本发明的治疗方法在至少一个所治疗的受试者中,优选地,在相当数量的所治疗的受试者中,更优选地,在大部分所治疗的受试者中产生相关疾病的有效治疗。
基于组合物的总重量,本发明的局部用药物组合物可包含优选约0.1%至约10%w/w,更优选约0.1%至5%,最优选约0.5%至约2%w/w的化合物。
组合物中的药学上可接受的赋形剂可以包括抗氧化剂、胶凝剂/水凝胶基质、pH调节剂/缓冲剂、渗透促进剂、防腐剂、螯合剂、湿润剂(humectant)、表面活性剂、乳化剂、增稠剂、溶剂、稳定剂等。本文中,本发明中的赋形剂/成分可以具有多种功能,例如,赋形剂可以用作表面活性剂和/或稳定剂和/或乳化剂等。
抗氧化剂的实例包括但不限于维生素C、维生素A和α-硫辛酸、抗坏血酸棕榈酸酯、焦亚硫酸钠、丁基羟基茴香醚(BHA)、丁基羟基甲苯(BHT)等中的一种或多种。
合适的胶凝剂/水凝胶基质可以包括但不限于瓜尔胶,黄原胶和卡拉胶,阴离子、非离子、阳离子和亲脂改性的瓜尔胶,聚丙烯酸(例如,卡波姆),聚甲基丙烯酸,纤维素树脂,聚乙二醇,羟烷基纤维素,羧烷基纤维素,聚亚烷基胺等中的一种或多种。
pH调节剂/缓冲剂的实例包括但不限于碳酸氢钠、碳酸氢钾、氢氧化镁、乳酸镁、葡萄糖酸镁、氢氧化铝、氢氧化铝/碳酸氢钠共沉淀物、氨基酸、甘氨酸铝、柠檬酸钠、酒石酸钠、醋酸钠、碳酸钠、多磷酸钠、多磷酸钾、焦磷酸钠、焦磷酸钾、磷酸氢二钠、磷酸氢二钾、磷酸三钠、磷酸三钾、磷酸钠、醋酸钠、偏磷酸钾、氧化镁、氢氧化镁、碳酸镁、硅酸镁、醋酸钙、甘油磷酸钙、氯化钙、氢氧化钙、乳酸钙、碳酸钙、碳酸氢钙、柠檬酸等中的一种或多种。
渗透促进剂的实例包括但不限于二乙二醇单乙醚,二甲基亚砜,丙二醇,肉豆蔻酸异丙酯(IPM),卡泊三烯(cal-cipotriene),去垢剂,软化剂,乙氧基二甘醇(Ethoxydiglycol),三醋精,丙二醇,苄醇,月桂醇聚醚硫酸钠,二甲基异山梨醇,肉豆蔻酸异丙酯,中链甘油三酯油(MCT油),薄荷醇,棕榈酸异丙酯,异硬脂酸异丙酯,单硬脂酸丙二醇酯,卵磷脂,己二酸二异丙酯,癸二酸二乙酯,油酸,油酸乙酯,尿素,油酸甘油酯,辛酸/癸酸甘油三酯,丙二醇二辛酸酯/二癸酸酯,月桂醇聚醚4(Laureth 4),油醇聚醚-2(Oleth-2),油醇聚醚-20,碳酸丙烯酯,壬苯醇醚-9,2-正-壬基-1,3-二氧戊环,C7至C14烃基取代的1,3-二氧戊环、1,3-二氧杂环已烷或缩醛,以及壬苯醇醚-15等中的一种或多种。
防腐剂可以是例如苯甲酸钠,丁基化羟基甲苯,丁基化羟基茴香醚,乙二胺四乙酸(EDTA),对羟基苯甲酸酯,氯丁醇,苯甲醇,苯乙醇,脱氢乙酸,山梨酸,苯扎氯铵,苄索氯铵,苯酚,硝酸苯汞,硫汞撒(thimerosal),对羟基苯甲酸甲酯、对羟基苯甲酸乙酯和/或对羟基苯甲酸丙酯中的一种或多种。
合适的溶剂的实例包括但不限于醇,蓖麻油,己二酸二异丙酯,乙氧基化醇,乙醇,柠檬酸脂肪醇酯,甘油,1,2,6-己三醇,己二醇,异丙醇,肉豆蔻酸异丙酯,棕榈酸异丙酯,矿物油,磷酸,聚乙二醇300,聚乙二醇400,聚乙二醇1450,聚乙二醇8000,聚乙二醇1000单鲸蜡基醚,聚乙二醇单硬脂酸酯,聚乙二醇400单硬脂酸酯,聚乙二醇,聚氧乙烯20鲸蜡硬脂基醚,聚氧丙烯15-硬脂基醚,聚山梨醇酯20,聚山梨醇酯40,聚山梨醇酯60,聚山梨醇酯80,聚山梨醇酯,碳酸丙烯酯,丙二醇,纯化水,SD醇40,饱和脂肪酸的甘油三酯等中的一种或多种。
合适的稳定剂或表面活性剂可以是例如离子型聚山梨醇酯表面活性剂、吐温20、吐温40、吐温60、吐温80,壬基酚聚乙二醇醚,(烷基酚-羟基聚氧乙烯),聚(氧-1,2-乙二烷基),α-(4-壬基酚)-ω-羟基-,支链(即NP-40表面活性剂),壬基酚聚乙二醇醚混合物(即/>NP-70(70%AQ)表面活性剂),苯氧基聚乙氧基乙醇及其聚合物如 不同等级的苄泽(Brij),十二烷基硫酸钠,鲸蜡醇,硬脂酸,聚氧乙烯硬脂酸酯(polyoxyl stearate)等中的一种或多种。
螯合剂的实例包括但不限于抗氧化剂,柠檬酸,依地酸二钠(EDTA),依地酸钙二钠,依地酸,苹果酸,麦芽酚,三胺五乙酸(pentetic acid),依地酸钠,依地酸三钠等。
湿润剂的实例包括但不限于甘油,丙二醇,山梨糖醇,聚乙二醇,多糖(如果糖、葡萄糖、麦芽糖等),玉米糖浆,多元醇,尿素和衍生物以及天然蜂蜜。优选的湿润剂是丙二醇和甘油。
增稠剂的实例包括但不限于硬脂酸,纤维素聚合物,卡波姆聚合物,卡波姆衍生物,纤维素衍生物,聚乙烯醇,泊洛沙姆,多糖等。
用于乳膏的油性基质的实例包括但不限于植物油(例如,蓖麻油)、白矿脂、矿物油等。
软膏基质的实例包括但不限于矿脂,脂肪油,羊毛脂,凡士林,甘油,石蜡,泊洛沙姆,聚乙二醇,硬脂酸,蜂蜡等。软膏基质改性剂的实例包括但不限于矿物油、液体石蜡等。
在一个实施方案中,本发明的局部用药物组合物为凝胶形式,并且包含约0.1%至约10%w/w的双醋瑞因或其类似物,约0.1%至约5%w/w的水凝胶基质,约2%至约50%w/w的湿润剂,以及约0.1%至约2.5%w/w的稳定剂/表面活性剂。
在一个实施方案中,本发明的局部用药物组合物为乳膏形式,并且包含约0.1%至约10%w/w的双醋瑞因或其类似物,约0.5%至约25%w/w的表面活性剂,约0.5至约25%w/w的油性基质,约2%至约50%w/w的湿润剂,以及水。
在一个实施方案中,本发明的局部用药物组合物为乳膏形式,并且包含部分A和部分B;其中部分A包含约0.1%至约10%w/w的双醋瑞因或其类似物,约1.5%至约40%w/w的增稠剂,约1%至约40%的油性基质,以及约0.4%至约10%w/w的表面活性剂;并且部分B包含约0.2%至约5%w/w的稳定剂,约0.6%至约15%w/w的湿润剂,以及水。
在一个实施方案中,本发明的局部用药物组合物为软膏形式,并且包含0.1%至约10%w/w的双醋瑞因或其类似物,约15%至约99%w/w的软膏基质,约0%至约60%w/w的基质改性剂,以及约0%至约10%w/w的表面活性剂。
优选地,本发明的局部用药物组合物为每日一次或每日两次的组合物。也就是说,为了达到所需的治疗效果,适宜每日施用一次或两次。
本发明的局部用药物组合物具有以下优点。首先,它们可以直接施用于受皮肤皮下病况影响的部位,绕过胃肠道途径并大大降低全身暴露。其次,它们易于应用,并因此对于患者更方便。第三,对于患有吞咽困难或不喜欢药物味道的患者,这些局部用制剂也比口服制剂更优选。第四,它们更容易实现持续暴露于靶部位。
本发明还涉及治疗炎性和/或过度增殖性和瘙痒性皮肤疾病以及具有上皮屏障功能障碍的疾病包括老化的皮肤和大疱性表皮松解症的方法,所述方法包括向需要其的受试者施用有效量的局部用药物组合物,其中所述组合物包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂;其中,当将组合物施用于受试者的皮肤时,在施用后大于90%(以数量计)的化合物在皮肤中保留至少约2小时,优选约4小时,甚至更优选约6小时,最优选约8小时。
本发明还涉及治疗炎性和/或过度增殖性和瘙痒性皮肤疾病以及具有上皮屏障功能障碍的疾病包括老化的皮肤和大疱性表皮松解症的方法,所述方法包括向需要其的受试者施用有效量的局部用药物组合物,其中所述组合物包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂;其中,当将组合物施用于受试者的皮肤时,自施用8小时后,化合物的浓度可以为例如约8至约20μg/克表皮组织,和/或约1至约3μg/克真皮组织。
本发明还涉及治疗炎性和/或过度增殖性和瘙痒性皮肤疾病以及具有上皮屏障功能障碍的疾病包括老化的皮肤和大疱性表皮松解症的方法,所述方法包括向需要其的受试者施用有效量的局部用药物组合物,其中所述组合物包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂;其中,当将组合物施用于受试者的皮肤时,自施用8小时后,化合物的浓度可以为例如约3至约6μg/克表皮组织,和/或约0.2至约2μg/克真皮组织。
本发明还涉及治疗高尿酸血症、与高尿酸血症相关的病症、骨关节炎和2型糖尿病的方法,所述方法包括向需要其的受试者施用有效量的局部用药物组合物,其中所述组合物包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂;其中,当将组合物施用于受试者的皮肤时,化合物在施用后约6小时内,更优选约4小时,最优选约2小时内从皮肤释放到体内。
在下文中,将参考以下实施例进一步说明本发明。然而,这些实施例仅用于说明的目的,而不是限制本发明的范围。
[制备实施例]双醋瑞因局部用组合物的制备
根据下表1至4制备三种不同形式(凝胶、乳膏和软膏)的七种双醋瑞因局部用组合物(G1、C1、C2和O1至O4)。通过Mastersizer 2000版本5.60测量各组合物中化合物的粒度(Dv90)。下表中列出的赋形剂/成分可具有多种功能,例如,一种赋形剂用作表面活性剂和/或稳定剂和/或乳化剂等。
表1.
表2.
表3.
表4.
[实施例1]双醋瑞因局部用组合物的扩散池研究
步骤:通过颈椎脱臼处死小鼠。去除全厚侧翼皮肤,并将其置于与受体相接触的扩散池中,所述受体相是具有30% PGE300的PBS(pH 5.4)(在37℃下)。将缓冲液以3至4mL/h的流速泵送穿过接收器隔室。将20μl的1%双醋瑞因凝胶(制剂G1)、1%双醋瑞因乳膏(制剂C1和C2)或1%双醋瑞因软膏(制剂O1、O2和O3)的剂量加入到供体隔室中的皮肤表面上。在0、1、2、4、6和8小时时收集接收器溶液。在用制剂处理8小时结束时,从扩散池取下皮肤,并用三个酒精棉签小心地清洁皮肤表面(无胶带剥离(tape-stripping))。使用手术刀片将表皮与真皮分离。将分离的表皮和真皮称重并切碎,并用0.5ml乙腈:乙酸:水(60:0.1:40)剧烈摇动1小时,提取两次。然后将皮肤提取物以14,500rpm离心20分钟。所有程序均在减光下进行。将皮肤提取物和接收器溶液储存在-20℃,直到用于通过HPLC分析双醋瑞因和大黄酸浓度(在实验期间双醋瑞因很容易转化为大黄酸)。从大黄酸累积渗透浓度-时间曲线的线性部分的斜率计算皮肤通量。结果总结如下。
[形式对渗透性和保留的影响]
渗透性
如图1所示,双醋瑞因凝胶制剂(G1)比乳膏和软膏制剂(C1和O1)更好地渗透角质层。自施用8小时后,每克表皮中大黄酸浓度为:G1为204.0μg,C1为16.1μg,O1为31.2μg;每克真皮中大黄酸浓度为:G1为11.9μg,C1为2.53μg,O1为3.14μg。
保留
如图2A和2B所示,对于凝胶制剂(G1),大黄酸在1小时后渗透皮肤组织并释放到接收器溶液中,对于乳膏制剂(C1),为2小时后,但对于软膏制剂(O1),大黄酸没有渗透皮肤组织并进入到接收器溶液中直至4小时,表明软膏制剂比凝胶和乳膏制剂具有更高的保留率和更长的保留时间。
结果表明,与乳膏或软膏制剂相比,凝胶制剂中的双醋瑞因/大黄酸对角质层具有更高的渗透性,并且与乳膏或凝胶制剂相比,软膏制剂中的双醋瑞因/大黄酸在皮肤靶部位的保留时间更长。在三种制剂中,凝胶制剂在皮肤靶部位的保留时间最短。
[粒度对渗透性和保留的影响]
图3显示,具有较小粒度的软膏制剂(O2)比具有较大粒度的软膏制剂(O3)渗透得更快。自施用8小时后,每克表皮中大黄酸浓度为:O2为10.7μg,O3为4.8μg;并且每克真皮中大黄酸浓度为:O2为1.6μg,O3为0.7μg。
图4显示,软膏制剂O2在4小时后释放大黄酸,软膏制剂O3直到8小时甚至更长时间才释放大黄酸。与O2相比,软膏制剂O3在皮肤层中表现出类似的化合物浓度,但具有更长的保留时间。
[实施例2]对比例
Wally等人公开了在常用的护理乳膏中含有1%双醋瑞因的乳膏制剂(Wally等人,Orphanet Journal of Rare Diseases,2013,第69期,第8卷)。在该乳膏制剂(对比制剂)和本发明的软膏制剂O3之间进行比较研究。结果如图5和6所示。
如图5所示,软膏制剂O3比对比制剂渗透角质层更多,并且在皮肤层中显示出更高的保留。此外,如图6所示,在4小时后,对比制剂中的大黄酸渗透皮肤组织并在接收器溶液中可检测到,但O3制剂中的大黄酸直到6小时才渗透皮肤组织进入到接收器溶液中。
结果表明,O3制剂比对比制剂具有更高的角质层渗透性、更高的保留率和更长的保留持续时间,表明使用O3制剂在皮肤层中能保持较高的药物浓度。
以上公开内容涉及详细的技术内容及其特征。本领域的技术人员可以基于所描述的本发明的公开和建议进行各种修改和替换,而不背离其特征。尽管如此,尽管在以上描述中没有充分公开这样的修改和替换,但是在所附的权利要求中基本上已经涵盖了它们。
Claims (21)
1.一种局部用药物组合物,其包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂,其中所述组合物是软膏、乳膏或凝胶的形式,并且,至少约90%体积的化合物具有约0.5至约35μm的粒度。
2.根据权利要求1所述的组合物,其是软膏或乳膏的形式。
3.根据权利要求1所述的组合物,其是软膏的形式。
4.根据权利要求3所述的组合物,其中,至少约90%体积的化合物具有约10至约30μm的粒度。
5.根据权利要求4所述的组合物,其中,至少约90%体积的化合物具有约12至约25μm的粒度。
6.根据权利要求3所述的组合物,其中,将所述组合物施用于受试者的皮肤时,在施用后大于90%(以数量计)的化合物在皮肤中保留至少约4小时。
7.根据权利要求6所述的组合物,其中,将所述组合物施用于受试者的皮肤时,在施用后大于90%(以数量计)的化合物在皮肤中保留至少约6小时。
8.根据权利要求7所述的组合物,其中,将所述组合物施用于受试者的皮肤时,在施用后大于90%(以数量计)的化合物在皮肤中保留至少约8小时。
9.根据权利要求1所述的组合物,其用于治疗炎性和/或过度增殖性和瘙痒性皮肤疾病,所述皮肤疾病选自特应性皮炎、银屑病、脓疱性银屑病、红斑痤疮、瘢痕瘤、增生性疤痕、痤疮、内塞顿综合征或其他瘙痒性皮肤病,包括结节性痒疹、老年人不明确瘙痒以及包括皮肤老化和大疱性表皮松解症在内的具有上皮屏障功能障碍的疾病。
10.根据权利要求9所述的组合物,其用于治疗大疱性表皮松解症。
11.根据权利要求1所述的组合物,其中所述化合物以总组合物的约0.1%至约10.0%w/w的量存在。
12.根据权利要求11所述的组合物,其中所述化合物以总组合物的约0.1%至5.0%w/w的量存在。
13.根据权利要求12所述的组合物,其中所述化合物以总组合物的约0.5%至约2.0%w/w的量存在。
14.根据权利要求1所述的组合物,其是每日一次或每日两次的组合物。
15.一种局部用组合物,其包含治疗有效量的、选自由双醋瑞因、大黄酸、单乙酰大黄酸及其盐或酯或前药组成的组的化合物,以及一种或多种药学上可接受的赋形剂,其中所述组合物是凝胶的形式,并且,至少约90%体积的化合物具有小于约1μm的粒度。
16.根据权利要求15所述的组合物,其中,当将所述组合物施用于受试者的皮肤时,所述化合物在施用后约6小时内从皮肤释放至体内。
17.根据权利要求15所述的组合物,其用于治疗骨关节炎、高尿酸血症、与高尿酸血症相关的病症和2型糖尿病。
18.根据权利要求15所述的组合物,其用于治疗骨关节炎。
19.一种治疗炎性和/或过度增殖性和瘙痒性皮肤疾病以及具有上皮屏障功能障碍的疾病的方法,其包括向需要其的受试者施用有效量的权利要求3的组合物。
20.根据权利要求19所述的方法,其中,所述具有上皮屏障功能障碍的疾病包括皮肤老化和大疱性表皮松解症。
21.一种治疗高尿酸血症、与高尿酸血症相关的病症、骨关节炎和2型糖尿病的方法,其包括向需要其的受试者施用有效量的权利要求15的组合物。
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