CN107205929A - 多泡沫体及其眼睑施用 - Google Patents
多泡沫体及其眼睑施用 Download PDFInfo
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- CN107205929A CN107205929A CN201680008192.8A CN201680008192A CN107205929A CN 107205929 A CN107205929 A CN 107205929A CN 201680008192 A CN201680008192 A CN 201680008192A CN 107205929 A CN107205929 A CN 107205929A
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Abstract
本发明提供了一种用于局部施用到受试者的上眼睑和/或下眼睑上的供使用的组合物,所述组合物包含多泡沫体。
Description
技术领域
本发明涉及盖伦制剂(galenic formulation)的一般领域中的易于施用的多泡沫体(polyaphron)。特别地,本发明涉及用于局部施用、优选地用于眼睑施用的含有至少一种多泡沫体的组合物。
背景技术
多泡沫体的介绍
多泡沫体是分散体。在本发明的含义中,“分散体”意指如下的一种系统,其中液体珠滴或固体颗粒分散在连续相中。在本发明中,术语“多泡沫体”指的是分散在连续相中的被称作“泡沫体”的液体珠滴,在所述连续相中,所述泡沫体是不可混溶的。所述分散相可以是亲水相或疏水相,前提条件是所述泡沫体在所述连续相中保持不可混溶。所述连续相可以是流体、液体或凝胶。
更确切地说,多泡沫体的分散相可以由分散在连续相中的复合泡沫体构成,所述泡沫体具有:
‐核心,其由与所述连续相不可混溶的材料构成;
‐中间层,其由与所述连续相相同的材料构成;
‐外层,其包括表面活性剂。
举例来说,在水包油多泡沫体中,泡沫体可以包括内核,所述内核是疏水性珠滴;中间层,所述中间层由水溶液制成;以及外层,所述外层包括表面活性剂。在水包油多泡沫体中,以多泡沫体的总重量计,疏水相可以占最多98重量%,并且鉴于大量的分散相,所述多泡沫体包括非常低量的表面活性剂(以多泡沫体的总重量计,通常在0.05重量%至5重量%、或0.1重量%至3重量%的范围)。
作为另一个示例,在油包水多泡沫体中,泡沫体可以包括内核,所述内核是水性珠滴;中间层,所述中间层由疏水性溶液制成;以及外层,所述外层包括表面活性剂。在油包水多泡沫体中,以多泡沫体的总重量计,所述亲水相可以占最多98重量%。
值得注意的是,与特征在于单一界面的乳液相反,多泡沫体可以具有多层结构构造,所述多层结构构造可以使它们具有显著的稳定性。
背景
在约40年前,多泡沫体首次被描述。US 4,486,333公开了一种使用作为疏水相的煤油、石油醚、四氯化碳、四氯化碳-环己烷混合物和作为亲水相的水或甲醇制备多泡沫体、特别是水包油多泡沫体的方法。
多泡沫体组合物被称为口服药物递送系统。举例来说,WO 2005/011628公开了作为多泡沫体组合物的呈立即剂型的亲脂性水难溶性药物的递送。
多泡沫体组合物可以用作用于输送活性成分的局部药物递送系统。举例来说,US4,999,198公开了向另一介质递送溶解在花生油和矿物油中的东莨菪碱(scopolamine);WO2008/110826公开了通过皮肤施用进行局部施用来运送皮质类固醇与维生素E的组合;EP1970049公开了用于在真皮使用包括维生素D的组合物以治疗诸如银屑病或皮炎的许多皮肤病况的局部用组合物。
最近,多泡沫分散体已经被用于眼科目的。举例来说,WO 2012/123515公开了一种用于递送不同的活性成分的方法,所述活性成分诸如抗生素(环孢菌素(cyclosporine)、万古霉素(vancomycine))、抗炎化合物(氟比洛芬(flurbiprofen)、氟替卡松(fluticasone))、前列腺素(拉坦前列素(latanoprost))。WO 2012/123515公开了待向人/动物角膜局部施用的滴眼剂。
技术问题
本申请人观测到当向患者的眼睛表面直接局部施用滴眼剂时,会出现各种问题。首先,一些患者不能自己施用滴眼剂。会出现局部施用的问题。此外,当分配滴眼剂时,患者想知道至少一滴滴眼剂是否已经到达靶标(角膜和/或结膜);这个问题在老年人群和儿童人群中会增大。因此,出现准确定量的问题。此外,即使在适当地向眼睛表面递送滴剂时,患者仍可能感到一定的不适或经历视力模糊。在眼部表面上滴注滴眼剂通常会触发反射性眨眼,从而在几秒内洗去大部分的滴眼剂。公认的是,在施用后2分钟内超过95%的滴眼剂从眼部表面被洗掉。
更重要的是,由于制剂中存在刺激性成分,因此向眼睛表面直接施用组合物可能引起刺激,特别是角膜刺激和/或结膜刺激。当治疗的主要靶标是眼睛时,此类后果可能是真正的问题。
眼睛治疗中的另一个关键问题是施用频率。每天施用滴眼剂若干次对于一些患者来说可能会变成真正的负担,并且患者对治疗的依从性可能显著降低。
这些与眼睛治疗组合物有关的不同问题使得本申请人构思并且实施易于施用的多泡沫体,所述多泡沫体能够靶向眼睛,同时避免了组合物对角膜的直接施用,并且还避免了不适、视力模糊和刺激。
眼睛治疗中的另一个问题是实现治疗剂在眼睛上的延长释放,以将所述治疗剂逐步地递送到眼睛的所靶向部分中。在短的持续时间内将大量的活性剂施用到眼睛上可能产生毒性浓度,并且因此可能对眼睛的所靶向部分有害。
因此,关注的是,在持续的时期内释放一定量的治疗剂,所述量足以实现治疗功效,而不会释放可能引起局部毒性的过量的治疗剂。延长递送持续时间的另一个优势在于施用频率可能减少并且依从性因此提高。
惊人的是,本申请人认识到多泡沫体可能是一种用于通过眼睑施用向受试者的眼睛持续和/或控制释放药物物质的有效媒介物。这一发现使得本申请人构思并且实施能够以可持续和/或控制的方式向受试者的眼睛上延长释放药物物质的多泡沫体。
发明内容
因此,在第一个方面,本发明涉及是或包含多泡沫体的组合物,其用于局部施用到受试者的至少一个眼睑上。在一个实施方案中,所述多泡沫体包含活性成分。
在一个实施方案中,本发明涉及含有至少一种多泡沫体的组合物,所述多泡沫体包围一成分,所述组合物用于向受试者的眼睛进行所述成分的眼睑施用,所述眼睑施用是借助于将多泡沫体局部施用到所述受试者的至少一个眼睑上而实现的。在一个实施方案中,所述成分是活性成分。
在第二个方面,本发明涉及用于将多泡沫体或其成分透皮递送到受试者的眼睛上以治疗所述受试者的眼睛疾病或眼睛病况的方法。本发明的方法可用于将多泡沫体的至少一种成分递送到眼睛的表面或眼睛的前段。
在第三个方面,本发明涉及用于制造本发明的至少一种多泡沫体的方法。
在第四个方面,本发明涉及用于将供使用的组合物施用到受试者的眼睑上的装置,其中所述组合物被沉积或浸渍或包被到所述装置上。
在第五个方面,本发明涉及包含本发明的装置和供使用的组合物的试剂盒。
在第六个方面,本发明涉及用于将成分持续和/或控制释放到受试者的眼睛上以治疗所述受试者的眼睛疾病或眼睛病况的方法。
具体实施方式
多泡沫体
因此,本发明涉及一种多泡沫体,其包含至少一种亲水相、至少一种疏水相以及至少一种表面活性剂。更优选地,本发明的多泡沫体包含:
-至少一种亲水相;
-至少一种疏水相;
-选自离子型表面活性剂和/或非离子型表面活性剂的至少一种表面活性剂;
-任选的至少一种添加剂,其选自抗氧化剂、渗透剂、粘度调节剂、pH值调节剂、缓冲剂、防腐剂、增溶剂、螯合剂;
-任选的至少一种活性成分。
亲水相
根据一个实施方案,本发明的多泡沫体是其中亲水相是水性组合物或水的多泡沫体。
所述水性组合物可以包含水可混溶的表面活性剂或聚合物、以及水。
疏水相
根据一个实施方案,本发明的多泡沫体是其中疏水相包含下组中的至少一种的多泡沫体,该组选自甘油的短链(C4至C6)脂肪酸单酯、二酯以及三酯;甘油的中链(C8至C12)脂肪酸单酯、二酯以及三酯;甘油的长链(C14和更长)饱和脂肪酸单酯、二酯以及三酯;甘油的长链(C14和更长)不饱和脂肪酸单酯、二酯以及三酯;植物油;杏仁油;巴巴苏油(babassuoil);黑加仑籽油;琉璃苣油;芥花油(canola oil);蓖麻油;椰子油;鳕鱼肝油;玉米油;棉籽油;月见草油;鱼油;葡萄籽油;芥菜籽油(grapeseed oil);燕麦油;橄榄油;棕榈仁油;棕榈油;花生油;菜籽油(rapeseed oil);红花油;芝麻油;鲨鱼肝油;角鲨烷;大豆油;葵花油;核桃油;小麦胚芽油;氢化蓖麻油;氢化椰子油;氢化棉籽油;氢化棕榈油;氢化大豆油;部分氢化的大豆油;氢化植物油;脂肪酸酯(例如油酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、异硬脂酸异丙酯……);丙二醇的短链(C4至C6)脂肪酸单酯和二酯;丙二醇的中链(C8至C12)脂肪酸单酯和二酯;丙二醇的长链(C14和更长)饱和脂肪酸单酯和二酯;丙二醇的长链(C14和更长)不饱和脂肪酸单酯和二酯;脂肪醇(例如肉豆蔻醇、油醇……);支链脂肪醇(例如辛基十二烷醇……);硅酮油;矿物油;矿脂;维生素E;维生素E乙酸酯;生育酚;生育酚乙酸酯;饱和脂肪酸;不饱和脂肪酸;磷脂。
优选地,本发明的多泡沫体的疏水相是或包含药学上可接受的油或药学上可接受的油的混合物。
在一个实施方案中,本发明的多泡沫体的疏水相不含磷脂。
在一个实施方案中,本发明的多泡沫体的疏水相包含MCT。在一个实施方案中,本发明的多泡沫体的疏水相由MCT组成。
在一个实施方案中,本发明的多泡沫体的疏水相包含矿物油。在一个实施方案中,本发明的多泡沫体的疏水相由矿物油组成。
在一个实施方案中,本发明的多泡沫体的疏水相包含三乙酸甘油酯。
表面活性剂
非离子型表面活性剂
在一个实施方案中,本发明的多泡沫体包含至少一种非离子型表面活性剂。有利地,所述至少一种非离子型表面活性剂选自以下各项的组:烷基聚二醇醚;烷基聚二醇酯;乙氧基化醇;聚氧乙烯脱水山梨糖醇脂肪酸酯;蓖麻油衍生物;聚氧乙烯脂肪酸酯;聚氧乙二醇氢化蓖麻油;聚氧乙二醇蓖麻油;脱水山梨糖醇脂肪酸酯(例如脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯);环氧乙烷和环氧丙烷的嵌段共聚物(例如泊洛沙姆(poloxamer)188、泊洛沙姆407);泊洛沙姆;泰洛沙泊(tyloxapol);聚山梨醇酯;蔗糖烷基酯;蔗糖烷基醚;甘油的短链(C4至C6)脂肪酸单酯和二酯;甘油的中链(C8至C12)脂肪酸单酯和二酯;甘油的长链(C14和更长)饱和脂肪酸单酯和二酯;甘油的长链(C14和更长)不饱和脂肪酸单酯和二酯;丙二醇的短链(C4至C6)脂肪酸单酯;丙二醇的中链(C8至C12)脂肪酸单酯;丙二醇的长链(C14和更长)饱和脂肪酸单酯;丙二醇的长链(C14和更长)不饱和脂肪酸单酯;聚氧甘油酯;聚氧乙烯烷基酯;聚氧乙烯醚;维生素E聚乙二醇丁二酸酯;烷基多糖苷。
离子型表面活性剂
在一个实施方案中,所述多泡沫体包含至少一种离子型表面活性剂。所述离子型表面活性剂可以是阳离子型表面活性剂或阴离子型表面活性剂。
有利地,所述至少一种离子型表面活性剂是选自以下各项的组的阳离子型表面活性剂:C10-C24伯烷基胺、叔脂族胺、季铵化合物、阳离子脂质(例如磷脂酰胆碱)、氨基醇、双胍盐、阳离子聚合物以及其两种或更多种的混合物。在一个优选的实施方案中,所述至少一种阳离子剂是季铵化合物,其优选地选自由以下各项组成的组:苯扎卤铵(benzalkoniumhalide)、劳拉卤铵(lauralkonium halide)、西曲溴铵(cetrimide)、十六烷基三甲基卤化铵、十四烷基三甲基卤化铵、十二烷基三甲基卤化铵、西曲卤铵(cetrimonium halide)、苄索卤铵(benzethonium halide)、山嵛基苄基二甲基卤化铵(behenalkonium halide)、西他卤铵(cetalkonium halide)、鲸蜡基乙基二甲基卤化铵(cetethyldimonium halide)、鲸蜡基卤化吡啶、苯度卤铵(benzododecinium halide)、卤化氯烯丙基乌洛托品(chlorallylmethenamine halide)、肉豆蔻基苄基二甲基卤化铵(myristalkonium halide)、硬脂基苄基二甲基卤化铵(stearalkonium halide)或其两种或更多种的混合物,卤化物优选地是氯化物或溴化物。
在一个实施方案中,所述至少一种离子型表面活性剂是选自以下各项的组的阴离子型表面活性剂:磷脂、卵磷脂、全氟辛酸盐、全氟辛烷磺酸盐、烷基硫酸盐、月桂基醚硫酸钠、烷基苯磺酸盐、皂或脂肪酸盐或其混合物。
表面活性剂的量
本发明的多泡沫体包含至少一种表面活性剂。有利地,以多泡沫体的总重量计,本发明的多泡沫体中表面活性剂的量在0.005重量%至5重量%、优选地0.05重量%至5重量%的范围。一般来说,在常规的乳液中,表面活性剂与油的比率在1/10至2/1的范围。在本发明的多泡沫体中,多泡沫体中表面活性剂与油的比率在1/50至1/40的范围;因此,表面活性剂在本发明的多泡沫体中的量比在常规的乳液中的量低得多。这种差异在有限的表面活性剂相关副作用方面赋予本发明的多泡沫体以与乳液相比明显的优势。
添加剂
在一个实施方案中,所述多泡沫体包含选自以下各项的组的添加剂:抗氧化剂、渗透剂、粘度调节剂、pH值调节剂或缓冲剂、防腐剂、增溶剂、螯合剂。添加剂的量可以由本领域技术人员根据药典标准和生物学标准来计算。
抗氧化剂
在一个实施方案中,所述多泡沫体包括选自以下各项的组的抗氧化剂:维生素E、亚硫酸氢钠、焦亚硫酸钠、无水硫代硫酸钠、柠檬酸一水合物、抗坏血酸棕榈酸酯和抗坏血酸、丁基羟基甲苯、丁基羟基茴香醚、没食子酸丙酯。这些抗氧化剂可以被单独使用或组合使用。抗氧化剂的量可以由本领域技术人员根据药典标准和生物学标准来计算。
渗透剂
在一个实施方案中,所述多泡沫体包含选自以下各项的组的至少一种渗透剂:甘油、丙二醇、氯化钠、氯化钾、山梨糖醇、甘露醇、木糖醇等。同样,渗透剂的量是根据药典标准和生物学标准来确定的。
粘度调节剂——本发明的多泡沫体的粘度
在一个实施方案中,所述多泡沫体包含选自以下各项的组的至少一种粘度调节剂:卡波姆(carbomer)、聚卡波非(polycarbophil)、纤维素衍生物(例如羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素……)、聚维酮(povidone)、共聚维酮(copovidone)、天然树胶(例如结冷胶(gellan gum)、瓜尔胶、黄原胶、琼脂、木葡聚糖……)、泊洛沙姆等。这些粘度调节剂可以被单独使用或组合使用,其量满足药典标准(在欧洲和美国)和生物学标准的要求。
在一个实施方案中,本发明的多泡沫体显示出在非常低的剪切速率(小于0.1s-1)下优于1Pa.s的粘度。在一个实施方案中,本发明的多泡沫体显示出在零剪切速率下优于1Pa.s的粘度。
使用本领域技术人员已知的流变仪设备(例如英国马尔文公司(Malvern UK)的旋转流变仪Kinexus),在25℃至35℃,在大气压(1atm)测量多泡沫体的粘度。
在一个实施方案中,所述多泡沫体表现出剪切稀化行为和触变材料的特征,这使得它更容易且更方便施用到受试者的至少一个眼睑上。
pH值调节剂或缓冲剂
在一个实施方案中,所述多泡沫体包含选自以下各项的至少一种pH值调节剂或缓冲剂:盐酸、柠檬酸、磷酸、乙酸、氢氧化钠、氢氧化钾、硼酸、硼砂、碳酸钠、碳酸氢钠等。pH值调节剂的量随最终的pH值而变化,所述最终pH值包括3.5至7.5。同样,pH值调节剂的量是根据药典标准和生物学标准来使用的。
防腐剂
在一个实施方案中,所述多泡沫体包含原样或组合的选自以下各项的至少一种防腐剂:苯扎氯铵(benzalkonium chloride)、苯甲醇、汞盐、硫柳汞、氯己定(chlorhexidine)、硼酸和/或其盐等。同样,防腐剂的量是根据药典标准和生物学标准来使用的。
增溶剂
在一个实施方案中,所述多泡沫体包含选自以下各项的至少一种增溶剂:乙醇、聚乙二醇、甘油、丙二醇、N-甲基吡咯烷酮、糖原糠醛、二甲基异山梨醇。同样,增溶剂的量是根据药典标准和生物学标准来使用的。
螯合剂
在一个实施方案中,所述多泡沫体包含选自以下各项的至少一种螯合剂:依地酸和其盐;乙二醇四乙酸和其盐;柠檬酸、偏磷酸、焦磷酸、多聚磷酸、苹果酸、酒石酸、植酸以及其盐;更优选地,选自由以下各项组成的组的至少一种类型:依地酸、柠檬酸、偏磷酸、多聚磷酸以及其盐;并且特别优选依地酸的盐。同样,螯合剂的量是根据药典标准和生物学标准来使用的。
水包油多泡沫体和制造方法
在一个实施方案中,所述多泡沫体是水包油多泡沫体,其中连续相包含水或亲水相或由水或亲水相组成,分散相包含具有疏水性内核的泡沫体或由具有疏水性内核的泡沫体组成。在这个实施方案中,以多泡沫体的总重量计,连续相的量可以在2重量%至50重量%,优选地2重量%至20重量%的水性组合物的范围;以多泡沫体的总重量计,泡沫体的量可以在50重量%至98重量%w/w的范围,优选地在70重量%至98重量%w/w的范围,甚至更优选地在80重量%至98重量%w/w的范围。在一个实施方案中,水包油多泡沫体包括具有0.1μm至100μm范围的平均直径的泡沫体。
在一个实施方案中,本发明的水包油多泡沫体是遵循以下方法制造的:搅拌水溶液,然后逐滴添加疏水相。优选地,在室温使用磁力搅拌或螺旋桨以200rpm至1000rpm搅拌水溶液,并且以允许自催化形成泡沫体的特定速率添加疏水相。
油包水多泡沫体和制造方法
在一个实施方案中,所述多泡沫体是油包水多泡沫体,其中连续相是疏水相并且分散相包含具有亲水性内核的泡沫体或由具有亲水性内核的泡沫体组成。在这个实施方案中,以多泡沫体的总重量计,连续相的量可以在2重量%至50重量%,优选地2重量%至20重量%的疏水相的范围;以多泡沫体的总重量计,泡沫体的量可以在50重量%至98重量%w/w的范围,优选地在70重量%至98重量%w/w的范围,甚至更优选地在80重量%至98重量%w/w的范围。在一个实施方案中,油包水多泡沫体包括具有0.1μm至100μm范围的平均直径的泡沫体。
在一个实施方案中,本发明的油包水多泡沫体是遵循以下方法制造的:搅拌油相,然后逐滴添加水溶液。优选地,在室温使用磁力搅拌或螺旋桨以200rpm至1000rpm搅拌水溶液,并且以允许自催化形成泡沫体的特定速率添加油相。
不含活性成分的多泡沫体
在一个实施方案中,所述多泡沫体不含任何活性成分,即不含药物。
在这个实施方案中,所述多泡沫体可以被认为是药学上可接受的媒介物。
在这个实施方案中,所述多泡沫体特别可用于治疗干眼病况,如例如干眼综合征或慢性干眼病(CDED),这两者在临床上被称为干燥性角膜结膜炎(KCS)。
具有活性成分的多泡沫体
在一个实施方案中,所述多泡沫体包含活性成分。在一个实施方案中,所述活性成分是有治疗意义的分子。
在一个实施方案中,所述活性成分选自:
-抗过敏剂,如色甘酸钠、安他唑啉(antazoline)、氯苯那敏(chlorpheniramine)、西替利嗪(cetirizine)、奥洛他定(olapatadine)、依匹斯汀(epinastine)、酮替芬(ketotifen)、氮卓斯汀(azelastine)、依美斯汀(emedastine)、左卡巴斯汀(levocabastine)、特非那丁(terfenadine)以及罗拉他定(loratadine);
-抗炎剂,如可的松(cortisone)、氢化可的松(hydrocortisone)、乙酸氢化可的松(hydrocortisone acetate)、地塞米松(dexamethasone)、地塞米松21-磷酸酯、地塞米松棕榈酸酯、氟氢松(fluorocinolone)、泼尼松(prednisone)、甲泼尼松(methylprednisone)、乙酸泼尼松龙(prednisolone acetate)、氟米龙(fluoromethalone)、曲安西龙(triamcinolone)、倍他米松(betamethasone)、氯替泼诺(loteprednol)、氟米松(flumethasone)、倍氯米松(beclomethasone)、二氟泼尼酯(difluprednate)和曲安奈德(triamcinolone acetonide)以及它们的衍生物;
-非类固醇抗炎剂,如水杨酸盐、吲哚美辛(indomethacin)、布洛芬(ibuprofen)、双氯芬酸(diclofenac)、氟比洛芬、昔康类(oxicams)、吡罗昔康(piroxicam)以及COX2抑制剂,如罗非昔布(rofecoxib)、尼美舒利(nimesulide)、奈帕芬胺(nepafenac);
-β肾上腺素能阻断剂,如噻吗洛尔(timolol)和其盐,包括顺丁烯二酸噻吗洛尔;盐酸左布诺洛尔(levobunolol hydrochloride)以及盐酸倍他洛尔(betaxololhydrochloride)、倍他洛尔、阿替洛尔(atenolol)、倍芬多尔(befundol)、美替洛尔(metipranolol)、佛司可林(forskolin)、卡替洛尔(carteolol);
-细胞因子、白细胞介素、前列腺素(以及抗前列腺素(antiprostaglandins)和前列腺素前体),如拉坦前列素、比马前列素(bimatoprost)、他氟前列素(tafluprost)或曲伏前列素(travoprost);
-环孢菌素、西罗莫司(sirolimus)、他克莫司(tacrolimus);
-抗氧化剂,如叶黄素;维生素,特别是维生素A;辅酶Q10、多不饱和脂肪酸以及其衍生物;
-碳酸酐酶抑制剂,如布林佐胺(brinzolamide)、多佐胺(dorzolamide)、乙酰唑胺(acetazolamide)、醋甲唑胺(methazolamide)、二氯苯磺胺(dichlorophenamide);
-抗病毒剂,如碘苷(idoxuridine)、三氟胸苷(trifluorotymidine)、阿昔洛韦(acyclovir)、伐昔洛韦(valaciclovir)、更昔洛韦(ganciclovir)、西多福韦(cidofovir)以及干扰素;
-抗生素,如氨基糖苷类、碳头孢烯(carbacephem)、碳青霉烯类(carbapenems)、头孢菌素类(cephalosporins)、糖肽类、青霉素类(penicillins)、多肽类、喹诺酮类(quinolones)、磺酰胺类、四环素类(tetracyclines)、氯四环素(chlortetracycline)、杆菌肽(bacitracin)、新霉素(neomycin)、多粘菌素、短杆菌肽(gramicidin)、头孢氨苄(cephalexin)、土霉素(oxytetracycline)、氯霉素(chloramphenicol)、卡那霉素(kanamycin)、利福平(rifampicin)、妥布霉素(tobramycin)、庆大霉素(gentamycin)、环丙沙星(ciprofloxacin)、氨基糖苷类(aminosides)、红霉素(erythromycin)、头孢他啶(ceftazidime)、万古霉素、亚胺培南(imipeneme);大环内酯类(macrolides)、阿奇霉素(azithromycin)、克拉霉素(clarithromycin)、氟喹诺酮类(fluroroquinolones);
-抗细菌剂,如磺酰胺类(sulfonamides)、磺胺嘧啶(sulfadiazine)、磺胺醋酰(sulfacetamide)、磺胺甲二唑(sulfamethizole)、磺胺异唑(sulfisoxazole)、呋喃西林(nitrofurazone)以及丙酸钠;
-和/或它们的衍生物;和/或它们的前药;和/或它们的前体;和/或其可接受的盐;单独或组合。
在一个实施方案中,所述活性成分选自拉坦前列素、他氟前列素、噻吗洛尔、多佐胺、奥洛他定、依匹斯汀、阿奇霉素、克拉霉素、环孢菌素A以及西罗莫司、地塞米松、地塞米松棕榈酸酯。
在一个实施方案中,所述活性成分是奥洛他定。在一个实施方案中,所述活性成分是依匹斯汀。在一个实施方案中,所述活性成分是克拉霉素。在一个实施方案中,所述活性成分是环孢菌素A。在一个实施方案中,所述活性成分是地塞米松棕榈酸酯。
在一个实施方案中,所述多泡沫体使活性成分稳定和/或防腐。
灭菌
在一个实施方案中,可以将多泡沫体灭菌。
灭菌方法的非限制性示例是加热,如通过高压灭菌;过滤、辐照以及气体灭菌。
形式
在一个实施方案中,本发明的多泡沫体可以是液体、流体、凝胶、粉剂、软膏剂、乳膏剂、贴剂、膜制剂或适用于眼睑施用的任何递送制剂。
优选地,所述多泡沫体具有适用于局部施用于眼睑皮肤上的粘度,并且以凝胶或乳膏剂、或软膏剂、或贴剂、或适用于通过眼睑施用供眼科使用的任何形式向受试者分配或施用。
包装
在一个实施方案中,所述多泡沫体以单一剂量包装;在另一个实施方案中,所述多泡沫体被包装在合适的多剂量容器中。
方法
向眼睑上施用——试剂盒
在一个方面,本发明涉及用于将多泡沫体局部施用到受试者的至少一个眼睑、上眼睑和/或下眼睑上的方法。
在一个实施方案中,通过局部涂敷在受试者的眼睛周围的皮肤上来施用多泡沫体。在一个实施方案中,通过涂敷在受试者的眼睑上来施用多泡沫体。在一个实施方案中,通过涂敷在受试者的上眼睑上来施用多泡沫体。在一个实施方案中,通过涂敷在受试者的下眼睑上来施用多泡沫体。
在另一个实施方案中,使用涂敷装置,如例如刷子或施用装置来施用所述多泡沫体。
本发明还涉及一种试剂盒,所述试剂盒包含容纳本发明的多泡沫体的容器和如上文所述的涂敷装置。
透皮递送
在另一个方面,本发明涉及用于透皮递送多泡沫体或其成分到受试者的眼睛上以治疗所述受试者的眼睛疾病或眼睛病况的方法。
在一个实施方案中,本发明的方法可用于将多泡沫体或其成分递送到眼睛的表面或眼睛的前段。
在一个实施方案中,本发明的方法可用于眼睛护理。
在一个实施方案中,所述多泡沫体包含作为添加剂的渗透增强剂,即增强多泡沫体或其成分向眼睛表面或眼睛前段的透皮渗透的化合物。
成分的持续和/或控制释放
在另一个方面,本发明涉及用于持续和/或控制释放成分到受试者的眼睛上以治疗所述受试者的眼睛疾病或眼睛病况的方法。
在一个实施方案中,通过将含有所述成分的本发明的多泡沫体施用到受试者的至少一个眼睑、上眼睑和/或下眼睑上来获得所述持续和/或控制释放。
在一个实施方案中,本发明的方法对于实现治疗剂的持续和/或控制释放施用来说是有效的。
在一个实施方案中,所述成分以持续方式和/或控制方式被释放1小时至2周、优选地6小时至1周、优选地12小时至5天范围的时间段。在一个具体的实施方案中,所述成分以持续方式和/或控制方式被释放1天至3天范围的时间段。
在一个实施方案中,所述持续和/或控制释放动力学可以取决于多泡沫体的配方。在一个具体的实施方案中,释放速率取决于多泡沫体的亲水相的性质。在一个具体的实施方案中,释放速率取决于多泡沫体的疏水相的性质。在一个具体的实施方案中,释放速率取决于多泡沫体中所包含的表面活性剂或表面活性剂的混合物的性质。在一个具体的实施方案中,释放速率取决于多泡沫体中所包含的表面活性剂或表面活性剂的混合物的浓度。
在一个实施方案中,所述持续和/或控制释放动力学可以取决于多泡沫体的粘度。在一个具体的实施方案中,当多泡沫体的粘度增加时,释放速率减小。
在一个实施方案中,所述持续和/或控制释放动力学可以取决于多泡沫体的平均珠滴尺寸。在一个具体的实施方案中,当多泡沫体的平均珠滴尺寸减小时,释放速率减小。
在一个实施方案中,所述持续和/或控制释放动力学可以取决于施用到受试者的眼睛上的多泡沫体的体积。
在一个实施方案中,持续和/或控制释放动力学可以适应受试者的确切需要。在一个具体的实施方案中,可以通过选择待被包含在多泡沫体中的表面活性剂或表面活性剂的混合物来使释放动力学适应受试者的确切需要。在一个具体的实施方案中,可以通过选择待被包含在多泡沫体中的表面活性剂或表面活性剂的混合物的适当的浓度来使释放动力学适应受试者的确切需要。在一个具体的实施方案中,可以通过改变多泡沫体的粘度和/或平均珠滴尺寸来使释放动力学适应受试者的确切需要。
在一个实施方案中,本发明的方法可用于将所述成分持续和/或控制释放到眼睛的表面或眼睛的前段。
在一个实施方案中,本发明的方法可用于眼睛护理。
眼睛疾病或眼睛病况
在本发明的含义中,眼睛疾病或眼睛病况是干眼病况,如例如干眼综合征或慢性干眼病,如干燥性角膜结膜炎(KCS)、特应性角膜结膜炎(AKC)以及春季角膜结膜炎(VKC);青光眼;眼部炎症病况,如例如角膜炎、角膜上皮糜烂、葡萄膜炎(包括前葡萄膜炎)、眼内炎症、过敏以及干眼综合征眼部感染、眼部感染、眼部过敏、角膜或结膜病变、癌性生长、糖尿病性黄斑水肿、年龄相关黄斑变性、角膜麻醉、瞳孔散大。
在一个实施方案中,所述眼睛病况可以是睑炎、青光眼、睑板腺(Meibomiangland)病症,如例如睑板腺功能障碍(MGD);以及干眼病况,如例如干眼综合征或慢性干眼病;糖尿病性角膜病或神经营养性角膜病。
在一个实施方案中,所述病况可以与毛囊蠕形螨(demodex folliculorum)感染相关。在一个实施方案中,所述病况是青光眼。在一个实施方案中,所述病况是前葡萄膜炎。
在另一个方面,本发明的多泡沫体用于治疗眼睛疾病或眼睛病况。
在另一个方面,本发明的多泡沫体用于制造用于治疗眼睛疾病或眼睛病况的药品或药物。
在另一个方面,本发明涉及治疗眼睛疾病或眼睛病况的方法,其中通过局部应用包含治疗剂的多泡沫体向有需要的患者施用治疗活性量的所述治疗剂。在一个实施方案中,所述方法包括将包含多泡沫体的组合物局部施用到受试者的上眼睑和/或下眼睑上的步骤。在一个实施方案中,所述局部应用是眼睑应用。
在一个实施方案中,将所述多泡沫体每天施用一次,持续4周。
在一个实施方案中,通过多泡沫体进行的眼睑施用减小了治疗对患者的毒性和/或副作用。
定义
在本发明中,以下术语具有以下含义:
‐‐“泡沫体”指的是由以下各项构成的复合珠滴:包含表面活性剂的外层,所述外层包围由与连续相相同的材料构成的中间层,所述中间层本身包围由与连续相不可混溶的相制成的核心。
‐‐“连续相”指的是包围分散相的相。
‐‐“分散相”指的是分散在连续相中的珠滴。
‐‐“眼睑”包括上眼睑,所述上眼睑从眉毛开始到由睫毛根部所确定的下限;以及下眼睑,所述下眼睑从眶下区开始到由睫毛根部所确定的界限。
‐‐“MCT”意指中链甘油三酯。
‐‐“有治疗意义的分子”意指有治疗病变、疾病的特定意义的任何分子。
‐‐“ND”意指“未测定”。
‐‐“眼睑施用”指的是局部应用到受试者的至少一个眼睑的外表面上。
‐‐“多泡沫体”指的是分散在连续相中的被称作泡沫体的液体珠滴。
附图说明
图1是示出了负载克拉霉素的多泡沫体28号、油性溶液29号以及软膏剂30号的体外功效测试的结果的图(实施例6)。
图2是示出了负载地塞米松的多泡沫体31号至33号的体外渗透测试的结果的图(实施例7)。
图3是示出了负载盐酸奥洛他定的多泡沫体21号至23号的体外皮肤渗透测试的结果的图(实施例8)。
图4是示出了负载克拉霉素的多泡沫体34号和溶液39号的体内功效测试的结果的直方图(实施例10)。
图5是示出了负载克拉霉素的多泡沫体34号和软膏剂40号的体内功效测试的结果的直方图(实施例11)。
图6是示出了负载克拉霉素的多泡沫体34号和乳液41号的体内功效测试的结果的直方图(实施例12)。
实施例
通过以下实施例进一步说明本发明。
实施例1:根据本发明的不含药物物质的水包油多泡沫体
组合物编号 | 1 | 2 | 3 | 4 | 5 | 6 |
MCT | 90 | 90 | 90 | 90 | 90 | 45 |
三乙酸甘油酯 | 45 | |||||
泊洛沙姆188 | 0.1 | 1.0 | ||||
泊洛沙姆407 | 0.1 | 1.0 | ||||
硬脂酸聚烃氧-40酯 | 1.0 | 0.1 | ||||
脱水山梨糖醇油酸酯 | 0.9 | |||||
水 | Qs 100 | Qs 100 | Qs 100 | Qs 100 | Qs 100 | Qs 100 |
表1:多泡沫体1号至6号的组成(量是以%重量/重量指示的)。
实施例2:根据本发明的包含环孢菌素A的水包油多泡沫体
表2:多泡沫体7号至15号的组成(量是以%重量/重量指示的)。
实施例3:根据本发明的包含地塞米松棕榈酸酯的水包油多泡沫体
组合物编号 | 16 | 17 | 18 |
地塞米松棕榈酸酯 | 0.8 | 0.8 | 0.8 |
MCT | 88.3 | 89.2 | 89.2 |
脱水山梨糖醇油酸酯 | 0.9 | ||
泊洛沙姆407 | 1 | 0.1 | |
硬脂酸聚烃氧-40酯 | 0.1 | ||
水 | qs 100 | qs 100 | qs 100 |
表3:多泡沫体16号至18号的组成(量是以%重量/重量指示的)。
实施例4:根据本发明的包含作为亲水性标记的荧光素钠或作为药物物质的盐酸
奥洛他定的油包水多泡沫体
组合物编号 | 19 | 20 | 21 | 22 | 23 |
荧光素钠 | 0.0005 | 0.05 | |||
盐酸奥洛他定 | 0.5 | 0.5 | 0.5 | ||
轻质矿物油 | 19 | 19 | 17.9 | 17.9 | 17.9 |
脱水山梨糖醇油酸酯 | 1 | 1 | 2 | 2 | 2 |
蔗糖三硬脂酸酯 | 0.1 | 0.1 | 0.1 | ||
甘油 | 5.0 | ||||
PEG 400 | 5.0 | ||||
水 | qs 100 | qs 100 | Qs 100 | Qs 100 | Qs 100 |
表4:多泡沫体19号和23号的组成(量是以%重量/重量指示的)。
实施例5:根据本发明的包含依匹斯汀作为药物物质的油包水多泡沫体
组合物编号 | 24 | 25 | 26 | 27 |
盐酸依匹斯汀 | 0.5 | 0.5 | 0.5 | 0.5 |
轻质矿物油 | 17.9 | 17.9 | 16.9 | 17.9 |
脱水山梨糖醇油酸酯 | 2 | 2 | 2 | 2 |
蔗糖三硬脂酸酯 | 0.1 | 0.1 | 0.1 | 0.1 |
肉豆蔻酸异丙酯 | 1 | |||
甘油 | 5 | |||
二乙二醇单乙醚 | 2.5 | |||
PEG 400 | 5 | 2.5 | 5 | |
水 | Qs 100 | Qs 100 | Qs 100 | Qs 100 |
表5:多泡沫体24号至27号的组成(量是以%重量/重量指示的)。
使用现有技术的激光衍射设备(德国的海洛斯新帕泰克公司(Helos Sympatec,Germany))来测量每一种多泡沫体的珠滴尺寸分布。粒度分布是基于体积(Dv)来测定的。已经使用现有技术的流变仪(英国马尔文公司的Kinexus)来测量每一种多泡沫体的粘度。
基于表6上所显示的组合物的物理属性,在所述系统的珠滴尺寸分布与粘度之间出现相关性:当组合物更具粘性时,珠滴尺寸分布更小。这些特征可能取决于多泡沫体的定性或定量组成。
组合物编号 | 24 | 25 | 26 | 27 |
珠滴尺寸分布(μm) | ||||
D(v,10)(μm) | 1.8 | 2.9 | 2.5 | 1.8 |
D(v,50)(μm) | 7.2 | 16.7 | 12.3 | 7.7 |
D(v,90)(μm) | 37.9 | 48.8 | 38.3 | 33.6 |
粘度(Pa.s) | ||||
初始粘度η0(Pa.s) | 4549 | 3398 | 5662 | 6744 |
表6:多泡沫体24号至27号的物理特性
实施例6:对包含克拉霉素的水包油多泡沫体的渗透的体外评价
使用安装有购自密理博公司(Millipore)(法国的莫尔塞姆(Molsheim,France))的Strat-M膜的Franz池设备评估克拉霉素的透皮渗透。Strat-M膜是用于模拟皮肤渗透的体外测试的合成膜。
将克拉霉素从多泡沫体(组合物28号)的扩散与从油性溶液(组合物29号)的扩散和从软膏剂(组合物30号)的扩散进行比较。通过超高效液相色谱(UPLC)测量经过72小时在接收隔室中克拉霉素的浓度。
评价下列制剂:
组合物编号 | 28 | 29 | 30 |
克拉霉素 | 1 | 1 | 1 |
Capmul PG8 | 50 | 56 | |
MCT | 39 | 43 | |
轻质矿物油 | 25 | ||
重质矿物油 | 25 | ||
矿脂 | 49 | ||
CKC | 0.005 | ||
聚山梨醇酯80 | 1 | ||
水 | Qs 100 |
表7:多泡沫体28号至30号的组成(量是以%重量/重量指示的)
如图1上所公开,应用软膏剂30号未引起透皮渗透,而克拉霉素从多泡沫体28号扩散。因此,这个实验明确证实多泡沫体在治疗剂的皮肤渗透方面相对于软膏剂的优越性。
克拉霉素从油性溶液29号扩散穿过膜,但是此类组合物不适用于局部应用于眼睑上,这是因为它的粘度(25mPa.s-33mPa.s)没有高到足以允许油性溶液保留到眼睑上。油性溶液将沿着眼睑流动和/或流到眼睛中。相反,由于多泡沫体28号的粘度(>1Pa.s)高到足以保留在眼睑上,因此它适用于眼睑施用。
此外,还如图1中所示,多泡沫体28号惊人地能够在超过72小时内有效地释放克拉霉素,而油性溶液29号立即释放克拉霉素。这证实多泡沫体的使用可以使得治疗剂通过皮肤持续和控制释放。
实施例7:对包含地塞米松的水包油多泡沫体的渗透的体外评价
使用安装有购自密理博公司(法国的莫尔塞姆)的Strat-M膜的Franz池设备评估地塞米松的透皮渗透。Strat-M膜是用于模拟皮肤渗透的体外测试的合成膜。
使用现有技术的激光衍射设备(德国的海洛斯新帕泰克公司)来测量每一种多泡沫体的珠滴尺寸分布。粒度分布是基于体积(Dv)来测定的。已经使用现有技术的流变仪(英国马尔文公司的Kinexus)来测量每一种多泡沫体的粘度。
对地塞米松从具有不同组成的多泡沫体(组合物31号至33号)的扩散进行比较。通过超高效液相色谱(UPLC)测量经过48小时在接收隔室中地塞米松的浓度。
评价下列制剂:
组合物编号 | 31 | 32 | 33 |
地塞米松 | 0.024 | 0.024 | 0.024 |
MCT | 89 | 90 | 90 |
脱水山梨糖醇油酸酯 | 0.9 | ||
泊洛沙姆407 | 1 | 0.1 | |
PEG-40硬脂酸酯 | 0.1 | ||
水 | Qs 100 | Qs 100 | Qs 100 |
表8:多泡沫体31号至33号的组成(量是以%重量/重量指示的)
基于表9上所显示的组合物的物理属性,在所述系统的珠滴尺寸分布与粘度之间出现相关性:当组合物更具粘性时,珠滴尺寸分布更小。这些特征可能取决于多泡沫体的定性或定量组成。
组合物编号 | 31 | 32 | 33 |
珠滴尺寸分布(μm) | |||
D(v,10)(μm) | 4.7 | 1.5 | 14.9 |
D(v,50)(μm) | 20.3 | 3.8 | 32.7 |
D(v,90)(μm) | 29.3 | 8.7 | 51.5 |
粘度(Pa.s) | |||
初始粘度η0(Pa.s) | 22 | 300 | 5 |
表9:多泡沫体31号至33号的物理特性
图2上所公开的结果明确证实多泡沫体能够在超过48小时内通过皮肤持续释放地塞米松。此外,它们证实多泡沫体的组成影响了地塞米松的释放曲线。
惊人的是,释放动力学取决于表面活性剂的性质。释放在其中表面活性剂是PEG-40硬脂酸酯和脱水山梨糖醇油酸酯的混合物的多泡沫体31号的情况下比在其中表面活性剂是泊洛沙姆的组合物32号和33号的情况下更快。
惊人的是,释放动力学还与组合物的粘度以及珠滴尺寸分布具有相关性。比较组合物32号和33号,提高表面活性剂的相对浓度使珠滴尺寸分布减小并且使粘度增加。这使得具有更小粒度的更具粘性的多泡沫体32号比具有更高粒度的不太具有粘性的多泡沫体33号具有更慢的动力学。
因此,可以例如通过作用于表面活性剂的性质和/或浓度来改变多泡沫体的定性和/或定量配方以控制从多泡沫体的释放动力学。
实施例8:对包含盐酸奥洛他定的油包水多泡沫体的渗透的体外评价
使用安装有购自密理博公司(法国的莫尔塞姆)的Strat-M膜的Franz池设备评估盐酸奥洛他定的透皮渗透。Strat-M膜是用于模拟皮肤渗透的体外测试的合成膜。
对盐酸奥洛他定从具有实施例4的表4中所公开的不同组成的多泡沫体(组合物21号-23号)的扩散进行比较。通过超高效液相色谱(UPLC)测量经过48小时在接收隔室中盐酸奥洛他定的浓度。
如图3中所示,当盐酸奥洛他定通过多泡沫体扩散时,也获得了持续和控制释放。
惊人的是,添加亲水性共溶剂(例如甘油、PEG 400)增强了穿过体外Strat-M膜的渗透,从而充当渗透增强剂。
实施例9:制造多泡沫体34号至38号的方法
使用包含克拉霉素的多泡沫体34号至38号进行体内评价(以下实施例10-13)。
根据下列方法制造下表10的多泡沫体34号:向以200rpm搅拌的含有聚山梨醇酯80SR(1g)的水相(8.995g)中逐滴添加含有CKC(0.005g)、丙二醇单辛酸酯(50g)以及克拉霉素(1g)的油相MCT(39g)。在所述过程开始时添加油相的速率是缓慢的(约每7秒一滴),但是在已经添加了20%的油相之后,加速以使得制备多泡沫体的总时间是约20分钟。
下表10的多泡沫体35号至38号是根据相同的制造方法制备的。
34 | 35 | 36 | 37 | 38 | |
克拉霉素 | 1 | 0.3 | 0.25 | 0.5 | - |
MCT | 39 | 39 | 47.88 | 47.75 | 39 |
丙二醇单辛酸酯 | 50 | 50 | 41.89 | 41.78 | 50 |
聚山梨醇酯80SR | 1 | 1 | 0.2 | 0.2 | 1 |
水 | qs 100 | qs 100 | qs 100 | qs 100 | qs 100 |
表10:多泡沫体34号至38号的组成(量是以%重量/重量指示的)
已经制备下表11的包含克拉霉素的乳液和软膏剂39号至42号以进行比较。
溶液39 | 软膏剂40 | 乳液41 | 乳液42 | |
克拉霉素 | 1 | 3 | 1 | 0.5 |
MCT | 39 | - | ||
丙二醇单辛酸酯 | 50 | - | 25 | 25 |
白矿脂 | - | 77.5 | - | - |
矿物油 | - | 12.1 | - | - |
聚山梨醇酯80SR | - | 2.5 | 2.5 | |
PEG-40硬脂酸酯 | 0.1 | - | - | - |
脱水山梨糖醇单油酸酯 | - | - | 2.5 | 2.5 |
磷酸氢钠 | 0.1 | |||
甘油 | 2 | - | 1.2 | 1.2 |
水 | qs 100 | - | qs 100 | qs 100 |
表11:制剂39号至42号的组成(量是以%重量/重量指示的)
实施例10:体内实验——多泡沫体34号的眼睑应用与将溶液39号分配于角膜上的
比较。
睑板腺闭塞是睑板腺功能障碍(MGD),其往往造成干眼症,并且还可能导致睑炎。
将多泡沫体34号(1%w/w的克拉霉素)每天一次局部应用到表现闭塞的睑板腺的受试者的眼睑上,持续4周。为了比较,将溶液39号(1%w/w克拉霉素)每天3次分配到受试者的角膜上,持续4周。在6只眼睛上评价每一种制剂(n=6)。结果示于图4上。
多泡沫体34号(1%w/w的克拉霉素)在四周治疗之后以与分配于角膜上的溶液39号(1%w/w克拉霉素)相同的比例减少闭塞腺体的数目。
此外,在临床上观测到局部应用于眼睑上的多泡沫体34号的毒性低于直接分配于角膜上的溶液39号的毒性。滴注到角膜上的溶液触发了角膜上皮的刺激和坏死,而对于眼睑应用多泡沫体34号,没有报告角膜毒性体征。
实施例11:体内实验——多泡沫体34号的眼睑应用与软膏剂40号的眼睑应用的比
较。
将多泡沫体34号(1%w/w的克拉霉素)每天一次局部应用于表现闭塞的睑板腺的受试者的眼睑上,持续4周。相比之下,将软膏剂40号(3%w/w的克拉霉素)每天一次局部应用于受试者的眼睑上,持续4周。在6只眼睛上评价每一种制剂(n=6)。结果示于图5上。
多泡沫体34号在四周治疗之后以与软膏剂40号相同的比例减少闭塞腺体的数目。然而,闭塞细胞数目的减少必须由以下事实来平衡,即软膏剂40号的浓度是多泡沫体34号的三倍。因此,在使用多泡沫体34号时,与软膏剂40号相比,诱导相同功效需要多泡沫体中减少量的克拉霉素。
多泡沫体34号的毒性特征类似于软膏剂40号的毒性特征,尽管所述软膏剂中克拉霉素的浓度是所述多泡沫体的三倍。对于多泡沫体34号没有观测到角膜毒性。
因此,眼睑应用多泡沫体34号允许使用减少量的克拉霉素并且呈现更好的安全特征。
实施例12:体内实验——多泡沫体34号的眼睑应用与乳液41号的角膜应用的比
较。
将多泡沫体34号(1%w/w的克拉霉素)每天一次局部应用于表现闭塞的睑板腺的受试者的眼睑上,持续4周。相比之下,将乳液41号(1%w/w的克拉霉素)每天3次局部应用于受试者的眼睑上,持续4周。在6只眼睛上评价每一种制剂(n=6)。结果示于图6上。
多泡沫体34号在一周治疗之后以比乳液41号更大的程度减少闭塞腺体的数目。
此外,与滴注于角膜上的乳液41号相比,多泡沫体34号表现出提高的安全特征。确实,在将多泡沫体34号应用到眼睑上之后没有报告角膜毒性体征,而在滴注乳液41号之后报告严重毒性(即角膜上皮坏死)。
实施例13:通过对多泡沫体37号和水包油乳液42号中的克拉霉素进行定量分析所
进行的稳定性测量
将多泡沫体37号(0.5%w/w克拉霉素)和水包油乳液42号(0.5%w/w克拉霉素)在40℃和60℃加热一周。在实验结束时测量克拉霉素的量并且与初始量进行比较。结果是以相对于克拉霉素的初始量的百分比指示的,并且呈现于表12中。
表12:在一周实验之后多泡沫体37号和乳液42号的稳定性
在40℃,在一周实验之后,在多泡沫体37号中回收了99%的活性成分,而在水包油乳液42号中仅回收了90%。在60℃,在水包油乳液42号中仅回收了72%的活性成分,而多泡沫体37号仍含有96%的活性成分。
与水包油乳液42号相比,多泡沫体37号因此使得克拉霉素的稳定性增强。
Claims (17)
1.一种用于局部施用到受试者的上眼睑和/或下眼睑上的供使用的组合物,所述组合物包含多泡沫体。
2.根据权利要求1所述的供使用的组合物,其用于将所述多泡沫体施用到受试者的上眼睑和/或下眼睑,所述施用借助于局部施用所述多泡沫体到所述受试者的上眼睑和/或下眼睑上。
3.根据权利要求1或2所述的供使用的组合物,其包含:
至少一种亲水相,
至少一种疏水相,
选自离子型表面活性剂和/或非离子型表面活性剂的至少一种表面活性剂,任选的至少一种添加剂,所述添加剂选自抗氧化剂、渗透剂、粘度调节剂、pH值调节剂、缓冲剂、防腐剂、增溶剂、螯合剂。
4.根据权利要求1至3中任一项所述的供使用的组合物,其进一步包含至少一种活性成分。
5.根据权利要求1至4中任一项所述的供使用的组合物,其用于眼睑施用活性成分到受试者的眼睛,所述眼睑施用借助于局部施用多泡沫体到所述受试者的上眼睑和/或下眼睑上。
6.根据权利要求1至5所述的供使用的组合物,其中所述使用是眼科用途。
7.根据权利要求1至6中任一项所述的供使用的组合物,其中所述多泡沫体是液体、流体、凝胶、粉剂、软膏剂、乳膏剂、贴剂、膜制剂。
8.根据权利要求1至7中任一项所述的供使用的组合物,其中所述多泡沫体包括平均尺寸范围为0.1μm至100μm的珠滴。
9.根据权利要求1至8中任一项所述的供使用的组合物,其中所述至少一种非离子型表面活性剂选自下组,所述组选自烷基聚二醇醚;烷基聚二醇酯;乙氧基化醇;聚氧乙烯脱水山梨糖醇脂肪酸酯;蓖麻油衍生物;聚氧乙烯脂肪酸酯;聚氧乙二醇氢化蓖麻油;聚氧乙二醇蓖麻油;脱水山梨糖醇脂肪酸酯;环氧乙烷和环氧丙烷的嵌段共聚物,如例如泊洛沙姆,优选地泊洛沙姆188、泊洛沙姆407;泰洛沙泊;聚山梨醇酯;蔗糖烷基酯;蔗糖烷基醚;甘油的短链脂肪酸单酯和二酯;甘油的中链脂肪酸单酯和二酯;甘油的长链饱和脂肪酸单酯和二酯;甘油的长链不饱和脂肪酸单酯和二酯;丙二醇的短链脂肪酸单酯;丙二醇的中链脂肪酸单酯;丙二醇的长链饱和脂肪酸单酯;丙二醇的长链不饱和脂肪酸单酯;聚氧甘油酯;聚氧乙烯烷基酯;聚氧乙烯醚;维生素E聚乙二醇丁二酸酯;烷基多糖苷。
10.根据权利要求1至9中任一项所述的供使用的组合物,其中油相选自甘油的短链脂肪酸单酯、二酯以及三酯;甘油的中链脂肪酸单酯、二酯以及三酯;甘油的长链饱和脂肪酸单酯、二酯以及三酯;甘油的长链不饱和脂肪酸单酯、二酯以及三酯;植物油;杏仁油;巴巴苏油;黑加仑籽油;琉璃苣油;芥花油;蓖麻油;椰子油;鳕鱼肝油;玉米油;棉籽油;月见草油;鱼油;葡萄籽油;芥菜籽油;燕麦油;橄榄油;棕榈仁油;棕榈油;花生油;菜籽油;红花油;芝麻油;鲨鱼肝油;角鲨烷;大豆油;葵花油;核桃油;小麦胚芽油;氢化蓖麻油;氢化椰子油;氢化棉籽油;氢化棕榈油;氢化大豆油;部分氢化的大豆油;氢化植物油;脂肪酸酯;丙二醇的短链脂肪酸单酯和二酯;丙二醇的中链脂肪酸单酯和二酯;丙二醇的长链饱和脂肪酸单酯和二酯;丙二醇的长链不饱和脂肪酸单酯和二酯;脂肪醇;支链脂肪醇;硅酮油;矿物油;矿脂;维生素E;维生素E乙酸酯;生育酚;生育酚乙酸酯;饱和脂肪酸;不饱和脂肪酸;磷脂。
11.根据权利要求1至10中任一项所述的供使用的组合物,其中所述活性成分来自抗过敏剂,如色甘酸钠、安他唑啉、氯苯那敏、西替利嗪、奥洛他定、依匹斯汀、酮替芬、氮卓斯汀、依美斯汀、特非那丁以及氯雷他定;
抗炎剂,如可的松、氢化可的松、乙酸氢化可的松、地塞米松、地塞米松21-磷酸酯、地塞米松棕榈酸酯、氟氢松、泼尼松、甲泼尼松、乙酸泼尼松龙、氟米龙、曲安西龙、倍他米松、氯替泼诺、氟米松、倍氯米松、二氟泼尼酯和曲安奈德以及它们的衍生物;
非类固醇抗炎剂,如水杨酸盐、吲哚美辛、布洛芬、双氯芬酸、氟比洛芬、昔康类、吡罗昔康以及COX2抑制剂,如罗非昔布、尼美舒利、奈帕芬胺;
β肾上腺素能阻断剂,如噻吗洛尔和其盐,包括顺丁烯二酸噻吗洛尔;盐酸左布诺洛尔以及盐酸倍他洛尔、倍他洛尔、阿替洛尔、倍芬多尔、美替洛尔、佛司可林、卡替洛尔;
细胞因子、白细胞介素、前列腺素(以及抗前列腺素和前列腺素前体),如拉坦前列素、比马前列素或曲伏前列素;
环孢菌素,如环孢菌素A;西罗莫司、他克莫司;
抗氧化剂,如叶黄素、维生素,特别是维生素A;辅酶Q10、多不饱和脂肪酸以及其衍生物;
碳酸酐酶抑制剂,如布林佐胺、多佐胺、乙酰唑胺、醋甲唑胺、二氯苯磺胺;
抗病毒剂,如碘苷、三氟胸苷、阿昔洛韦、伐昔洛韦、更昔洛韦、西多福韦以及干扰素;
抗生素,如氨基糖苷类、碳头孢烯、碳青霉烯类、头孢菌素类、糖肽类、青霉素类、多肽类、喹诺酮类、磺酰胺类、四环素类、氯四环素、杆菌肽、新霉素、多粘菌素、短杆菌肽、头孢氨苄、土霉素、氯霉素、卡那霉素、利福平、妥布霉素、庆大霉素、环丙沙星、氨基糖苷类、红霉素、头孢他啶、万古霉素、亚胺培南;大环内酯类、克拉霉素、阿奇霉素、氟喹诺酮类;
抗细菌剂,如磺酰胺类、磺胺嘧啶、磺胺醋酰、磺胺甲二唑、磺胺异唑、呋喃西林以及丙酸钠;
和/或它们的衍生物;和/或它们的前药;和/或它们的前体;和/或其可接受的盐;单独或组合。
12.根据权利要求1至11中任一项所述的供使用的组合物,其中所述活性成分选自拉坦前列素、噻吗洛尔、多佐胺、奥洛他定、依匹斯汀、阿奇霉素、克拉霉素、环孢菌素A以及西罗莫司、地塞米松、地塞米松棕榈酸酯。
13.根据权利要求1至12中任一项所述的供使用的组合物,其中所述活性成分以控制和/或持续方式被释放12小时至5天、优选地1天至3天范围的时间段。
14.一种用于将根据权利要求1至13中任一项所述的供使用的组合物施用到受试者的上眼睑和/或下眼睑上的装置,其中所述组合物被沉积或浸渍或包被到所述装置上。
15.一种试剂盒,所述试剂盒包含根据权利要求14所述的装置和/或根据权利要求1至13中任一项所述的供使用的组合物。
16.一种用于透皮递送多泡沫体或其成分到受试者的眼睛上以治疗所述受试者的眼睛疾病或眼睛病况的方法,其包括局部施用根据权利要求1至12中任一项所述的组合物到所述受试者的上眼睑和/或下眼睑的步骤。
17.一种用于持续和/或控制释放成分到受试者的眼睛上以治疗所述受试者的眼睛疾病或眼睛病况的方法,其包括局部施用根据权利要求1至12中任一项所述的组合物到所述受试者的上眼睑和/或下眼睑上的步骤。
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ES2797376T3 (es) | 2013-01-24 | 2020-12-02 | Palvella Therapeutics Inc | Composiciones para la administración transdérmica de inhibidores de mTOR |
WO2018129364A1 (en) | 2017-01-06 | 2018-07-12 | Palvella Therapeutics Llc | Anhydrous compositions of mtor inhibitors and methods of use |
CN109820825A (zh) * | 2017-11-23 | 2019-05-31 | 河北嘉硕生物科技有限公司 | 一种用于治疗眼部疾病的药物组合物 |
SG11202010742UA (en) * | 2018-05-01 | 2020-11-27 | Chibi Inc | Liquid depot for non-invasive sustained delivery of agents to the eye |
JP2021530463A (ja) | 2018-07-02 | 2021-11-11 | パルヴェラ セラピューティクス、インク. | mTOR阻害剤の無水組成物および使用方法 |
KR20210130769A (ko) * | 2019-02-20 | 2021-11-01 | 에이아이 테라퓨틱스, 인코포레이티드 | 국소 라파마이신 제형 및 안면 혈관섬유종 및 다른 피부 장애에서의 이의 용도 |
US20230210809A9 (en) * | 2020-10-03 | 2023-07-06 | Pruvyc Pharma, LLC | Method for Treating Pruritus |
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- 2016-02-02 CN CN201680008192.8A patent/CN107205929B/zh active Active
- 2016-02-02 KR KR1020247005121A patent/KR20240023714A/ko not_active Application Discontinuation
- 2016-02-02 KR KR1020177023578A patent/KR102638112B1/ko active IP Right Grant
- 2016-02-02 CN CN202210879763.2A patent/CN115192517A/zh active Pending
- 2016-02-02 EP EP16702437.1A patent/EP3253365A1/en active Pending
- 2016-02-02 TW TW105103254A patent/TWI756168B/zh active
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- 2016-02-02 WO PCT/EP2016/052188 patent/WO2016124601A1/en active Application Filing
- 2016-02-02 US US15/547,909 patent/US20180015166A1/en not_active Abandoned
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2018
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JP2024071469A (ja) | 2024-05-24 |
JP2022163213A (ja) | 2022-10-25 |
CA2975535A1 (en) | 2016-08-11 |
JP2018503670A (ja) | 2018-02-08 |
HK1244431A1 (zh) | 2018-08-10 |
KR102638112B1 (ko) | 2024-02-20 |
WO2016124601A1 (en) | 2016-08-11 |
TWI756168B (zh) | 2022-03-01 |
JP6839653B2 (ja) | 2021-03-10 |
JP7460707B2 (ja) | 2024-04-02 |
KR20170129112A (ko) | 2017-11-24 |
US20180015166A1 (en) | 2018-01-18 |
CA2975535C (en) | 2024-05-28 |
TW201636006A (zh) | 2016-10-16 |
RU2758335C2 (ru) | 2021-10-28 |
CN107205929B (zh) | 2022-06-24 |
RU2017127485A3 (zh) | 2019-09-04 |
KR20240023714A (ko) | 2024-02-22 |
CN115192517A (zh) | 2022-10-18 |
JP2021001217A (ja) | 2021-01-07 |
EP3253365A1 (en) | 2017-12-13 |
RU2017127485A (ru) | 2019-03-04 |
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