CN110520097B - Mtor抑制剂的无水组合物及其使用方法 - Google Patents
Mtor抑制剂的无水组合物及其使用方法 Download PDFInfo
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- CN110520097B CN110520097B CN201880007899.6A CN201880007899A CN110520097B CN 110520097 B CN110520097 B CN 110520097B CN 201880007899 A CN201880007899 A CN 201880007899A CN 110520097 B CN110520097 B CN 110520097B
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Abstract
本文披露了用于局部递送mTOR抑制剂的组合物和方法。在一个实施例中,无水组合物包含一种或多种mTOR抑制剂、一种或多种溶剂、一种或多种胶凝剂和一种或多种抗氧化剂。本文还披露了使用此类组合物治疗皮肤障碍的方法。
Description
优先权段落
本申请要求2017年1月6日提交的题为“mTOR抑制剂的无水组合物和使用方法(Anhydrous compositions of mTOR inhibitors and methods of use)”的美国临时申请号62/443,117的优先权,该临时申请通过引用结合到本文中。
发明内容
本文披露了用于局部递送mTOR抑制剂的组合物和方法。在一个实施例中,无水组合物包含有效量的一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种胶凝剂和一种或多种抗氧化剂。在一些实施例中,mTOR抑制剂以总组合物的约0.1重量%至约20重量%存在。在一些实施例中,溶剂以总组合物的约1重量%至约99.9重量%存在。在一些实施例中,胶凝剂以总组合物的约0.1重量%至约5重量%存在。在一些实施例中,抗氧化剂以总组合物的约0.001重量%至约1重量%存在。
在另外的实施例中,治疗有此需要的受试者的皮肤障碍的方法包括局部施用有效量的无水组合物,所述无水组合物包含有效量的一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种胶凝剂和一种或多种抗氧化剂。在一些实施例中,mTOR抑制剂以总组合物的约0.1重量%至约20重量%存在。在一些实施例中,溶剂以总组合物的约1重量%至约99.9重量%存在。在一些实施例中,胶凝剂以总组合物的约0.1重量%至约5重量%存在。在一些实施例中,抗氧化剂以总组合物的约0.001重量%至约1重量%存在。
附图说明
图1描绘了施用雷帕霉素组合物(O3、NA21、NA22、NA23、NA17、NA19、NA25、AG14、NA26、NA24、TD201)后雷帕霉素(ng)在组织(组合的表皮和真皮)中的总平均沉积量。使用与平均值的1个标准偏差确定每个误差条(n=5)。
图2描绘了施用雷帕霉素组合物(O3、NA21、NA22、NA23、NA17、NA19、NA25、AG14、NA26、NA24、TD201)后,分别从表皮和真皮回收的雷帕霉素(ng)的总平均量。使用与平均值的1个标准偏差确定每个误差条(n=5)。
图3描绘了施用雷帕霉素组合物(NA22、NA28、NA33、NA34、O11、TD201)后,雷帕霉素(ng)在组织(组合的表皮和真皮)中的总平均沉积量。使用与平均值的1个标准偏差确定每个误差条(n=5)。
图4描绘了施用雷帕霉素组合物(NA22、NA28、NA33、NA34、O11、TD201)后,分别从表皮和真皮回收的雷帕霉素(ng)的总平均量。使用与平均值的1个标准偏差确定每个误差条(n=5)。
具体实施方式
在提供的一系列值的情况下,意图是该范围的上限和下限之间的每个中间值以及该范围内的任何其他陈述或中间的值包含在本公开内容中。例如,如果指出1μm至8μm的范围,则意图明确披露2μm、3μm、4μm、5μm、6μm和7μm,以及大于或等于1μm的值的范围且小于或等于8μm的值的范围。
如在本申请和权利要求中所使用的,单数形式“一(a)”,“一(an)”和“所述(the)”包括复数形式,除非上下文另有明确规定。另外,术语“包括(includes)”表示“包含(comprises)”。
如本文所使用的,所有要求保护的数字术语应被理解为术语“约”置于其前,这意味着加或减使用它的数字的数值的10%。因此,声称“50%”意味着“约50%”并且包括45%-55%的范围。
术语“患者”和“受试者”是可互换的并且可用于意指可用本发明的化合物治疗的任何生物机体。因此,术语“患者”和“受试者”可包括但不限于任何非人哺乳动物、灵长类动物或人。在一些实施例中,“患者”或“受试者”是哺乳动物,诸如小鼠、大鼠、其他啮齿类动物、兔、狗、猫、猪、牛、绵羊、马、灵长类动物、或人。在一些实施例中,患者或受试者是成人、儿童或婴儿。在一些实施例中,患者或受试者是人。
当与mTOR抑制剂结合使用时,“施用”意指向患者施用mTOR抑制剂,从而mTOR抑制剂对其靶向的组织产生积极影响。本文所述的mTOR抑制剂可以单独施用或与其他药物活性剂组合(同时或连续)施用。例如,mTOR抑制剂可以与其他抗癌或抗肿瘤剂组合施用,或与其他用于治疗皮肤障碍的疗法组合施用。在一些实施例中,本文所述的mTOR抑制剂还可以与其他治疗剂组合施用(即,作为组合的组合物或作为单独的组合物)。
组合物的“有效量”是计算的预定量,用以达到所需效果,即改进、预防或改善患者的不期望病症、疾病或症状。适当时,本方法考虑的活性可以包括治疗和/或预防性治疗。根据本发明所给予的药剂获得治疗和/或预防效果的具体剂量当然将通过病例周围的具体情况确定,包括例如,所施用的化合物、施用途径、和正在治疗的病症。有效给药量可由医师根据包括治疗病症、施用化合物的选择、和选择的施用途径等有关情况确定。
本文所用的术语“载体”包括载体、赋形剂和稀释剂,意指材料、组合物或载体,如:液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料,其涉及携带或运输药物、化妆品或其他药剂穿过组织层(如角质层或棘层)。
与“包括(including)”,“含有(containing)”或“特征在于(characterized by)”同义的过渡术语“包含(comprising)”是包含性的或开放式的,并且不排除另外的、未列举的要素或方法步骤。相反,过渡短语“由……组成”排除了权利要求中未指定的任何要素、步骤或成分。过渡短语“基本上由……组成”将权利要求的范围限制于指定的材料或步骤和“那些不会对要求保护的发明的基本和新颖特征产生实质影响的材料或步骤”。在将术语“包含”用作过渡短语的实施例或权利要求书中,此类实施例还可以设想用术语“由……组成”或“基本上由……组成”替换术语“包含”。
术语“治疗”在本文中用于例如治疗皮肤障碍或全身病症的方法,并且通常包括施用化合物或组合物,所述化合物或组合物降低医学病症症状的频率或延迟其发作,或相对于未接受化合物或组合物的受试者,增强受试者组织表面的预期组织治疗区域的质地、外观、颜色、感觉或水合作用。这可以包括以改善或稳定受试者病症的方式逆转、减少或阻止病症的症状、临床体征和潜在病理学。
除非另有说明,否则术语“障碍”在本公开中用于表示疾病、病症或疾患,并且可与其互换使用。
适当时,本文披露的重量百分比可以是重量-重量或重量-体积百分比。
本文披露了mTOR抑制剂的无水组合物。在一些实施例中,无水组合物包含一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种胶凝剂和一种或多种抗氧化剂。
在一些实施例中,mTOR抑制剂的无水组合物在表皮中具有约120-990微摩尔的Cmax,在真皮中具有约36-350微摩尔的Cmax。在一些实施例中,mTOR抑制剂的无水组合物在表皮中具有约15-24小时的Tmax。在一些实施例中,通过可接受的局部生物利用度研究测量,无水组合物被认为与如本文所述的包含mTOR抑制剂的无水组合物是生物等效的或基本上生物等效的。
在一些实施例中,无水组合物包含至少一种mTOR抑制剂。mTOR抑制剂的非限制性实例是雷帕霉素(西罗莫司)、依维莫司、吡美莫司、地磷莫司、特罗莫司、佐他莫司、雷帕霉素前药AP-23573、AP-23481、torin-1、torin-2、WYE-354、达托利司、沃他利司、奥帕利司、阿托利司、维妥舍替、吉托利司、WYE-125132、BGT226、palomid 529、GDC-0349、XL388、CZ415、CC-223、ABT-578、SF1126、PKI-587、INK128、AZD8055、NVPBE235、AZD2014、biolimus A9(乌罗莫司)、GSK2126458、OSI027、PP121、WYE-687、WAY-600、XL765、PI-103、BEZ235、KU-0063794、Torkinib(PP242)、PF-04691502及其药学上可接受的盐、水合物、溶剂化物或无定形固体,以及其组合。
在一些实施例中,mTOR抑制剂还包括TOR复合物1的特异性抑制剂,TOR复合物2的特异性抑制剂等。在一个实施例中,可用于抑制TOR复合物2的药剂包括但不限于小分子、核酸、蛋白质和抗体。小分子包括但不限于吡啶酮喹啉、吡唑并嘧啶和吡啶并嘧啶。在另一个实施例中,抑制TOR复合物1和2的小分子包括Torin 1、Torin 2、torkinib(PP242)、PP30、KU-0063794、WAY-600、WYE-687、WYE-354、AZD8055、INK128、OS1027、AZD2014、奥帕利司、渥曼青霉素、LY294002、PI-103、BGT226、XL765和NVP-BEZ235。在进一步的实施例中,抑制剂包括但不限于反义寡核苷酸、siRNA、shRNA及其组合。在进一步的实施例中,抑制TOR复合物2的药剂不会抑制TOR复合物1。
在一些实施例中,无水组合物可以进一步包含调节mTOR途径的其他化合物,例如他克莫司、二甲双胍等。
在一些实施例中,mTOR抑制剂以总组合物的约0.1重量%至约20重量%,总组合物的约0.1重量%至约15重量%,总组合物的约0.1重量%至约10重量%,总组合物的约0.1重量%至约4.5重量%,总组合物的约0.1重量%至约2重量%,或总组合物的约0.1重量%至约1重量%,以及这些值中任两个之间的任何单独的量或任何范围存在。在一些实施例中,本文披露的重量百分比可以是重量-重量或重量-体积百分比。非限制性实例包括约0.1重量%、约0.5重量%、约0.8重量%、约1重量%、约1.5重量%、约2重量%、约2.5重量%、约3重量%、约3.5重量%、约4重量%、约4.5重量%、约5重量%、约10重量%、约15重量%或约20重量%。在一些实施例中,mTOR抑制剂是雷帕霉素,并且以总组合物的约0.1重量%至约10重量%存在。
在一些实施例中,调节mTOR途径的化合物以总组合物的约0.1重量%至约20重量%,总组合物的约0.1重量%至约15重量%,总组合物的约0.1重量%至约10重量%,总组合物的约0.1重量%至约4.5重量%,总组合物的约0.1重量%至约2重量%,或总组合物的约0.1重量%至约1重量%,以及这些值中任两个之间的任何单独的量或任何范围存在。在一些实施例中,本文披露的重量百分比可以是重量-重量或重量-体积百分比。非限制性实例包括约0.1重量%、约0.5重量%、约1重量%、约1.5重量%、约2重量%、约2.5重量%、约3重量%、约3.5重量%、约4重量%、约4.5重量%、约5重量%、约10重量%、约15重量%或约20重量%。
在一些实施例中,无水组合物可含有一种或多种促进mTOR抑制剂溶解的溶剂。在一些实施例中,溶剂包括醇、多元醇、酰胺、酯、丙二醇醚及其混合物。醇或多元醇的非限制性实例包括乙醇、异丙醇、丁醇、苄醇、乙二醇、丙二醇、PEG 400、PEG 3350、SR-PEG 400、SR-DMI、油醇、蓖麻油、miglyol 810、液体石蜡、丙二醇二辛酸酯/二癸酸酯、丁二醇及其异构体、甘油、甘油三乙酸酯、季戊四醇、山梨糖醇、甘露醇、卡毕醇P(二乙二醇单乙醚)、卡毕醇HP、己二酸二异丙酯、二甲基异山梨醇、聚乙二醇、聚丙二醇、聚乙烯醇、羟丙基甲基纤维素和其他纤维素衍生物、环糊精和环糊精衍生物以及其混合物。酰胺的实例包括2-吡咯烷酮、2-哌啶酮、ε-己内酰胺、N-烷基吡咯烷酮、N-羟烷基吡咯烷酮、N-烷基哌啶酮、N-烷基己内酰胺、二甲基乙酰胺、聚乙烯吡咯烷酮以及其混合物。酯的实例包括丙酸乙酯、柠檬酸三丁酯、乙酰基柠檬酸三乙酯、乙酰基柠檬酸三丁酯、柠檬酸三乙酯、油酸乙酯、辛酸乙酯、丁酸乙酯、三乙酸甘油酯、丙二醇单乙酸酯、丙二醇二乙酸酯、ε-己内酯及其异构体、δ-戊内酯和其异构体、β-丁内酯及其异构体以及其混合物。
在一些实施例中,溶剂包括苄醇、DMSO、二甘醇、丙二醇单辛酸酯(Capryol 90)、二乙二醇单乙醚四氢糠醇聚乙二醇醚(glycofurol)、丁二醇、丙二醇、二乙二醇、三乙二醇以及其组合。更优选地,在一些实施例中,溶剂包括丙二醇单辛酸酯、苄醇、四氢糠醇聚乙二醇醚以及其组合。在一些实施例中,无水组合物不含乙醇。在一些实施例中,无水组合物含有小于10重量%、小于8重量%、小于6重量%、小于4重量%或小于2重量%的苄醇。在一些实施例中,无水组合物不含苄醇。
在一些实施例中,溶剂以总组合物的约1重量%至约99.9重量%,总组合物的约1重量%至约90重量%,总组合物的约1重量%至约80重量%,总组合物的约1重量%至约70重量%,总组合物的约1重量%至约60重量%,总组合物的约1重量%至约50重量%,总组合物的约1重量%至约40重量%,总组合物的约1重量%至约30重量%,总组合物的约80重量%至约99.9重量%,总组合物的约85重量%至约99.9重量%,总组合物的约90重量%至约99.9重量%,或总组合物的约95重量%至约99.9重量%存在。非限制性实例包括约1重量%、约25重量%、约40重量%、约50重量%、约60重量%、约75重量%、约80重量%、约85重量%、约90重量%、约92重量%、约94重量%、约95重量%、约96重量%、约97重量%、约99重量%或约99.9重量%。
在一些实施例中,无水组合物包含一种或多种胶凝剂,例如泊洛沙姆和卡波姆。泊洛沙姆的非限制性实例是泊洛沙姆P-188、泊洛沙姆P-138、泊洛沙姆P-237、泊洛沙姆P-288、泊洛沙姆P-124、泊洛沙姆P-338和泊洛沙姆P-407。其他嵌段共聚物,如聚(乙二醇/DL丙交酯共-甘油酯)聚(ε-己内酰胺)、羟丙基纤维素三12-羟基硬脂酸甘油酯、羟基硬脂酸甘油酯、碳酸丙烯酯、聚乙烯吡咯烷也可以用作胶凝剂。可以使用的卡波姆的非限制性实例是卡波姆981、卡波姆934、卡波姆934P、卡波姆940、卡波姆941、卡波姆1342、聚卡波非和聚卡波非钙。在一个优选的实施例中,胶凝剂选自羟丙基纤维素、卡波姆981、卡波姆934P、三12-羟基硬脂酸甘油酯、羟基硬脂酸甘油酯、碳酸丙烯酯、聚乙烯吡咯烷以及其组合。在一些实施例中,胶凝剂以总组合物的约0.1重量%至约5重量%,总组合物的约0.1重量%至约4重量%,总组合物的约0.1重量%至约3重量%,总组合物的约0.1重量%至约2重量%,或总组合物的约0.1重量%至约1重量%存在。
在一些实施例中,无水组合物包含一种或多种抗氧化剂,例如抗坏血酸、维生素E及其衍生物、α-生育酚、ψ-生育酚、δ-生育酚、抗坏血酸棕榈酸酯、没食子酸丙酯(PG)、没食子酸辛酯、十二烷基没食子酸酯、丁基化羟基苯甲醚(BHA)和丁基化羟基甲苯(BHT)、和D-α-生育酚聚乙二醇1000琥珀酸酯。在一些实施例中,抗氧化剂以总组合物的约0.001重量%至约1重量%,总组合物的约0.001重量%至约0.5重量%,总组合物的约0.001重量%至约0.1重量%,总组合物的约0.001重量%至约0.05重量%,或总组合物的约0.001重量%至约0.01重量%存在。
在一些实施例中,无水组合物包含有效量的一种或多种mTOR抑制剂(其以总组合物的约0.1重量%至约20重量%存在),一种或多种溶剂(其以总组合物的约1重量%至约99重量%存在),一种或多种胶凝剂(其以总组合物的约0.1重量%至约5重量%存在),和一种或多种抗氧化剂(其以总组合物的约0.001重量%至约1重量%存在)。
在一些实施例中,无水组合物包含有效量的一种或多种mTOR抑制剂(其以总组合物的约0.1重量%至约10重量%存在),一种或多种溶剂(其以总组合物的约1重量%至约70重量%存在),和一种或多种胶凝剂(其以总组合物的约0.1重量%至约4重量%存在),和一种或多种抗氧化剂(其以总组合物的约0.01重量%至约1重量%存在)。
在一些实施例中,无水组合物包含有效量的一种或多种mTOR抑制剂(其以总组合物的约1重量%至约10重量%存在),一种或多种溶剂(其以总组合物的约10重量%至约70重量%存在),一种或多种胶凝剂(其以总组合物的约1重量%至约5重量%存在),和一种或多种抗氧化剂(其以总组合物的约0.01重量%至约0.5重量%存在)。
在一些实施例中,无水组合物包含有效量的一种或多种mTOR抑制剂(其以总组合物的约1重量%至约5重量%存在),一种或多种溶剂(其以总组合物的约10重量%至约50重量%存在),一种或多种胶凝剂(其以总组合物的约1重量%至约4重量%存在),和一种或多种抗氧化剂(其以总组合物的约0.001重量%至约0.01重量%存在)。
在一些实施例中,无水组合物包含有效量的一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种抗氧化剂并且没有胶凝剂。
在一些实施例中,mTOR抑制剂的无水组合物还包含聚合物表面活性剂、保湿剂、冷却剂、流变改性剂、pH调节剂、防腐剂及其组合。
在一些实施例中,mTOR抑制剂的无水组合物包含一种或多种聚合物表面活性剂。具有表面活性剂性质的聚合物(聚合物表面活性剂)可以是但不限于疏水改性的聚丙烯酸(商品名PemulenTM TR-I和TR-2)、基于丙烯酰胺基烷基磺酸和环状N-乙烯基羧酰胺的共聚物(商品名AVC)、基于丙烯酰胺基烷基磺酸和疏水改性的甲基丙烯酸的共聚物(商品名/>HMB)、和丙烯酰胺基烷基磺酸的均聚物(商品名Granthix APP)。另一类值得注意的聚合物乳化剂包括疏水改性的交联的阴离子丙烯酸共聚物,包括无规聚合物,但也可以以其他形式存在,例如嵌段、星形、接枝等。在一个实施例中,疏水改性的交联的阴离子丙烯酸共聚物可以由至少一种酸性单体和至少一种疏水性烯键式不饱和单体合成。合适的酸性单体的实例包括那些可被碱中和的烯键式不饱和酸单体。合适的疏水性烯键式不饱和单体的实例包括含有碳链长度为至少约3个碳原子的疏水链的那些单体。可以是合适的聚合物表面活性剂的其他材料可包括以商品名/>销售的环氧乙烷/环氧丙烷嵌段共聚物、改性纤维素聚合物,例如由商品名/>(羟丙基纤维素)描述的那些改性纤维素聚合物、单体阴离子表面活性剂、单体两性表面活性剂、甜菜碱以及其组合。其他合适的聚合物表面活性剂包括基于丙烯酰胺基烷基磺酸和环状N-乙烯基羧酰胺和/或线性N-乙烯基羧酰胺(例如/>AVC和/>HMB)和甜菜碱的共聚物。在优选的实施例中,聚合物表面活性剂包括泊洛沙姆P-188、泊洛沙姆P-138、泊洛沙姆P-237、泊洛沙姆P-288、泊洛沙姆P-124、泊洛沙姆P-338、泊洛沙姆P-407、D-α-生育酚聚乙二醇1000琥珀酸酯、Brij 020以及其组合。在一些实施例中,聚合物表面活性剂以总组合物的约0.1重量%至约50重量%,总组合物的约0.1重量%至约40重量%,总组合物的约0.1重量%至约30重量%,总组合物的约0.1重量%至约20重量%,或总组合物的约0.1重量%至约10重量%存在。
在一些实施例中,mTOR抑制剂的无水组合物还可包含一种或多种保湿剂或润肤剂组分,例如矿物油、二甲硅油、环甲硅油、胆固醇或其组合。在一些实施例中,无水组合物包括液体润肤剂,例如多羟醇、多元醇、糖类、甘油三酯、烃类、硅氧烷、脂肪酸、脂肪酯、脂肪醇以及其掺混物。在一些实施例中,保湿剂以总组合物的约0.5重量%至约10重量%,总组合物的约0.5重量%至约8重量%,总组合物的约0.5重量%至约6重量%,总组合物的约0.5重量%至约4重量%,或总组合物的约0.5重量%至约1重量%存在。
在一些实施例中,mTOR抑制剂的无水组合物包含一种或多种冷却剂,例如L-薄荷醇、对薄荷烷-3,8-二醇、异胡薄荷醇、薄荷氧基丙-1,2-二醇、乳酸薄荷酯(例如ML)、姜辣素、icilin、茶树油、水杨酸甲酯、樟脑、薄荷油、N-乙基-对薄荷烷-3-甲酰胺、3-(对薄荷烷-3-甲酰胺基)乙酸乙酯、2-异丙基-N,2,3-三甲基丁酰胺、薄荷酮甘油缩酮、薄荷酮甘油缩醛、coolact 10;WS3、WS5、WS23、戊二酸薄荷酯以及其混合物。在一些实施例中,冷却剂以总组合物的约0.5重量%至约10重量%,总组合物的约0.5重量%至约8重量%,总组合物的约0.5重量%至约6重量%,总组合物的约0.5重量%至约4重量%,或总组合物的约0.5重量%至约2重量%存在。
在一些实施例中,本文披露的无水组合物不含水。在一些实施例中,本文披露的无水组合物基本上不含水。在一些实施例中,本文披露的无水组合物在总组合物中含有少于1%的水。在一些实施例中,本文披露的无水组合物在总组合物中含有少于0.5%的水。在一些实施例中,本文披露的无水组合物在总组合物中含有少于0.1%的水。
在一些实施例中,mTOR抑制剂的无水组合物还包含流变改性剂、pH调节剂、防腐剂以及其组合。
本发明的组合物还可进一步包含具有增稠性质的聚合物(流变改性剂)。在一个实施例中,具有增稠性质的聚合物可以是疏水改性的交联丙烯酸酯共聚物(Ultrez 20)。也可以使用具有类似性质的其他聚合物。具有增稠性质的聚合物的非限制性实例可包括PEG-150二硬脂酸酯、PEG-7甘油基椰油酸酯、PEG-200氢化甘油基棕榈酸酯、PEG-120甲基葡萄糖二油酸酯、羧基亚甲基聚合物、羧基乙烯基聚合物、丙烯酸酯、C10-C30烷基丙烯酸酯交联聚合物、肉豆蔻酸异丙酯以及其组合。在一些实施例中,具有增稠性质的聚合物可占约0.1重量%至约3重量%。在另一个实施例中,具有增稠性质的聚合物可以以总组合物的0.4重量%至约1.0重量%的量存在。在一个实施例中,具有增稠性质的聚合物占总组合物的约0.5重量%至约0.75重量%。在一些实施例中,增稠聚合物可与表面活性剂聚合物混合。
在一些实施例中,本发明的组合物可进一步包含非水性pH调节剂或非水性缓冲剂,其存在于组合物中用以中和和/或活化增稠聚合物,以促进具有所需流变性质的组合物的形成。可以使用本领域已知的并且适用于皮肤接触施用的任何无水碱或缓冲系统。在一个实施例中,碱可包括三乙醇胺、乙二胺四乙酸四钠(EDTA)、碱金属氢氧化物如氢氧化钠(NaOH)、弱酸盐如乳酸铵、柠檬酸钠、抗坏血酸钠或其混合物。碱组分还提供了实用性,因为可以将整个组合物的pH调节至有利于最小化由于pH效应引起的皮肤刺激的范围。在一些实施例中,本发明的组合物还可以包括无水酸或缓冲系统的酸组分,并且可以使用本领域已知的并且适合人体皮肤接触的任何酸。可用于本发明组合物并通常用于调节局部组合物的pH的酸的实例包括但不限于:柠檬酸、乳酸、抗坏血酸、酒石酸和盐酸,以及这些和类似酸的组合。在一些实施例中,将磷酸盐缓冲系统用于组合物中。在一些实施例中,组合物还包含磷酸盐缓冲系统和Brij 020。在一些实施例中,将磷酸盐/柠檬酸盐缓冲系统用于组合物中。在一些实施例中,组合物含有磷酸盐/柠檬酸盐缓冲液和Brij020。组合物的pH值的具体实例包括约pH 4、约pH 4.5、约pH 5、约pH 5.6、约pH 6、约pH 7、约pH 7.4、约pH 8、以及这些值中任两个之间的范围。
本文披露的组合物可进一步包含用以防止有害微生物生长的防腐剂。虽然微生物倾向于在水相中生长,但微生物也可以存留于油相中。因此,在本发明的组合物中优选使用在油中具有溶解性的防腐剂。通常,十分之一重量百分比至百分之一重量百分比的防腐剂就足够了。用于化妆品和药物的传统防腐剂是对羟基苯甲酸的烷基酯。最近投入使用的其他防腐剂包括乙内酰脲衍生物、丙酸盐、阳离子表面活性剂如苯扎氯铵;苄醇、山梨酸和各种季铵化合物。化妆品化学家熟悉适当的防腐剂,并经常选择他们以满足防腐剂挑战测试并提供产品稳定性。用于本发明优选的无水组合物的特别优选的防腐剂是苯氧基乙醇、苯乙醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、咪唑烷基脲和季铵-15。应该考虑组合物的用途和防腐剂与组合物中其他成分之间可能的不相容性来选择防腐剂。
在一些实施例中,无水组合物是用于mTOR抑制剂的受控释放的持续释放组合物,用以减少所施用药剂的快速摄取和全身吸收。持续(或受控)释放是指在经一段时间内,mTOR抑制剂从组合物中逐渐释放。虽然可能存在初始爆发阶段,但在一些实施例中,优选的是,释放显示相对线性的动力学,从而在释放期间提供mTOR抑制剂的恒定供应。释放期可在约1小时至约8小时之间变化,这取决于皮肤障碍及其预期用途。该组合物可进一步包含用以促进缓慢释放的各种可生物降解的聚合物,例如聚丙交酯(PLA)、聚乙交酯(PGA)、聚丁二酸丁二醇酯(PBS)、聚羟基烷酸酯(PHA)、聚己内酯酸内酯(PCL)、聚羟基丁酸酯(PHB)、乙醇酸戊基(PHV)、PHB和PHV共聚物(PHBV)和聚乳酸(PLA)-聚乙二醇(PEG)共聚物(PLEG)。在一些实施例中,优选的聚合物是127。
在一些实施例中,本文披露的无水组合物的黏度通常是稠液体或凝胶的黏度,但可以达到糊状稠度。通常,黏度最小为约5,000、10,000或15,000,优选约20,000至最大约12,000,000、2,000,000或甚至约600,000cP。
mTOR抑制剂的无水组合物可根据需要包含其他成分。例如,其可含有另外的活性成分,例如,皮质类固醇、抗生素、抗真菌剂和/或抗病毒剂。此外,其可包含一种或多种其他赋形剂,例如渗透增强剂(DMSO、 薄荷醇、油酸、正烷醇、1-烷基-2-吡咯烷酮、N,N-二甲基烷酰胺和1,2-烷二醇等)等。
在一些实施例中,组合物可进一步包含其他皮肤护理剂,包括但不限于视黄醇、类固醇、防晒剂、水杨酸盐、米诺环素、抗真菌剂、肽、抗体、利多卡因和同类物及其组合。在一些实施例中,其他皮肤护理剂包括N-酰基氨基酸化合物,包括例如N-酰基苯丙氨酸、N-酰基酪氨酸和同类物及其异构体,包括其D和L异构体、盐、衍生物和混合物。合适的N-酰基氨基酸的实例是N-十一碳烯酰基-L-苯丙氨酸,可以商品名商购获得。其他皮肤活性剂包括但不限于Lavandox、Thallasine 2、六胜肽(Argireline)NP、Gatuline In-Tense和Gatuline Expression、Myoxinol LS 9736、Syn-ake和/>SesaflashTM、N-乙酰基D-葡糖胺、泛醇(例如,可从Alps制药公司(Alps Pharmaceutical Inc.)获得的DL泛醇)、生育酚烟酸酯、过氧化苯甲酰、3-羟基苯甲酸、类黄酮(例如,黄烷酮、查尔酮)、法呢醇、植烷三醇、乙醇酸、乳酸、4-羟基苯甲酸、乙酰水杨酸、2-羟基丁酸、2-羟基戊酸、2-羟基己酸、顺式视黄酸、反式视黄酸、视黄醇、视黄酯(例如丙酸视黄酯)、植酸、N-乙酰基-L-半胱氨酸、硫辛酸、生育酚及其酯(例如,生育酚乙酸酯:DL-α-生育酚乙酸酯,购自卫材公司(Eisai))、壬二酸、花生四烯酸、四环素、布洛芬、萘普生、酮洛芬、氢化可的松、对乙酰氨基酚、间苯二酚、苯氧乙醇、苯氧基丙醇、苯氧异丙醇、2,4,4'-三氯-2'-羟基二苯醚、3,4,4'-三氯二苯脲、吡啶酮乙醇胺盐、盐酸利多卡因、克霉唑、咪康唑、酮康唑、硫酸新霉素、茶碱及其混合物。
可以将一种或多种防晒剂掺入本发明的无水组合物中。可以使用各种防晒剂,包括对氨基苯甲酸衍生物,例如对-(2-乙基己基)二甲基氨基苯甲酸酯,和二苯甲酮衍生物,例如(2-羟基-4-甲氧基苯基)苯基甲酮、MexorylTM SX和MexorylTM XL、对苯二亚甲基二樟脑磺酸和甲酚曲唑三硅氧烷。其他非限制性实例包括二苯甲酮(羟苯甲酮和舒利苯酮)、肉桂酸酯(辛基甲氧基肉桂酸酯和甲氧桂乙酯)、水杨酸酯(胡莫柳酯)邻氨基苯甲酸酯、TiO2、阿伏苯宗、双-乙基乙氧苯酚甲氧苯基三嗪(bemotrizinol)、bisoctrizole、3-(4-甲基亚苄基)-樟脑、西诺沙酯、苯甲酸二乙氨基羟基苯甲酰己酯、二苯甲酮、甲酚曲唑三硅氧烷、依茨舒、乙基己基三嗪酮、胡莫柳酯、邻氨基苯甲酸酯、奥克立林、水杨酸辛酯、二乙基己基丁酰胺基三嗪酮、异戊烯基-4-甲氧基肉桂酸酯、辛基-二甲基-对氨基苯甲酸、辛基-甲氧基肉桂酸酯、氧苯酮、聚硅氧烷-15、水杨酸三乙醇胺和ZnO。本发明组合物中使用的防晒剂的确切量将根据对太阳有害射线所需的防护程度而变化。
本发明的无水组合物还可包含用以使组合物着色的一种或多种颜料,和用以使组合物对嗅觉系统舒缓的香料,例如Firmenich和Co.66.001/NY/G香料油。存在于组合物中的这些成分的量将取决于所需的特定效果。
在实施例中,无水组合物可以是固体剂型,包括但不限于局部剂型,包括但不限于溶液、粉末、流体悬浮液、半固体、软膏、糊剂、乳膏、洗剂、凝胶、果冻和泡沫;以及肠外剂型,包括但不限于溶液、悬浮液和干粉。活性成分可以与药学上可接受的稀释剂、填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、疏水媒介物、乳化剂、缓冲剂、湿润剂、保湿剂、增溶剂、防腐剂等一起包含在此类组合物中。这些化合物的药物组合物还可包括合适的固体或凝胶相载体或赋形剂。这些载体或赋形剂的实例包括但不限于碳酸钙、磷酸钙、明胶和聚合物(比如,例如聚乙二醇)。
在一些实施例中,本文披露的无水组合物可以是糊剂、液体、洗剂、喷雾剂、气溶胶、粉末、软膏、乳膏、漱口水、牙膏、泡沫、凝胶、固体棒及其组合的形式。在一些实施例中,本文披露的组合物易于涂抹、快速吸收、保湿、不油腻、对患者皮肤无刺激、使用美观并具有清凉效果。
在实施例中,文中所述组合物可以配制成液体。用于局部施用的液体剂型可包括稀释剂,比如例如醇、二醇、油等。此类组合物还可包括润湿剂或乳化剂。在一些实施例中,实施例的组合物可以配制成水包油或油包水乳液。乳膏可以是油包水(w/o)乳液,其中水相分散在油相中,或水包油(o/w)乳液,其中油分散在水基中。软膏通常是指更粘稠的水包油乳膏。传统的软膏基质(即载体)包括烃(凡士林、蜂蜡等)植物油、脂肪醇(胆固醇、羊毛脂、羊毛醇、硬脂醇等)或硅酮。不溶性固体如淀粉、氧化锌、碳酸钙或滑石也可用于软膏和乳膏中。上述组合物的凝胶形式可以通过在聚合物网络或胶体固体颗粒网络中捕获大量含水或含水-醇液体来形成。这种聚合物或胶体(胶凝剂或增稠剂)通常以低于10重量%的浓度存在并且包括羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、甲基纤维素、海藻酸钠、海藻酸、果胶、黄芪胶、角叉菜、琼脂、粘土、硅酸铝、卡波姆等。
在一些实施例中,本文披露的组合物中的mTOR抑制剂在延长的时间段内是稳定的。例如,在一些实施例中,组合物中的mTOR抑制剂在约4℃至约50℃的温度范围内稳定12-36个月。在一些实施例中,组合物中的mTOR抑制剂在约4℃至约45℃的温度范围内稳定12-36个月。在一些实施例中,组合物中的mTOR抑制剂在约4℃至约40℃的温度范围内稳定12-36个月。在一些实施例中,组合物中的mTOR抑制剂在约4℃至约35℃的温度范围内稳定12-36个月,在一些实施例中,组合物中的mTOR抑制剂在约4℃至约30℃的温度范围内稳定12-36个月。
本文还披露了治疗受试者的皮肤障碍的方法。在一些实施例中,治疗受试者的皮肤障碍的方法包括局部施用有效量的无水组合物,所述无水组合物包含有效量的一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种胶凝剂和一种或多种抗氧化剂。
在一些实施例中,治疗受试者的皮肤障碍的方法包括局部施用有效量的无水组合物,所述无水组合物包含有效量的一种或多种mTOR抑制剂,一种或多种溶剂和一种或多种抗氧化剂。
可以通过无水组合物治疗的皮肤障碍的非限制性实例包括足底角化过度、水疱、结节性硬化、脂溢性角化病、毛发角化病、大疱性表皮松解症、多发性微指状角化过度、持久性豆状角化过度、淤积性皮炎、局灶性肢端角化过度、毛囊角化过度、苔藓样角化病(扁平苔藓、硬化性苔藓)、慢性糜烂性口腔苔藓、Conradi-Eltinermann、表皮松解性鱼鳞病、变异性红斑角化病、高起鱼鳞病、KID综合征、内瑟顿(Netherton)综合征、奥莫斯得(Olmsted)综合征、雷弗素姆氏病、舍格伦-拉松(Sjogren-Larsson)综合征、光化性角化病、先天性厚甲症、多汗症、疣、老茧、皮炎(接触性皮炎、药物性皮炎、过敏性皮炎、钱币状皮炎、口周皮炎、神经性皮炎、脂溢性皮炎和特应性皮炎)、牛皮癣、痤疮、痈病、蜂窝织炎、疖病、肉芽肿、黑棘皮病、脚癣、细菌性阴道病、龟头炎、隆突性皮肤纤维肉瘤、基底细胞癌、鳞状细胞癌、黑色素瘤、默克细胞癌、瘢痕疙瘩、囊性淋巴管瘤、海绵状淋巴管瘤、静脉畸形、表皮痣、臭汗症、皮肤癣菌病、念珠菌病、甲癣、皮癣(白癣、足癣、甲癣、手癣、股癣、体癣、头癣、面癣、须癣、叠瓦癣、黑癣、花斑癣、隐匿性癣)、湿疹、汗疱性湿疹、褥疮性溃疡、脓疮、丹毒、多形性红斑、脓疱疮、昆虫叮咬、生殖器疣、血管瘤、疱疹、荨麻疹、多汗症、丝虫病、痣、狼疮、痱子、挤奶人结节、传染性软疣、蝇蛆病、疥疮、皮肤幼虫移行症、疖性蝇蛆病、迁移性蝇蛆病、虱子病、蜘蛛痣、脂膜炎、甲沟炎、类天疱疮、糠疹、外阴瘙痒、酒渣鼻、滴虫、阴道酵母菌感染、白癜风、干皮症、血管纤维瘤、Bannayan-Riley-Ruvalcaba综合征、基底细胞痣综合征、Birt-Hogg-Dube综合征、蓝色橡皮泡痣综合征、考登病(Cowden disease)、皮肤T细胞淋巴瘤、弥漫性微囊性淋巴管畸形、单纯性大疱性表皮松解症、乳房外帕吉特病(extramammary paget)、家族性多发性盘状纤维瘤、海利-海利(Hailey-Hailey)病、婴幼儿血管瘤、幼年型息肉息肉综合征、卡波西肉瘤、卡波西形(Kaposiform)血管内皮瘤、瘢痕疙瘩、Lhermitte-Duclos综合征、转移性黑色素瘤、Muir-Torre综合征、神经纤维瘤病、非黑色素瘤皮肤癌、口腔移植抗宿主病、寻常型天疱疮、Peutz-Jeghers综合征、葡萄酒色斑、普罗特斯(Proteus)综合征、普罗特斯(Proteus)样综合征、马夫奇综合征难治性血管内皮瘤(refractoryhemangioendotheliomas in Maffucci syndrome)、斯特奇-韦伯(Sturge-Weber)综合征、犬遗传性足跖角化过度(HFH)、表皮结节病、皮肤卡斯尔门病、大疱性类天疱疮及其组合。
在一些实施例中,所治疗的皮肤障碍是血管纤维瘤。在一些实施例中,所治疗的皮肤障碍是先天性厚甲症。在一些实施例中,治疗先天性厚甲症的症状,并且症状选自疼痛、瘙痒或其组合。
在一些实施例中,组合物的施用是通过局部施用。
在一些实施例中,局部施用mTOR抑制剂的无水组合物,并且mTOR抑制剂通过吸收到达表皮和真皮层。在一些实施例中,无水组合物的局部施用不会导致mTOR抑制剂的全身吸收。
在一些实施例中,无水组合物的局部施用导致mTOR抑制剂递送至皮肤表皮。在一些实施例中,无水组合物的局部施用导致mTOR抑制剂递送至表皮和真皮。
在一些实施例中,治疗皮肤障碍的方法包括局部施用无水组合物,所述无水组合物包含一种或多种mTOR抑制剂(其以总组合物的约0.1重量%至约20重量%存在),一种或多种溶剂(其以总组合物的约1重量%至约99重量%存在),一种或多种胶凝剂(其以总组合物的约0.1重量%至约5重量%存在),和一种或多种抗氧化剂(其以总组合物的约0.001重量%至约1重量%存在)。在一些实施例中,组合物可进一步包含聚合物表面活性剂,保湿剂,冷却剂,流变改性剂,pH调节剂,防腐剂及其组合。在一些实施例中,无水组合物不含胶凝剂。
在一些实施例中,可以将无水组合物局部施用于皮肤,优选通过在皮肤上手动摩擦施加的量以彻底涂覆皮肤。摩擦动作优选是轻柔摩擦或按摩至少约5秒,优选约5至约30秒以遍及皮肤。存在于皮肤上的水分或水可能由于连续摩擦和按摩而乳化无水组合物,导致在皮肤上原位形成乳液。
本发明的一些实施例涉及治疗受试者脱发的方法。在一些实施例中,治疗脱发的方法包括向有此需要的受试者施用有效量的无水组合物,所述无水组合物包含有效量的一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种胶凝剂和一种或多种抗氧化剂。在实施例中,与毛发、毛干、毛囊、毛球、油腺及其组分有关的疾病的治疗包括例如脱发、头皮屑、脂溢性皮炎、斑秃、毛发病、癣、头癣、毛囊炎、模式脱发、休止期脱发、乳痂、拔毛癖、牵引性脱发、结节性脆发症、脱发性毛囊炎、头虱感染、前额纤维化脱发、非瘢痕性脱发、石棉状糠疹、头皮切割性蜂窝组织炎、颈项部瘢痕性痤疮、念珠状发、虱病、全秃、假斑状秃发、泡沫毛发畸形、毛发管型、多毛症、毛发内生、念珠状发、头发过早变白、模式脱发、套叠性脆发症等。
可将本文披露的组合物局部施用于身体的选定区域,期望在该区域减少毛发生长。例如,可将组合物施用于面部,特别是面部的胡须区域,即面颊、颈部、上唇和下巴。该组合物还可以用作其他脱毛方法的辅助剂,包括剃须、打蜡、机械脱毛、化学脱毛、电解和激光辅助脱毛。除了减少头发之外,作出其创意外观的其他作用是并发的皮肤益处。该组合物还可以施用于腿部、手臂、躯干或腋窝。该组合物适用于例如减少女性中不需要的毛发的生长。在人中,组合物可以每天施用一次或两次,或甚至更频繁,以实现感觉到的毛发生长减少。例如,当毛发生长速度减慢,对去除的需要减少,受试者感觉到处理部位上的毛发较少时,或者定量地,当去除毛发的重量(即毛发质量)降低时,证明毛发生长减少。
本发明的一些实施例涉及治疗受试者的干眼症的方法。在一些实施例中,治疗干眼症的方法包括向有此需要的受试者施用有效量的无水组合物,所述无水组合物包含一种或多种mTOR抑制剂,一种或多种溶剂,一种或多种胶凝剂和一种或多种抗氧化剂。
在一些实施例中,本发明的无水组合物可以例如施用于膏药、贴剂、绷带或薄膜。在一些实施例中,通过使用超声技术辅助局部递送。将超声能量施加在组织上并帮助组合物扩散通过组织。
在实施例中,本文披露的组合物可以是透皮贴剂的形式。透皮贴剂可以是任何常规形式,比如例如条带、纱布、薄膜等。贴剂材料可以是非织造的或织造的(例如,纱布敷料)。也可以在加工过程中层压出层。其可以是非封闭的或封闭的,但后者对于背衬层是优选的。优选地,贴剂被气密密封用于储存(例如,箔包装)。贴剂可以保持在皮肤上,并且贴剂的组分可以使用各种粘合剂保持在一起。例如,透皮贴剂可以是创可贴型装置的形式,或者其可以包装在小的金属或塑料“杯子”中,使用粘合剂、胶带或外部织物或皮带将其绑在适当的部位上,类似于手表的一部分。整个贴剂可以是一次性的或可以是可再填充的。在一些实施例中,本文披露的组合物可以涂覆在绷带上,与生物粘合剂混合,或包含在敷料中。
在一些实施例中,手动泵可用于分配mTOR抑制剂无水组合物。例如,手动泵可以被配置成在由政府管理机构批准的相应标签规定的公差范围内分配所需剂量的mTOR抑制剂。手动泵每次泵动作可输送0.5-10mL组合物,例如每次泵动作1、2、3、4或5mL组合物。在一些实施例中,mTOR抑制剂组合物可与药学上可接受的手动泵一起包装。
在一些实施例中,无水组合物可以通过他们保留活性的任何途径以常规方式施用。例如,mTOR抑制剂的无水组合物可以通过包括但不限于局部、透皮或经皮的途径施用。因此,化合物的施用模式(单独或与其他药物组合)可以是,但不限于,舌下,或通过使用阴道乳膏、栓剂、子宫托、阴道环、直肠栓剂、以及经皮和局部形式例如贴剂和乳膏、乳液、凝胶。
当然,施用的组合物的特定量将由其使用的特定环境决定,包括施用的组合物、皮肤状况、使用者的年龄、皮肤障碍的程度和类似的考虑因素。例如,剂量可取决于所治疗的具体动物、受试者的年龄、体重和健康状况、同时治疗的类型(如果有的话)和治疗频率。本领域技术人员(例如,临床医生)可以容易地确定这些因素中的许多因素。通常,组合物的单次施用将局部施用以充分覆盖受影响的皮肤区域。可根据需要进行后续施用以递送所需水平的mTOR抑制剂。
在一些实施例中,组合物可以每天施用一次、两次、三次、四次、五次或更多次,并且施用可以进行至少1个月、2个月、3个月、4个月、6个月、8个月或12个月。
在一些实施例中,组合物可根据需要施用一次、每日一次、每日两次、每日三次、每周一次、每周两次、每隔一周、每隔一天等,持续一个或多个给药周期。给药周期可包括施用约1周、约2周、约3周、约4周、约5周、约6周、约7周、约8周、约9周或约10周。在该周期之后,随后的周期可以在约1、2、3、4、5、6、7、8、9、10、11或12周后开始。治疗方案可包括1、2、3、4、5或6个周期,每个周期间隔开约1、2、3、4、5、6、7、8、9、10、11或12周。
在实施例中,治疗皮肤障碍的方法包括施用本文所述的无水组合物,其中所述方法不进一步包括用于治疗皮肤障碍的任何另外的医学或治疗干预。
在实施例中,治疗皮肤障碍的方法包括施用本文所述的无水组合物,其中mTOR抑制剂是用于治疗皮肤障碍所施用的唯一活性剂。
在一些实施例中,所述方法可包括多种额外步骤,包括例如在施用部位清洁表面组织等。
在实施例中,所述方法可以进一步包括在施用本文所述的组合物之前,期间或之后对组织表面进行除垢或清创。在实施例中,用于对组织表面除垢或清创的方法可包括电磁辐射、激光、皮肤磨损、化学剥离、超声、加热、冷却或通过针。
在实施例中,通过磨蚀对组织表面进行除垢或清创。皮肤外层或表皮的磨损(皮肤磨损)对于平滑或混合疤痕,瑕疵或可能由例如痤疮、日晒和老化引起的其他皮肤状况是合乎需要的。用于磨损皮肤的标准技术通常被分成两个领域,称为皮肤磨削和微晶皮肤磨削。两种技术都去除了称为角质层的表皮部分,身体将其解释为轻度损伤。然后身体取代损失的皮肤细胞,产生新的皮肤外层。此外,尽管存在与手术相关的轻度水肿和红斑,但由于新的皮肤外层,皮肤看起来和感觉更光滑。
在实施例中,组织表面用微晶皮肤磨削除垢或清创。微晶皮肤磨削通常是指由于通过发射沙子或沙砾流的手持件进行机械摩擦而去除皮肤表面的过程。例如,手持件可用于引导含有微小氧化铝、氯化钠或碳酸氢钠晶体的气流。随着手持件的每次通过,沙砾的动量趋向于磨损皮肤的两到三个细胞层。替代地,新的“无晶体”微晶皮肤磨削技术使用没有沙砾流的金刚石尖头手持件。
在实施例中,组织表面用电磁辐射进行除垢或清创,例如使用所谓的点阵激光治疗。举例来说,这种方法采用电磁辐射(EMR),其具有在约1,850与100,000纳米之间的一个或多个波长并且具有在约1飞秒(1×10-15s)与10毫秒(10×10-3s)之间的脉冲宽度,注量范围为约1J/cm2至300J/cm2。在其他实例中,组织用具有约2,200与5,000纳米之间的一个或多个波长的电磁辐射进行除垢或清创。在又其他实例中,组织用具有约190与320纳米之间的一个或多个波长的电磁辐射进行除垢或清创,注量范围为1J/cm2至300J/cm2。任选地,选择用于对组织部分清创的条件使组织损伤的凝固区域最小化,例如通过将凝固区域保持在围绕烧蚀空隙的相对小的直径。
电磁辐射(EMR),特别是以激光或其他光学辐射的形式,已经用于各种化妆品和医学应用,包括用于皮肤病学、牙科学、眼科学、妇科学、五官科学和内科学。对于大多数皮肤病学应用,可以使用将EMR递送至一个或多个靶组织表面的装置进行EMR治疗。EMR治疗通常被设计成(a)向组织递送一个或多个特定波长(或特定连续波长范围)的能量以诱导特定的化学反应,(b)向组织递送能量以引起温度升高或(c)向组织递送能量以损坏或破坏细胞或细胞外结构,例如用于皮肤重塑。在美容手术(例如皮肤再生)期间用于治疗皮肤的装置的实例包括LuxIR、/>1540、1440和2940Fractional Handpieces、ReliantSR Laser以及科医人公司(Lumenis)、阿尔玛激光公司(Alma Lasers)、斯科顿公司(Sciton)的类似装置和许多其他装置。
在实施例中,所述方法还可包括在施用本文所述组合物之前,期间或之后的光动力疗法。光动力疗法是一种微创两步医疗手术,其使用称为光敏剂的可光活化药物来治疗一系列疾病。首先,施用光敏剂,并且一旦其渗透靶组织,然后通过暴露于特定波长的一定剂量的电磁(通常是光)辐射来激活光敏剂。本文披露的组合物可含有光敏剂。在实施例中,本文可使用任何合适的光敏剂或药剂混合物。通常,这些将吸收约380nm至约900nm范围内的辐射。如本文所用,“光敏剂”或“光敏制剂”优选意指当与特定波长的辐射接触时形成单线态氧或热能的化合物。光敏剂的非限制性实例包括氨基乙酰丙酸酯、卟啉、卟啉衍生物、菌绿素、异菌绿素、酞菁、萘酞菁、焦脱镁叶绿酸、sapphyrin、得克萨卟啉、四氢卟吩、紫茜素、卟烯、吩噻嗪和金属络合物,例如但不限于锡、铝、锌、镥和锡本紫红素乙酯(SnET2)及其组合。
本发明的组合物还可以与其他活性成分或其他相容的药物或化合物组合施用,其中这种组合被认为是实现本文所述方法的所需效果所需或有利的。
通过参考以下非限制性实例,可以进一步理解本发明和说明所用方法和材料的实施例。
实例
实例1:
以下描述了示例性无水组合物:
实例2
以下描述了示例性无水组合物:
实例3
以下描述了示例性无水组合物:
组分 | 重量% | 作用 |
辛酸/癸酸甘油三酯 | 30.45% | 药物溶剂 |
卡毕醇 | 10% | 共溶剂 |
三缩四乙二醇(Glycofural) | 25% | 共溶剂 |
丙二醇 | 5% | 皮肤渗透增强剂/溶剂 |
肉豆蔻酸异丙酯 | 8% | 润肤剂/增稠剂 |
WS5 | 1.05% | 冷却剂 |
雷帕霉素 | 2.2% | API |
抗坏血酸棕榈酸酯 | 0.3% | 抗氧化剂 |
环甲硅油 | 10% | 润肤剂 |
二甲硅油 | 5% | 润肤剂 |
卡波姆 | 3% | 胶凝剂 |
实例4:
以下描述了示例性无水组合物(NA 17):
实例5:
以下描述了示例性无水组合物(NA 19):
实例6:
以下描述了示例性无水组合物(NA 21):
实例7:
以下描述了示例性无水组合物(NA 22):
实例8:
以下描述了示例性无水组合物(NA 23):
实例9:
以下描述了示例性无水组合物(NA 24):
实例10:
以下描述了示例性无水组合物(NA 25):
实例11:
以下描述了示例性无水组合物(NA 26):
实例12:
以下描述了示例性软膏组合物(O3):
组分 | 重量% | 作用 |
雷帕霉素 | 4.59 | API |
PEG400 | 34.34 | 溶剂 |
卡必醇P | 47.998 | 渗透增强剂/溶剂 |
PEG 3350 | 13 | 溶剂 |
没食子酸丙酯 | 0.05 | 抗氧化剂 |
抗坏血酸棕榈酸酯 | 0.02 | 抗氧化剂 |
α-生育酚 | 0.002 | 抗氧化剂 |
实例13:
以下描述了示例性含水组合物(TD201):
实例14:
以下描述了示例性无水组合物(NA 28):
实例15:
以下描述了示例性无水组合物(NA 33):
实例16:
以下描述了示例性无水组合物(NA 34):
实例17:
以下描述了示例性软膏组合物(O 11):
组分 | 重量% | 作用 |
雷帕霉素 | 2.5 | API |
PEG400 | 43 | 溶剂 |
丙二醇 | 1.5 | 渗透增强剂/溶剂 |
卡必醇P | 29.45 | 渗透增强剂/溶剂 |
水 | 7.8 | 溶剂 |
苄醇 | 2 | 溶剂 |
油醇 | 0.75 | 溶剂 |
PEG 3350 | 13 | 溶剂 |
没食子酸丙酯 | 0.05 | 抗氧化剂 |
抗坏血酸棕榈酸酯 | 0.02 | 抗氧化剂 |
α-生育酚 | 0.002 | 抗氧化剂 |
实例18:
离体皮肤渗透试验
将人供体皮肤置于上隔室与下隔室之间。下隔室填充有接收液。将各种雷帕霉素组合物施用于面向上隔室的皮肤表面上(11种制剂(即O3、NA21、NA22、NA21、NA17、TD201、NA19、NA25、AG14、NA26和NA24),n=6个重复,剂量10mg/cm2)并放置24小时。使用正位移移液管将制剂(约10mg/cm2)施加到1mL注射器的柱塞。将制剂(10+/-0.5mg)施用于皮肤表面并使用柱塞遍布在扩散区域上。在施用之前和之后,记录柱塞的重量,由此计算剂量/细胞。
在该时间段之后,从皮肤表面擦去过量的雷帕霉素组合物,并将皮肤层分成角质层、表皮和真皮。使用胶带剥离程序将角质层从人体皮肤除去。通过在60℃下干燥加热2分钟将表皮与真皮分离。用90:10v/v乙醇:水溶剂混合物从各层中提取雷帕霉素,并量化。还分析了下隔室中的接收液中雷帕霉素的存在。
如所预期的,24小时后在皮肤表面上发现最大量的雷帕霉素。此外,似乎存在于表皮中的药物多于角质层或真皮层。此外,随着时间的推移,表皮和真皮中定量的雷帕霉素的量增加。在整个试验期间的任何时间点都没有在接收液中检测到雷帕霉素,这表明雷帕霉素没有完全通过皮肤层。
如图1和2所示,渗透试验的结果显示,与TD201相比,施用所有制剂后表皮药物回收率的相似性,NA24除外,其中从TD201皮肤回收的药物量高8倍。与TD201相比,从O3观察到真皮中的药物量显著更高(p<0.02),但是所有其他制剂在统计学上是相当的,但NA21,NA22和NA23表现出比在TD201中观察到的更高的平均真皮水平。当考虑将药物递送至总组织,即组合的表皮和真皮时,所有制剂显示出与TD201在统计学上相似的药物回收率。
此外,如图3和4所示,渗透试验的结果表明,与O11相比,施用NA22、NA33和NA28后,显著更高量的雷帕霉素被递送至表皮(p<0.05),而所有其他比较在统计学上是相似的(即TD201表现类似于所有无水制剂)。此外,当考虑皮肤药物递送水平时,NA22优于TD201、NA34和O11,在该皮肤层中的沉积显著高于上述制剂(p<0.05)。结果表明,与制剂TD201相比,NA22表现出增强的真皮药物递送和相当的表皮递送。
总之,与含水组合物AG14和TD201相比,无水组合物在皮肤层中显示出显著量的雷帕霉素沉积。
实例19:评估局部生物利用度
皮肤药代动力学(DPK)研究
皮肤药代动力学(DPK)方法与应用于角质层的血液、血浆、尿PK方法相当。DPK包括关于时间的药物浓度测量,并提供关于药物摄取、表观稳态水平和基于角质层浓度-时间曲线的角质层药物消除的信息。
试验和参考产品的施用和去除:在不会干扰或损坏角质层/皮肤情况下使用模板标记治疗区域。治疗区域的大小取决于多种因素,包括药物强度、分析灵敏度、药物扩散程度和暴露时间。角质层对某些环境因素是高度敏感的。为避免偏倚并保持在试验方便性和准确性的限度内,治疗部位和手臂将随机化。如下面更详细描述的,摄取、稳态和消除阶段可以在受试者的右臂与左臂之间随机化。每个阶段的暴露时间点可以在每个臂上的各个部位之间随机化。特定暴露时间点的试验和参考产品可以施用于部位以最小化差异。试验和参考产品应根据之前开发和验证的SOP同时施用于相同的受试者。预先标记的部位将用预定量的产品(例如,5mg/sq cm)治疗并用非封闭的护罩覆盖。仅在产品标签中建议时使用封闭。将在指定的时间点根据SOP进行药物产品的去除,使用多个棉签或Q-tip避免角质层损伤。在某些油性制剂如软膏的情况下,在皮肤剥离之前可能需要用温和的肥皂洗涤该区域。如果进行洗涤,其将成为SOP的一部分。
施用部位和时长:生物利用度/生物等效性(BA/BE)研究将包括角质层中药物摄取和皮肤中药物消除的测量。将使用最少八个部位来评估每种产品的摄取/消除。在角质层中达到稳态的时间将用于确定样品的时间。例如,如果药物在3小时内达到稳态,则可以选择治疗后0.25、0.5、1和3小时以确定摄取,并且可以使用4、6、8和24小时来评估消除。将选择每个受试者的零时间点(远离测试部位的对照部位)以提供基线数据。如果在两个前臂上研究测试/参考药物产品,则可以指定一个臂上的随机选择的部位来测量药物摄取/稳态。然后可以指定对侧臂上的部位来测量药物消除。在药物摄取过程中,过量的药物去除和角质层剥离时间都是相同的,因此在去除过量药物后立即剥离角质层。在消除期中,过量的药物将在稳态时间点从这些部位除去,并且将在接下来的时间经24小时收获角质层以提供对消除期的估计。
样品收集:首先使用市售产品(例如D-Squame,Transpore),用两个胶带条/盘施用去除前1-2层角质层,进行皮肤剥离。这前两个胶带包含通常未被吸收(与渗透或吸收相反)的药物,因此将与其余的带条分开分析。来自每个部位的剩余角质层将以指定的时间间隔剥离。这通过用额外的10个胶带条剥离部位来实现。将从给定时间点获得的所有十个带条组合和提取,其中药物含量使用经验证的分析方法确定。该值通常表示为量/面积(例如,ng/cm2),以保持报告值的一致性。可以计算数据以获得测试和参考产品的整个药物浓度-时间曲线、Cmax-ss、Tmax-ss和AUC。
皮肤剥离程序:
评估药物摄取:测试和/或参考药物产品将同时施用于多个部位。在适当的间隔后,用组织或棉签轻轻擦拭三次,从特定部位去除过量的药物。使用来自初步研究的信息,将确定用于评估药物摄取的样品收集的适当时间。使用均匀的压力重复施加胶带两次,丢弃前两个胶带条。将在同一部位继续剥离以收集另外十个角质层样品。应注意避免污染其他场所。将在其他指定时间点对每个部位重复该过程。从组合的十次皮肤剥离中提取药物,并使用经验证的分析方法确定浓度。将结果表示为每平方厘米胶带处理区域的药物量。
评估药物消除:测试和参考药物产品将同时施用于基于初步研究结果选择的多个部位。将允许足够的暴露时间以达到明显的稳态水平。如前所述,将去除皮肤表面的过量药物,包括前两次皮肤剥离。将基于初步研究以多个时间间隔使用十个连续的胶带条收集皮肤剥离样品,并且将分析药物含量。
度量和统计分析:将构建角质层药物浓度对时间曲线图,以产生Cmax、Tmax和AUC的角质层度量。通过构建测试和参考平均值之间的比率的90%置信区间(CI),将测试α=0.05显著性水平下的两个单侧假设的AUC和Cmax。将报告单个受试者参数以及概要统计(平均值、标准差、变异系数、90%CI)。对于测试产品为BE,测试和参考处理的平均值比率(基于对数转换数据的群体几何平均值)的90% CI对于AUC将落在80-125%内,对于Cmax将落在70-143%内。
体内真皮开放流微灌注
在真皮开放流微灌注(dOFM)中,将一个细中空管插入皮肤表面下方,穿过皮肤部分几英寸宽然后退出。将类似于体液的液体注入管中;皮肤下面的一部分管是多孔的,因此任何已经通过皮肤外层施加和吸收的药物都会进入流动的液体,然后将其收集用于分析。在局部施用皮肤病药物产品后,dOFM可以可靠地测量皮肤中药物的变化量。
Claims (18)
1.一种mTOR抑制剂的局部无水组合物,其包含:
基于组合物的总重量的2.5重量%至4.5重量%的雷帕霉素或其药学上可接受的盐,
基于组合物的总重量的80重量%至97重量%的溶剂,其中所述溶剂为基于组合物的总重量的1重量%至30重量%的己二酸二异丙酯,基于组合物的总重量的1重量%至30重量%的甘油,基于组合物的总重量的40重量%至60重量%的聚乙二醇,以及基于组合物的总重量的1重量%至30重量%的异丙醇,
基于组合物的总重量的0.1重量%至5重量%的胶凝剂,以及
基于组合物的总重量的0.001重量%至1重量%的抗氧化剂,
其中,该组合物的总重量为100重量%,以及
其中,所述局部无水组合物的pH值为4至6。
2.根据权利要求1所述的局部无水组合物,其中所述溶剂以所述组合物的总重量的90%至97%存在。
3.根据权利要求1所述的局部无水组合物,其中所述组合物还包含聚合物表面活性剂、保湿剂、冷却剂、流变改性剂、pH调节剂、防腐剂及其组合。
4.根据权利要求1所述的局部无水组合物,其中所述组合物包含:
所述组合物的3重量%至4.5重量%的雷帕霉素;
所述组合物的40重量%至60重量%的聚乙二醇;
所述组合物的15重量%的异丙醇;
所述组合物的15重量%的己二酸二异丙酯;
所述组合物的10重量%的甘油;
所述组合物的0.1重量%至1重量%的羟丙基纤维素;
所述组合物的0.001重量%至0.1重量%的抗氧化剂;以及
缓冲液。
5.根据权利要求1所述的局部无水组合物,其中所述组合物包含:
所述组合物的3.9重量%的雷帕霉素;
所述组合物的15重量%的异丙醇;
所述组合物的55.3重量%的聚乙二醇;
所述组合物的15重量%的己二酸二异丙酯;
所述组合物的10重量%的甘油;
所述组合物的0.75重量%的羟丙基纤维素;
所述组合物的0.05重量%的没食子酸丙酯;
所述组合物的0.02重量%的抗坏血酸棕榈酸酯;
所述组合物的0.002重量%的α-生育酚;以及
缓冲液。
6.根据权利要求1所述的局部无水组合物,其中所述组合物是局部无水凝胶组合物。
7.根据权利要求1所述的局部无水组合物,其中所述组合物不含苯甲醇。
8.根据权利要求1所述的局部无水组合物,其还包含另外一种药学上可接受的赋形剂。
9.权利要求1-8中任一项所述的局部无水组合物在制备用于治疗受试者的皮肤障碍的药物中的用途。
10.根据权利要求9所述的用途,其中所述皮肤障碍选自由以下组成的组:足底角化过度、水疱、结节性硬化、脂溢性角化病、毛发角化病、大疱性表皮松解症、多发性微指状角化过度、持久性豆状角化过度、局灶性肢端角化过度、毛囊角化过度、苔藓样角化病、慢性糜烂性口腔苔藓、Conradi-Eltinermann、表皮松解性鱼鳞病、变异性红斑角化病、高起鱼鳞病、KID综合征、内瑟顿综合征、奥莫斯得综合征、雷弗素姆氏病、舍格伦-拉松综合征、光化性角化病、先天性厚甲症、多汗症、疣、老茧、皮炎、牛皮癣、痤疮、痈病、蜂窝织炎、疖病、肉芽肿、黑棘皮病、细菌性阴道病、龟头炎、隆突性皮肤纤维肉瘤、基底细胞癌、鳞状细胞癌、黑色素瘤、默克细胞癌、瘢痕疙瘩、囊性淋巴管瘤、海绵状淋巴管瘤、静脉畸形、臭汗症、念珠菌病、甲癣、皮癣、湿疹、褥疮性溃疡、脓疮、丹毒、多形性红斑、脓疱疮、昆虫叮咬、血管瘤、疱疹、荨麻疹、丝虫病、痣、狼疮、痱子、挤奶人结节、蝇蛆病、疥疮、皮肤幼虫移行症、虱子病、脂膜炎、甲沟炎、类天疱疮、糠疹、外阴瘙痒、酒渣鼻、滴虫、阴道酵母菌感染、白癜风、干皮症、血管纤维瘤、Bannayan-Riley-Ruvalcaba综合征、基底细胞痣综合征、Birt-Hogg-Dube综合征、蓝色橡皮泡痣综合征、考登病、皮肤T细胞淋巴瘤、弥漫性微囊性淋巴管畸形、乳房外帕吉特病、家族性多发性盘状纤维瘤、海利-海利病、幼年型息肉综合征、卡波西肉瘤、卡波西形血管内皮瘤、瘢痕疙瘩、Lhermitte-Duclos综合征、Muir-Torre综合征、神经纤维瘤病、非黑色素瘤皮肤癌、口腔移植抗宿主病、寻常型天疱疮、Peutz-Jeghers综合征、葡萄酒色斑、普罗特斯综合征、普罗特斯样综合征、马夫奇综合征难治性血管内皮瘤、斯特奇-韦伯综合征、犬遗传性足跖角化过度(HFH)、表皮结节病、皮肤卡斯尔门病、大疱性类天疱疮及其组合。
11.根据权利要求9所述的用途,其中所述皮肤障碍选自由以下组成的组:扁平苔藓、硬化性苔藓、接触性皮炎、药物性皮炎、过敏性皮炎、钱币状皮炎、口周皮炎、神经性皮炎、脂溢性皮炎、特应性皮炎、白癣、足癣、甲癣、手癣、股癣、体癣、头癣、面癣、须癣、叠瓦癣、黑癣、花斑癣和隐匿性癣。
12.根据权利要求9所述的用途,其中所述皮肤障碍选自由以下组成的组:淤积性皮炎、汗疱性湿疹、生殖器疣、传染性软疣、脚癣、表皮痣、蜘蛛痣、疖性蝇蛆病、迁移性蝇蛆病和婴幼儿血管瘤。
13.根据权利要求9所述的用途,其中所述皮肤障碍是先天性厚甲症或其症状。
14.根据权利要求9所述的用途,其中所述皮肤障碍是血管纤维瘤。
15.根据权利要求9所述的用途,其中所述皮肤障碍是基底细胞痣综合征。
16.根据权利要求9所述的用途,其中所述皮肤障碍是大疱性表皮松解症。
17.根据权利要求9所述的用途,其中所述皮肤障碍是单纯性大疱性表皮松解症。
18.根据权利要求9所述的用途,其中所述皮肤障碍是转移性黑色素瘤。
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