CN111295188A - 调节毛发生长的组合物和方法 - Google Patents
调节毛发生长的组合物和方法 Download PDFInfo
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- CN111295188A CN111295188A CN201880063141.4A CN201880063141A CN111295188A CN 111295188 A CN111295188 A CN 111295188A CN 201880063141 A CN201880063141 A CN 201880063141A CN 111295188 A CN111295188 A CN 111295188A
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- acid
- electron transport
- transport chain
- inhibitor
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Abstract
本公开涉及含有电子传递链(ETC)抑制剂的药物组合物,所述药物组合物能够促进毛发生长。本公开还涉及促进毛发生长或治疗影响毛发生长的病症或障碍如秃发或脱发的方法。
Description
相关申请的交叉引用
本申请要求保护在2017年9月29日提交的美国临时专利申请号62/566,031的权益。该申请的内容在此通过引用以其整体并入。
背景技术
毛囊干细胞(HFSC)经历连续几轮静止(静止期),期间间隔着与毛发周期的开始有关的短暂增殖时期(静止期-生长期过渡)。众所周知,HFSC的增殖或激活是毛发周期进展的先决条件。尽管治疗选择有所进步,但秃发和脱发仍然是无法在所有个体中被成功治疗的病症。现有的一些治疗给使用者带来不便,另一些则需要手术干预或其他侵入性程序。需要另外的疗法。
发明内容
在某些方面,本公开提供了包含电子传递链(ETC)的抑制剂的药物组合物。在某些实施方案中,所述药物组合物被配制用于局部施用。
在某些方面,本公开提供了促进毛发生长的方法,其包括向患者施用治疗有效量的本文所述的组合物。
附图说明
图1A至图1D显示用ETC抑制剂的局部处理可以促进毛发周期。图1A:将小鼠在第50天(静止期)剃毛并每隔一天用苯乙双胍(5uM)局部处理,持续2-3周。图像展现了在10天和16天响应于苯乙双胍处理而出现的新的色素沉着及随后的毛发生长,并且H和E染色确认了毛发周期的进展(下图)。图1B:对处理和对照中毛发周期变化的定量。对13只媒介物处理的和9只苯乙双胍处理的雄性小鼠进行定量。图1C:用显微镜评估并定量表皮、真皮和皮下组织厚度的变化。图1D:HFSC(Sox9)和增殖(Ki-67)的标记物的免疫组织化学证明HFSC响应于苯乙双胍、鱼藤酮和抗霉素A的ETC抑制而被激活。A和C的比例尺指示50微米。D的比例尺指示25微米。
图2A和图2B显示局部ETC抑制增加了乳酸产生。图2A:将小鼠用指示的ETC抑制剂局部处理48小时。将总表皮分离,裂解并进行LDH活性测定。相对LDH活性表示为两只不同的动物在30min内的活性比率。图2B:将小鼠用ETC抑制剂局部处理48小时(上图)或10天(下图)。将总表皮分离,提取代谢物并对其进行代谢组学研究。热图指示与糖酵解和TCA循环相关的代谢物的相对水平。
图3A至图3D显示用ETC抑制剂的局部处理可以促进毛发周期。图3A:将小鼠在第50天(静止期)剃毛并每隔一天用抗霉素A或鱼藤酮局部处理,持续2-3周。图像展现了响应于鱼藤酮或抗霉素A处理而出现的新的色素沉着,并且H和E染色确认了毛发周期的进展(下图)。图3B:对处理和对照中毛发周期变化的定量。用13只媒介物处理的、11只鱼藤酮处理的和9只抗霉素A处理的雄性动物进行定量。图3C:用显微镜评估并定量表皮、真皮和皮下组织厚度的变化。图3D:进行免疫定位以检测由于局部施加ETC抑制剂而引起炎症的迹象。将经媒介物和ETC抑制剂二者处理的皮肤针对磷酸化EGFR(趋化因子受体)、CD11b(巨噬细胞的标记物)和IL6(趋化因子)进行免疫染色。将来自具有增生性表皮的受伤动物的经媒介物处理的皮肤用作炎症标记物的阳性对照。比例尺指示50微米。
图4A和图4B。用ETC抑制剂处理可以加速老龄小鼠的毛发周期。图4A:将雌性小鼠在17个月龄时剃毛,然后每隔一天用媒介物或指示的ETC抑制剂处理长达30天。随时间推移拍摄的图像指示,在剃毛后,在老龄小鼠中ETC抑制促进毛发更完全的再生。右侧提供了两对动物出现的表型的定量。显示的数据代表各10只小鼠的三个独立实验。图4B:在A所描绘的毛发周期实验结束时,从来自经ETC抑制剂处理的皮肤的分选HFSC分离出代谢物。热图显示了指示的代谢物的相对水平。
具体实施方式
尽管许多信号传导途径已经参与对成年毛囊干细胞(HFSC)和毛发周期的激活的控制,但对于干细胞控制的细胞内在机制知之甚少。乳酸产生已被鉴定为毛囊干细胞活性的关键细胞内在调节物,这表明细胞代谢在干细胞激活中是重要的。转基因方法已被用于表明电子传递链(ETC)的转基因阻断导致毛囊的退化。然而,本公开提供了组合物和方法,与ETC的完全消融相反,通过所述组合物和方法对ETC活性的药理学消除可以促进毛发周期激活而没有显著的细胞毒性。此外,本文提供的代谢数据表明,ETC抑制导致增加Ldh酶的丙酮酸可及性,因此增加乳酸产生,这可以促进毛发周期的激活。最后,这种ETC抑制类型甚至可以用于加速老龄小鼠的毛发周期。这些结果指向了一种促进毛囊干细胞激活的出乎意料且安全的方法。
在过去的三十年中,已经鉴定了许多信号传导途径作用于HFSC,以既促进静止又促进其激活。关于HFSC调节的内在机制,对于表皮中单个细胞类型的细胞代谢知之甚少。一般而言,已经假定体细胞主要利用电子传递链(ETC)从通过葡萄糖的摄取和加工产生的丙酮酸产生能量,同时早期的胚细胞和癌细胞也被认为依赖于由丙酮酸产生乳酸。HFSC还使通过ETC的能量产生与乳酸产生保持平衡。先前定义表皮中代谢活性的工作集中在整个毛囊上的酶活性的测量。另外,一些研究使用靶向整个表皮(包括毛囊)的转基因模型以使ETC组分缺失。这些研究表明,ETC的基因阻断导致毛囊的退化。然而,尚不清楚对ETC复合物的抑制(与ETC复合物的基因消融相反)会影响细胞代谢还是会影响命运决定。
本公开显示抑制ETC活性引起HFSC的增殖并促进毛发生长。如本文所用,术语“ETC抑制剂”包括能够抑制ETC复合物I、II、III或IV,优选抑制ETC复合物I或III的任何药剂。这些复合物中的每一种的抑制剂是本领域已知的。ETC复合物I的抑制剂包括二甲双胍、苯乙双胍、丁双胍、鱼藤酮、表小檗碱、粉蝶霉素A、阿米妥、辣椒素、氟哌啶醇、利培酮、布比卡因、利多卡因、氟烷、丹曲林、苯妥英(phenyloin)、氯贝特和非诺贝特(fenofibrat)。ETC复合物II的抑制剂包括丙二酸钠、噻吩甲酰三氟丙酮、环磷酰胺和酮康唑。ETC复合物III的抑制剂包括抗霉素A、对乙酰氨基酚、异氟烷和七氟烷。ETC复合物IV的抑制剂包括头孢噻啶、头孢唑啉和头孢噻吩。某些ETC抑制剂大体描述于美国专利号8,993,587中,该专利通过引用并入本文,如同在此完整阐述。
在某些方面,本公开提供了配制用于局部施用的包含电子传递链(ETC)的抑制剂的药物组合物。如本文所述,ETC抑制剂引起HFSC的增殖,从而可以促进毛发的生长。
在某些实施方案中,所述电子传递链抑制剂是电子传递链复合物I、II、III或IV的抑制剂。在某些实施方案中,所述电子传递链抑制剂是二甲双胍、苯乙双胍、丁双胍、鱼藤酮、表小檗碱、粉蝶霉素A、阿米妥、辣椒素、氟哌啶醇、利培酮、布比卡因、利多卡因、氟烷、丹曲林、苯妥英、氯贝特、非诺贝特、丙二酸钠、噻吩甲酰三氟丙酮、环磷酰胺、酮康唑、抗霉素A、对乙酰氨基酚、异氟烷、七氟烷、头孢噻啶、头孢唑啉或头孢噻吩;或其药学上可接受的盐。
在某些实施方案中,所述电子传递链抑制剂是电子传递链复合物I或III的抑制剂。在某些实施方案中,电子传递链抑制剂是二甲双胍、苯乙双胍、丁双胍、鱼藤酮、表小檗碱、粉蝶霉素A、阿米妥、辣椒素、氟哌啶醇、利培酮、布比卡因、利多卡因、氟烷、丹曲林、苯妥英、氯贝特、非诺贝特、抗霉素A、对乙酰氨基酚、异氟烷或七氟烷。在某些实施方案中,电子传递链抑制剂是鱼藤酮、苯乙双胍或抗霉素A。
在某些方面,本公开提供了促进毛发生长的方法,其包括向患者施用治疗有效量的本文所述的包含ETC抑制剂的组合物。在某些实施方案中,所述病症或障碍是秃发或脱发。
药物组合物
本发明的组合物和方法可用于治疗有需要的个体。在某些实施方案中,个体是哺乳动物,例如人或非人哺乳动物。当施用于动物(如人)时,所述组合物或化合物优选作为包含例如本文公开的化合物和药学上可接受的载体的药物组合物施用。药学上可接受的载体是本领域熟知的,并且包括例如水溶液(如水或生理缓冲盐水)或其他溶剂或媒介物(如二醇、甘油、油(如橄榄油)或可注射的有机酯)。在优选的实施方案中,当此类药物组合物用于人施用时,尤其是用于侵入性施用途径(即,避免通过上皮屏障转运或扩散的途径,例如注射或植入),所述水溶液是无热原的或基本上无热原的。可选择赋形剂,例如以实现药剂的延迟释放或选择性地靶向一种或多种细胞、组织或器官。药物组合物可以是剂量单位形式,如片剂、胶囊(包括分散型胶囊和明胶胶囊)、颗粒剂、用于复原的亲液胶体、粉剂、溶液剂、糖浆剂、栓剂、注射剂等。所述组合物还可以存在于透皮递送系统如皮肤贴剂中。所述组合物还可以存在于适于局部施用的溶液如洗剂、乳膏剂或软膏剂中。
药学上可接受的载体可含有生理上可接受的药剂,所述药剂用于例如稳定化合物如本文公开的化合物、增加所述化合物的溶解度或增加所述化合物的吸收。此类生理上可接受的药剂包括例如碳水化合物(例如葡萄糖、蔗糖或葡聚糖)、抗氧化剂(例如抗坏血酸或谷胱甘肽)、螯合剂、低分子量蛋白质或其他稳定剂或赋形剂。药学上可接受的载体(包括生理上可接受的药剂)的选择取决于例如组合物的施用途径。所述制剂或药物组合物可以是自乳化药物递送系统或自微乳化药物递送系统。药物组合物(制剂)也可以是已将例如如本文公开的化合物掺入其中的脂质体或其他聚合物基质。例如包含磷脂或其他脂质的脂质体是无毒的、生理上可接受的并且可代谢的载体,其制备和施用相对容易。
本文采用短语“药学上可接受的”指在合理医学判断范围内,适用于与人类和动物组织接触而没有过量毒性、刺激、过敏反应或其他问题或并发症、与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。
本文所用的术语“药学上可接受的载体”意指药学上可接受的材料、组合物或媒介物,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。在与配制品的其他成分相容并且不损伤患者的意义上,每种载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括:(1)糖,如乳糖、葡萄糖和蔗糖;(2)淀粉,如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,如可可脂和栓剂蜡;(9)油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,如丙二醇;(11)多元醇,如甘油、山梨糖醇、甘露醇和聚乙二醇;(12)酯,如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲溶液;以及(21)药物配制品中使用的其他无毒相容物质。
药物组合物(制剂)可以通过许多施用途径中的任一种施用于受试者,所述施用途径包括例如口服(例如,施加于舌头的呈水性或非水性溶液或混悬液的顿服药(drenches)、片剂、胶囊(包括分散型胶囊和明胶胶囊)、丸剂、粉剂、颗粒剂、糊剂);通过口腔粘膜吸收(如舌下);皮下;透皮(例如作为施加在皮肤上的贴剂);以及局部(例如,作为施加在皮肤上的乳膏剂、软膏剂或喷雾剂)。所述化合物也可配制用于吸入。在某些实施方案中,化合物可以仅溶解或悬浮于无菌水中。合适的施用途径和适合于其的组合物的细节可见于例如美国专利号6,110,973、5,763,493、5,731,000、5,541,231、5,427,798、5,358,970和4,172,896,以及其中引用的专利中。
配制品可以方便地以单位剂型提供,并且可以通过药学领域熟知的任何方法制备。可与载体材料组合以产生单一剂型的活性成分的量将根据所治疗的宿主和特定的施用方式而变化。可与载体材料组合以产生单一剂型的活性成分的量通常是产生治疗效果的化合物的量。通常,在100%中,该量的范围为约1%至约99%的活性成分,优选约5%至约70%,最优选约10%至约30%。
制备这些配制品或组合物的方法包括使活性化合物(如本文公开的化合物)与载体和任选的一种或多种辅助成分缔合的步骤。一般而言,通过使本文公开的化合物与液体载体或细粉状固体载体或两者均一且密切地缔合,然后根据需要使产物成形来制备配制品。
适于口服施用的本发明配制品可以呈胶囊(包括分散型胶囊和明胶胶囊)、扁囊剂、丸剂、片剂、锭剂(使用调味基质,通常为蔗糖和阿拉伯胶或黄蓍胶)、亲液胶体、粉剂、颗粒剂形式或作为水性液体或非水性液体中的溶液或混悬液,或作为水包油或油包水液体乳液,或作为酏剂或糖浆,或作为软锭剂(使用惰性基质,如明胶和甘油,或蔗糖和阿拉伯胶)和/或作为口腔清洗剂等,各自含有预定量的本文公开的化合物作为活性成分。组合物或化合物还可以大丸剂、药糖剂或糊剂形式施用。
为了制备用于口服施用的固体剂型(胶囊(包括分散型胶囊和明胶胶囊)、片剂、丸剂、糖锭剂、粉剂、颗粒剂等),将活性成分与一种或多种药学上可接受的载体(如柠檬酸钠或磷酸二钙)和/或以下物质中的任一种混合:(1)填充剂或增量剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)增湿剂,如甘油;(4)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;(5)溶液缓凝剂,如石蜡,(6)吸收促进剂,如季铵化合物;(7)润湿剂,如鲸蜡醇和单硬脂酸甘油酯;(8)吸附剂,如高岭土和膨润土;(9)润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠以及它们的混合物;(10)络合剂,如改性和未改性的环糊精;以及(11)着色剂。在胶囊(包括分散型胶囊和明胶胶囊)、片剂及丸剂的情况下,药物组合物还可包含缓冲剂。在使用诸如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等赋形剂的软填充和硬填充的明胶胶囊中还可以采用相似类型的固体组合物作为填充剂。
可通过任选地与一种或多种辅助成分一起压制或模制来制备片剂。可使用粘合剂(例如,明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,淀粉乙醇酸钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备压缩片剂。可通过在合适机器中模制用惰性液体稀释剂润湿的粉末状化合物的混合物来制备模制片剂。
药物组合物的片剂和其他固体剂型,如糖锭剂、胶囊(包括分散型胶囊和明胶胶囊)、丸剂和颗粒剂,可以任选地用包衣和壳(例如肠溶衣和药物配制领域中熟知的其他包衣)刻痕或制备。它们也可以进行配制以便使用例如羟丙基甲基纤维素(采用不同比例以提供所需的释放曲线)、其他聚合物基质、脂质体和/或微球来提供其中的活性成分的缓慢或受控释放。它们可以通过例如细菌截留过滤器过滤,或通过掺入呈无菌固体组合物形式的灭菌剂来进行灭菌,可在将要使用前将所述灭菌剂溶解于无菌水或一些其他无菌可注射介质中。这些组合物也可以任选地含有乳浊剂,并且可以具有如下组成,使得它们仅在或优先在胃肠道的某一部分中任选地以延迟方式释放一种或多种活性成分。可以使用的包埋组合物的实例包括聚合物质和蜡。在适当情况下,活性成分也可以是具有一种或多种上述赋形剂的微包封形式。
可用于口服施用的液体剂型包括药学上可接受的乳液、用于复原的亲液胶体、微乳液、溶液、混悬液、糖浆和酏剂。除活性化成分之外,液体剂型还可含有本领域中常用的惰性稀释剂,例如水或其他溶剂、环糊精及其衍生物、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(尤其是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇及脱水山梨糖醇的脂肪酸酯,以及它们的混合物。
除惰性稀释剂之外,口服组合物还可包含佐剂,如润湿剂、乳化剂和助悬剂、甜味剂、调味剂、着色剂、芳香剂和防腐剂。
除活性化合物之外,混悬液还可含有助悬剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶,以及它们的混合物。
用于局部或透皮施用的剂型包括粉剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂和吸入剂。活性化合物可以在无菌条件下与药学上可接受的载体以及与可能需要的任何防腐剂、缓冲液或推进剂混合。
除活性化合物之外,软膏剂、糊剂、乳膏剂和凝胶剂还可含有赋形剂,如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌,或它们的混合物。
除活性化合物之外,粉剂和喷雾剂还可含有赋形剂,如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂可另外含有常用的推进剂(如氯氟烃)和挥发性的未取代的烃(如丁烷和丙烷)。
透皮贴剂具备将本文公开的化合物受控递送至身体的附加优势。此类剂型可通过将活性化合物溶解或分散于合适的介质中来制备。吸收增强剂也可用于增加化合物通过皮肤的通量。这种通量的速率可通过提供速率控制膜或将化合物分散于聚合物基质或凝胶中来控制。
如本文所用的短语“肠胃外施用”和“经肠胃外施用”意指除肠内和局部施用之外的施用方式,通常通过注射,并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心脏内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、被膜下、蛛网膜下、脊柱内和胸骨内注射和输注。适于肠胃外施用的药物组合物包含一种或多种活性化合物与一种或多种药学上可接受的无菌等渗水性或非水性溶液、分散液、混悬液或乳液或无菌粉末的组合,可在即将使用前将所述无菌粉末复原成无菌可注射溶液或分散液,所述注射液或分散液可含有抗氧化剂、缓冲剂、抑菌剂、使配制品与预期受者的血液等渗的溶质或助悬剂或增稠剂。
可用于本发明的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)及其合适的混合物、植物油如橄榄油,以及可注射的有机酯如油酸乙酯。例如,可通过使用包衣材料(如卵磷脂)、通过维持所需的粒度(在分散体的情况下)以及通过使用表面活性剂来维持适当的流动性。
这些组合物还可含有佐剂,如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等)来确保防止微生物的作用。还可以期望在组合物中包含等渗剂如糖、氯化钠等。另外,可以通过包含延迟吸收的药剂如单硬脂酸铝和明胶来实现可注射药物形式的延长吸收。
在一些情况下,为了延长药物的作用,可期望减缓来自皮下或肌内注射的药物的吸收。这可通过使用具有不良水溶性的结晶或非晶形材料的液体混悬液来实现。则药物的吸收速率取决于其溶出速率,而溶出速率又取决于晶体粒度和晶形。可选地,通过将药物溶解或悬浮于油媒介物中来实现肠胃外施用的药物形式的延迟吸收。
通过在可生物降解的聚合物如聚丙交酯-聚乙交酯中形成主题化合物的微胶囊化基质来制备可注射的贮库形式。根据药物与聚合物的比率,以及所用的特定聚合物的性质,可以控制药物释放速率。其他可生物降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。也通过将药物包埋在与身体组织相容的脂质体或微乳液中来制备贮库式可注射配制品。
对于在本发明的方法中的使用,活性化合物可原样提供或以药物组合物形式提供,所述药物组合物含有例如0.1%至99.5%(更优选0.5%至90%)的活性成分以及药学上可接受的载体。
引入方法也可通过可再装填或可生物降解的装置提供。近年来,已开发并体外测试了各种缓释聚合物装置,以用于药物(包括蛋白质生物药物)的受控递送。多种生物相容性聚合物(包括水凝胶),包括可生物降解和不可降解的聚合物,可用于形成用于在特定靶位点持续释放化合物的植入物。
药物组合物中活性成分的实际剂量水平可以改变,以获得对于特定患者、组合物和施用方式有效实现所需治疗效果而不会对患者造成毒性的活性成分的量。
所选剂量水平取决于多种因素,包括所用的特定化合物或化合物组合或其酯、盐或酰胺的活性、施用途径、施用时间、所用一种或多种特定化合物的排泄速率、治疗的持续时间、与所用一种或多种特定化合物组合使用的其他药物、化合物和/或材料、所治疗患者的年龄、性别、体重、状况、一般健康状态和先前的病史,以及医学领域熟知的类似因素。
具有本领域普通技能的医生或兽医可以容易地确定和开出所需药物组合物的治疗有效量。例如,所述医生或兽医可以低于所需的水平开始药物组合物或化合物的剂量,以实现所需的治疗效果,并逐渐增加剂量直至实现所需效果。“治疗有效量”意指足以引发所需治疗效果的化合物浓度。通常,应当理解,化合物的有效量将根据受试者的体重、性别、年龄和病史而变化。影响有效量的其他因素可包括但不限于患者病症的严重程度、所治疗的障碍、化合物的稳定性,以及(如果需要)与本文公开的化合物一起施用的另一类治疗剂。可通过多次施用药剂来递送更大的总剂量。确定功效和剂量的方法是本领域技术人员已知的(Isselbacher等人(1996),Harrison’s Principles of Internal Medicine,第13版,1814-1882,以引用方式并入本文)。
一般来讲,用于本发明组合物和方法中的活性化合物的合适日剂量将是作为有效产生治疗效果的最低剂量的化合物的量。这种有效剂量通常取决于上述因素。
如果需要,活性化合物的有效日剂量可以作为一个、两个、三个、四个、五个、六个或更多个子剂量在全天中以适当的间隔分开施用,任选地以单位剂型施用。在本发明的某些实施方案中,活性化合物可以每天施用两次或三次。在优选的实施方案中,活性化合物每天施用一次。
接受该治疗的患者是任何有需要的动物,包括灵长类动物,尤其是人;以及其他哺乳动物,如马、牛、猪、绵羊、猫和狗;家禽;和一般的宠物。
在某些实施方案中,本发明的化合物可以单独使用或与另一种类型的治疗剂联合施用。
本公开包括本文公开的药剂的药学上可接受的盐在本发明的组合物和方法中的用途。在某些实施方案中,本发明的所考虑盐类包括但不限于烷基、二烷基、三烷基或四烷基铵盐类。在某些实施方案中,本发明的所考虑盐类包括但不限于L-精氨酸、苯乙胺(benenthamine)、苄星青霉素、甜菜碱、氢氧化钙、胆碱、地阿诺、二乙醇胺、二乙胺、2-(二乙氨基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海巴明(hydrabamine)、1H-咪唑、锂、L-赖氨酸、镁、4-(2-羟乙基)吗啉、哌嗪、钾、1-(2-羟乙基)吡咯烷、钠、三乙醇胺、氨丁三醇和锌盐类。在某些实施方案中,本发明的所考虑盐类包括但不限于Na、Ca、K、Mg、Zn或其他金属盐类。在某些实施方案中,本发明的所考虑盐类包括但不限于1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙磺酸、2-氧代戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、乙酸、己二酸、l-抗坏血酸、l-天冬氨酸、苯磺酸、苯甲酸、(+)-樟脑酸、(+)-樟脑-10-磺酸、癸酸(capric acid,decanoic acid)、己酸(caproic acid,hexanoic acid)、辛酸(caprylic acid,octanoicacid)、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、d-葡庚糖酸、d-葡萄糖酸、d-葡萄糖醛酸、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、l-苹果酸、丙二酸、扁桃酸、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、扑酸、磷酸、丙酸、l-焦谷氨酸、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、l-酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸和十一碳烯酸盐类。
药学上可接受的酸加成盐也可以作为如与水、甲醇、乙醇、二甲基甲酰胺等的各种溶剂化物的形式存在。也可以制备此类溶剂化物的混合物。这种溶剂化物的来源可以是来自结晶的溶剂、是制备或结晶的溶剂中固有的或者是这种溶剂中外来的。
润湿剂、乳化剂和润滑剂(如月桂基硫酸钠和硬脂酸镁)以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以存在于组合物中。
药学上可接受的抗氧化剂的实例包括:(1)水溶性抗氧化剂,如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等;(2)油溶性抗氧化剂,如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;以及(3)金属螯合剂,如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
定义
除非本文另外定义,否则本申请中所使用的科学和技术术语将具有由本领域普通技术人员通常所理解的含义。通常,本文所述的与以下结合使用的命名以及其技术是本领域中熟知和常用的那些:化学、细胞和组织培养、分子生物学、细胞和癌症生物学、神经生物学、神经化学、病毒学、免疫学、微生物学、药理学、遗传学以及蛋白质及核酸化学。
除非另有说明,否则通常根据本领域中熟知的常规方法并且如整个本说明书中所引用和讨论的各种通用和更具体的参考文献所描述来执行本公开的方法和技术。参见例如,“Principles of Neural Science”,McGraw-Hill Medical,纽约,纽约州(2000);Motulsky,“Intuitive Biostatistics”,Oxford University Press,Inc.(1995);Lodish等人,“Molecular Cell Biology,第4版”,W.H.Freeman&Co.,纽约(2000);Griffiths等人,“Introduction to Genetic Analysis,第7版”,W.H.Freeman&Co.,纽约州(1999);和Gilbert等人,“Developmental Biology,第6版”,Sinauer Associates,Inc.,桑德兰,马萨诸塞州(2000)。
除非本文另有定义,否则本文中使用的化学术语根据本领域中的常规用法来使用,如由“The McGraw-Hill Dictionary of Chemical Terms”,Parker S.,Ed.,McGraw-Hill,旧金山,加利福尼亚州(1985)所举例说明。
所有以上以及本申请中提及的任何其他出版物、专利和公开专利申请均通过引用明确地并入本文。如有矛盾,以包括其具体定义在内的本说明书为准。
本文使用术语“药剂”来表示化学化合物(如有机或无机化合物、化学化合物的混合物)、生物大分子(如核酸、抗体(包括其部分以及人源化、嵌合和人抗体以及单克隆抗体)、蛋白质或其部分(例如肽)、脂质、碳水化合物)、或由生物材料(如细菌、植物、真菌或动物(尤其是哺乳动物)细胞或组织)制成的提取物。药剂包括例如结构已知的药剂和结构未知的药剂。
“患者”、“受试者”或“个体”可互换使用并且是指人类或非人类动物。这些术语包括哺乳动物如人类、灵长类动物、家畜动物(包括牛、猪等)、伴侣动物(例如,犬、猫科动物等)以及啮齿动物(例如,小鼠和大鼠)。
“治疗”病症或患者是指采取措施以获得有益的或所需的结果,包括临床结果。如本文所用以及本领域中所熟知的,“治疗”是用于获得有益的或所需的结果(包括临床结果)的方式。有益的或所需的临床结果可以包括但不限于一种或多种症状或病症的缓解或改善、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病扩散的预防、疾病进程的延缓或减慢、疾病状态的改善或缓和以及缓解(无论是部分缓解或是全部缓解),无论是可检测的或是不可检测的。“治疗”还可意指与不接受治疗的情况下的预期存活相比延长存活。
术语“预防”是本领域公认的,并且当关于病症(如局部复发(例如,疼痛))、疾病(如癌症)、证候(如心力衰竭)或任何其他医学病症使用时,是在本领域中所熟知的,并且包括施用组合物,相对于不接受所述组合物的受试者,所述组合物减少所述受试者的医学病症的症状的频率,或延缓其发病。因此,癌症的预防包括例如相对于未治疗对照群体,减少接受预防性治疗的患者群体中可检测癌性生长的数量,和/或相对于未治疗对照群体,延缓治疗群体中可检测癌性生长的出现,例如,减少或延缓统计上和/或临床上显著的量。
向受试者“施用(administering或administration)”物质、化合物或药剂可以使用本领域的技术人员已知的各种方法之一来进行。例如,化合物或药剂可通过以下方式施用:静脉内、经动脉、真皮内、肌内、腹膜内、皮下、经眼、舌下、口服(通过摄取)、鼻内(通过吸入)、脊柱内、脑内以及透皮(通过吸收,例如通过皮肤管)。化合物或药剂还可以适当地通过可再装填或可生物降解聚合物装置或其他装置(例如贴剂和泵),或者提供所述化合物或药剂的延长的、缓慢的或受控的释放的配制品引入。施用还可例如进行一次、多次和/或在一个或多个延长时间段内进行。
向受试者施用物质、化合物或药剂的适当方法还将取决于例如受试者的年龄和/或身体状况以及化合物或药剂的化学和生物特性(例如,溶解性、可消化性、生物可用性、稳定性以及毒性)。在一些实施方案中,化合物或药剂例如通过摄取向受试者口服施用。在一些实施方案中,口服施用的化合物或药剂处于延长释放或缓慢释放的配制品中,或者使用用于此缓慢或延长释放的装置来施用。
如本文所用,短语“联合施用”是指两种或更多种不同的治疗剂的任何形式的施用,使得当先前施用的治疗剂在体内仍然有效时施用第二药剂(例如,两种药剂同时在患者中有效,其可以包括两种药剂的协同效应)。例如,不同的治疗化合物可以以相同的配制品或分开的配制品同时或依次施用。因此,接受这种治疗的个体可以受益于不同治疗剂的组合作用。
药物或药剂的“治疗有效量”或“治疗有效剂量”是药物或药剂当向受试者施用时将具有预期的治疗效果的量。完整治疗效果不一定通过施用一次剂量就出现,并且可能仅在施用一系列剂量之后才出现。因此,可以一次或多次施用来施用治疗有效量。受试者所需的精确有效量将取决于例如受试者的体型、健康和年龄,以及受治疗的病症(如癌症或MDS)的性质和程度。熟练技术人员可易于通过常规实验确定给定情况的有效量。
实施例
现已对本发明进行了大体描述,通过参考以下实施例将更易于理解本发明,将这些实施例包括在内仅仅是为了阐明本发明的某些方面和实施方案,并不意图限制本发明。
实施例1:ETC活性对HFSC激活的影响
为了确定对ETC活性的操纵是否会影响HFSC激活,在毛发周期的休止期内将ETC组分的多种抑制剂局部施加于小鼠。通过将活性成分悬浮于PLO Ultramax凝胶(卵磷脂有机凝胶)中来制备局部配制品。在出生后第50天,毛囊处于静止期,即毛囊干细胞处于静止的休止期,直到下一个毛发周期在第70-80天开始为止。鱼藤酮、苯乙双胍和抗霉素A分别是复合物I和复合物III的已确定的抑制剂。将动物在出生后第47天剃毛,并每48小时在剃毛区域用指示的化合物或媒介物处理,持续指示的持续时间。在3-4次处理(8-12天)后,通过黑色小鼠的皮肤的色素沉着判断,经ETC抑制剂处理的动物开始在宏观上显示毛发周期激活的迹象,而经媒介物处理的小鼠至少20天内没有显示显著的色素沉着(图1A和图3A)。鼠皮肤的表皮在诱导毛发周期后发生色素沉着,这指示黑色素细胞的生成,所述黑色素细胞将色素(黑色素)注入进而形成毛干的角化细胞以及毛囊间上皮中的角化细胞中。因此,在经ETC抑制剂处理的小鼠中于8-12天后观察到的色素沉着的诱导最有可能指示该处理所诱导的毛发周期激活。
实施例2:ETC抑制的组织的病理学
为了证明由ETC抑制诱导的色素沉着实际上是由于毛囊干细胞激活的变化所致,收获组织并对其进行病理学检查。组织学分析显示,用ETC抑制剂处理的背部皮肤中的毛囊促进正常的静止期到生长期过渡(图1B和图3B)。这些发现也与先前的研究形成鲜明对比,所述先前的研究显示ETC的转基因消除导致毛囊退化。
实施例3:皮肤厚度测量
为了确定由ETC抑制驱动的毛发周期诱导是否典型,在不同的处理阶段测量了每层皮肤的厚度。如图1C所示,所有的ETC抑制剂都增加了表皮、真皮、尤其是皮下组织的厚度,这表明脂肪细胞的显著扩增。对ETC抑制的皮肤的分析显示了处理后一周HFSC中Ki67的显著增加,这是HFSC响应于ETC抑制而激活的证据(图1D和图3D)。为了确定ETC抑制剂的施加是否促进炎症(这可以解释毛发周期数据),在处理后评估了趋化因子反应的各种标记物和炎性免疫细胞的存在。这些测量没有提供响应于ETC抑制的明显炎症的证据(图3D)。
实施例4:代谢测量
为了确定鱼藤酮、苯乙双胍和抗霉素A引起的ETC抑制对细胞代谢的影响,对代谢途径进行了两次测量。首先,在从用ETC抑制剂处理48小时的表皮分离的细胞上对LDH活性进行了定量(图2A)。接下来,使用代谢组学对经过和未经过48小时或10天处理的分选HFSC进行了研究。这些分析指示了响应于鱼藤酮、苯乙双胍和抗霉素A引起的ETC抑制,乳酸水平以及几种其他糖酵解中间体的增加(图2B)。
实施例5:ETC抑制对老龄小鼠的影响
随着小鼠的衰老,已知毛发周期会变长,使得在剃毛后只有背部皮肤的部分在1-2个月内显示毛发再生。将多个批次的老龄小鼠(至少17个月)用ETC抑制剂处理30天,以确定这种代谢操纵是否即使在休眠的毛囊中也可以刺激毛发周期。苯乙双胍、鱼藤酮或抗霉素A的局部施加都在与更年幼小鼠相似的时程中导致整个背部皮肤更完全的毛发再生(图4A)。与在更年幼的动物中一样,用这些ETC抑制剂处理导致如代谢组学所测量的乳酸池水平升高(图4B)。
通过引用并入
本文提及的所有出版物和专利都是通过引用以其整体特此并入,如同将每个单独的出版物或专利明确地且单独地指示为通过引用并入一般。在出现矛盾的情况下,以本申请(包括本文中的任何定义)为准。
等效物
虽然已经讨论了本发明的具体实施方案,但是上述说明书是说明性的而不是限制性的。在阅读本说明书和以下权利要求之后,本发明的许多变化对于本领域技术人员将变得显而易见。本发明的全部范围应通过参考权利要求及其等效物的全部范围以及说明书以及此类变化来确定。
Claims (9)
1.一种包含电子传递链抑制剂和药学上可接受的赋形剂的药物组合物,其中所述药物组合物被配制用于局部施用。
2.如权利要求1所述的药物组合物,其中所述电子传递链抑制剂是电子传递链复合物I、II、III或IV的抑制剂。
3.如权利要求1所述的药物组合物,其中所述电子传递链抑制剂是二甲双胍、苯乙双胍、丁双胍、鱼藤酮、表小檗碱、粉蝶霉素A、阿米妥、辣椒素、氟哌啶醇、利培酮、布比卡因、利多卡因、氟烷、丹曲林、苯妥英、氯贝特、非诺贝特、丙二酸钠、噻吩甲酰三氟丙酮、环磷酰胺、酮康唑、抗霉素A、对乙酰氨基酚、异氟烷、七氟烷、头孢噻啶、头孢唑啉或头孢噻吩;或其药学上可接受的盐。
4.如权利要求2所述的药物组合物,其中所述电子传递链抑制剂是电子传递链复合物I或III的抑制剂。
5.如权利要求4所述的药物组合物,其中所述电子传递链抑制剂是二甲双胍、苯乙双胍、丁双胍、鱼藤酮、表小檗碱、粉蝶霉素A、阿米妥、辣椒素、氟哌啶醇、利培酮、布比卡因、利多卡因、氟烷、丹曲林、苯妥英、氯贝特、非诺贝特、抗霉素A、对乙酰氨基酚、异氟烷或七氟烷。
6.如权利要求5所述的药物组合物,其中所述电子传递链抑制剂是鱼藤酮、苯乙双胍或抗霉素A。
7.一种促进毛发生长的方法,所述方法包括向患者施用治疗有效量的如权利要求1-6中任一项所述的组合物。
8.一种治疗影响毛发生长的病症或障碍的方法,所述方法包括向患者施用治疗有效量的如权利要求1-6中任一项所述的组合物。
9.如权利要求8所述的方法,其中所述病症或障碍是秃发或脱发。
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