CN113710225A - 活性剂在皮肤内的递送和保留 - Google Patents
活性剂在皮肤内的递送和保留 Download PDFInfo
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- CN113710225A CN113710225A CN202080026763.7A CN202080026763A CN113710225A CN 113710225 A CN113710225 A CN 113710225A CN 202080026763 A CN202080026763 A CN 202080026763A CN 113710225 A CN113710225 A CN 113710225A
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Abstract
本申请描述了包括能够渗透皮肤的药剂的***的合成、调配物和用途。
Description
相关申请
本申请要求于2019年4月19日提交的美国临时专利申请第62/836,402号的优先权,所述申请的全部内容特此通过引用并入。
发明内容
本公开提供了涉及用于递送和保留在皮肤中赋予治疗性或美容性活性的分子的载剂的多种见解。在皮肤内递送和/或保留美容剂或治疗剂的能力是非常令人期望的。在许多情况下,增强此类药剂的递送和/或保留可以显著增加治疗的功效和安全性。除了其它方面外,本公开还提供了6-氨基-2-氰基苯并噻唑(CBT)和其类似物增强此类活性物的递送和/或保留的用途。
附图说明
图1包括小图A-C,展示了CBT官能化实体:用CBT装饰的颗粒(A)、用单个CBT部分官能化的活性物(B)以及用多个CBT部分官能化的活性物(C)的实例。
图2示出了用于皮肤渗透研究的gly-CBT和HA-CBT的化学结构。
图3包括列A-F,示出了在应用PBS(列A、B)、gly-CBT(列C、D)和HA-CBT(列E、F)之后猪皮肤切片的明视场(列A、C、E)图像和荧光(列B、D、F)图像。
图4示出了在表皮-X组织***物上应用后gly-CBT分布的量化和显微镜检查:在供体溶液、受体溶液中通过吸光度检测并在6小时温育之后从组织***物中提取的应用的gly-CBT的分数(A);在PBS应用之后组织的冷冻切片的明视场(左)和荧光图像(右)(B);以及在gly-CBT应用之后组织的冷冻切片的明视场(左)和荧光图像(右)(C)。
图5包括小图A-D,示出了用HPLC测量的在供体隔室和受体隔室中并且在应用gly-CBT(A)和gly-Luc(B)之后从组织***物中提取的CBT物种的分布;在调配物应用之后未检测到的gly-CBT和gly-Luc的级分(C);以及在提取CBT物种之后在UV灯下组织***物(PBS(左)和gly-CBT(右))的图像(D)。
图6示出了相对于用PBS处理的组织,用阳性对照(5%SDS)、HA-CBT和gly-CBT处理的表皮组织的细胞活力。基于EPI-200-SIT指南,相对细胞活力大于50%表明无刺激性。
图7包括小图A和B,示出了用IR标记的HA(A)和IR标记的HA-CBT(B)处理的人皮肤切片的荧光图像。在两个样品(GFP过滤器)中均观察到皮肤的自体荧光,而仅在用IR标记的HA-CBT(Cy5过滤器)处理的样品中观察到IR标记的HA物种。
定义
约:当在本文中用于提及值时,术语“约”是指在上下文中与所引用值类似的值。通常,熟悉上下文的本领域的技术人员将理解所述上下文中“约”所涵盖的相关差异程度。例如,在一些实施例中,术语“约”可以涵盖在参考值的25%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或更小的范围内的值。
施用:如本文所使用的,术语“施用”通常是指向受试者或***施用组合物,以实现作为组合物或包含在组合物中的药剂的递送。本领域的普通技术人员将意识到,可以在适当情况下用于向例如人的受试者施用的各种途径。例如,在一些实施例中,施用可以是经眼施用、经口施用、肠胃外施用、局部施用等。在一些特定实施例中,施用可以是经支气管施用(例如,通过支气管滴注)、经颊施用、皮肤施用(其可以是或包括例如局部到真皮、皮肤内、皮肤间、透皮等中的一或多种)、肠内施用、动脉内施用、皮肤内施用、胃内施用、髓内施用、肌肉内施用、鼻内施用、腹膜内施用、鞘内施用、静脉内施用、心室内施用、特定器官内(例如,肝内)施用、粘膜施用、经鼻施用、经口施用、直肠施用、皮下施用、舌下施用、局部施用、气管施用(例如,通过气管内滴注)、***施用、玻璃体施用等。在一些实施例中,施用可以只涉及单剂量。在一些实施例中,施用可以涉及固定数量剂量的应用。在一些实施例中,施用可以涉及给药,所述给药是间歇性给药(例如,在时间上分隔的多个剂量)和/或周期性给药(例如,由共同的时间段分隔的单独剂量)。在一些实施例中,施用可以涉及连续给药(例如,灌注)至少所选时间段。
类似物:如本文所使用的,术语“类似物”是指与参考物质共享一或多个特定结构特征、元素、组分或部分的物质。通常,“类似物”示出与参考物质显著的结构相似性,例如共享核心或共识结构,但在某些离散方式上也有所不同。在一些实施例中,类似物是可以例如通过化学操纵参考物质从参考物质中产生的物质。在一些实施例中,类似物是可以通过执行与产生参考物质的合成过程基本上类似(例如,共享多个步骤)的合成过程产生的物质。在一些实施例中,类似物是通过或可以是通过执行与用于产生参考物质的合成过程不同的合成过程产生的。
药剂:通常,如本文所使用的,术语“药剂”可以用于指任何化学类别的化合物或实体,包含例如多肽、核酸、糖类、脂质、小分子、金属或其组合或络合物。在适当情况下,如本领域的技术人员从上下文中清楚的,所述术语可以用于指作为或包括细胞或生物体或其级分、提取物或组分的实体。可替代地或另外,如上下文将清楚的,所述术语可以用于指天然产品,因为其存在于自然中和/或从自然中获得。在一些情况下,再次如根据上下文将清楚的,所述术语可以用于指一或多个人造实体,因为其是通过人手的动作设计、工程化和/或生产的和/或不存在于自然中。在一些实施例中,药剂可以以分离形式或纯形式利用;在一些实施例中,药剂可以以天然形式利用。在一些实施例中,可能的药剂可以作为例如可以被筛选以鉴定或表征其内的活性剂的集合或库的形式提供。在一些情况下,术语“药剂”可以是指作为或包括聚合物的化合物或实体;在一些情况下,所述术语可以是指包括一或多个聚合部分的化合物或实体。在一些实施例中,术语“药剂”可以是指不是聚合物和/或基本上不含任何聚合物和/或一或多种特定聚合部分的化合物或实体。在一些实施例中,所述术语可以是指缺少或基本上不含任何聚合部分的化合物或实体。
脂肪族:如本文所使用的,术语“脂肪族”或“脂肪族基团”意指完全饱和或含有一或多个不饱和单元的直链(即,无支链)或支链、经取代或未经取代的烃链,或者完全饱和或含有一或多个不饱和单元但不是与分子的其余部分具有单个连接点的芳香族(在本文中也称为“碳环”、“碳环的”、“脂环族”或“环烷基”)的单环烃或双环烃。除非另有说明,否则脂肪族基团含有1-6个脂肪族碳原子。在一些实施例中,脂肪族基团含有1-5个碳原子。在一些实施例中,脂肪族基团含有1-4个碳原子。在一些实施例中,脂肪族基团含有1-3个碳原子,并且在一些实施例中,脂肪族基团含有1-2个碳原子。在一些实施例中,“碳环的”(或“脂环族”或“碳环”或“环烷基”)是指完全饱和或含有一或多个不饱和单元但不是与分子的其余部分具有单个连接点的芳香族的单环C3-C8烃。合适的脂肪族基团包含但不限于直链或支链的经取代的或未经取代的烷基、烯基、炔基和其杂化物,如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。
亚烷基:术语“亚烷基”是指二价烷基。“亚烷基链”是聚亚甲基,即,-(CH2)n-,其中n为正整数,优选地1到6、1到4、1到3、1到2或2到3。经取代的亚烷基链是一或多个亚甲基氢原子被取代基替代的聚亚甲基。合适的取代基包含下文针对经取代的脂肪族基团描述的那些取代基。
芳基:单独使用或作为较大部分的一部分使用如在“芳烷基”、“芳烷氧基”或“芳氧基烷基”中使用的术语“芳基”是指具有共五到十四个环成员的环体系,其中所述体系中的至少一个环是芳香族的,并且其中所述体系中的每个环含有3到7个环成员。术语“芳基”可以与术语“芳基环”可互换地使用。在本发明的某些实施例中,“芳基”是指芳香族环体系,并且示范性基团包含可以携带一或多个取代基的苯基、联苯基、萘基、蒽基等。如其在本文中所使用的,术语“芳基”的范围内还包含芳香族环与一或多个非芳香族环稠合的基团,如茚满基、邻苯二甲酰亚胺基、萘基亚胺基、菲啶基或四氢萘基等。
相关:如果一个事件或实体的存在、水平和/或形式与另一个事件或实体的存在、水平和/或形式有关,则两个事件或实体彼此“相关”,如所述术语在本文所使用。例如,如果特定实体(例如,多肽、基因特征、代谢物、微生物等)的存在、水平和/或形式与疾病、病症或病状的发病率和/或易感性有关(例如,跨相关群体),则所述特定实体被认为与特定疾病、病症或病状相关。在一些实施例中,如果两个或两个以上实体直接或间接相互作用,使得其在物理上彼此接近和/或保持彼此接近,则其在物理上彼此“缔合”。在一些实施例中,物理上彼此缔合的两个或两个以上实体彼此共价连接;在一些实施例中,物理上彼此缔合的两个或两个以上实体不是彼此共价连接的,而是例如通过氢键、范德华相互作用(van derWaals interaction)、疏水性相互作用、磁性和其组合非共价缔合的。
生物相容的:如本文所使用的,术语“生物相容的”是指当放置成与活组织例如在体内接触时不会对此类组织造成显著伤害的材料。在某些实施例中,如果材料不对细胞有毒性,则所述材料是“生物相容的”。在某些实施例中,如果材料在体外对细胞的加成导致小于或等于20%的细胞死亡和/或其在体外的施用未诱导显著炎症或其它此类不利作用,则所述材料是“生物相容的”。
相当:如本文所使用的,术语“相当”是指可能彼此不完全相同但足够相似以允许在其之间进行比较使得本领域的技术人员将了解可以基于所观察到的差异或相似性而合理地得出结论的两种或两种以上药剂、实体、情形、条件组等。在一些实施例中,相当的条件组、情形、个体或群体由多个基本上相同的特征和一个或小数量的不同特征表征。本领域的普通技术人员将理解,在上下文中,对于两个或两个以上此类药剂、实体、情形、条件组等,在任何给定情况下被视为相当所需的同一性程度如何。例如,本领域的普通技术人员将了解,当通过足以保证以下合理结论的数量和类型的基本上相同的特征表征时,多组情形、个体或群体彼此相当:在不同组情形、个体或群体下或利用不同组情形、个体或群体获得的结果或观察到的现象的差异由被改变的那些特征的变化引起或指示所述变化。
与……相对应:如本文在多肽、核酸和化学化合物的上下文中所使用的,术语“与……相对应”通过与适当的参考化合物或组合物进行比较来指定化合物或组合物中例如氨基酸残基、核苷酸残基或化学部分的结构元素的位置/同一性。例如,在一些实施例中,聚合物中的单体残基(例如,多肽中的氨基酸残基或多核苷酸中的核酸残基)可以被鉴定为“与适当参考聚合物中的残基相对应”。例如,本领域的普通技术人员将理解,为了简单起见,可以使用基于参考相关聚合物的规范编号***来指定聚合物中的残基,使得例如“与参考聚合物的位置190处的残基相对应”的残基实际上不必是所关注聚合物中的第190个残基,而是指与参考聚合物中位置190处的残基相对应的残基;本领域的普通技术人员将容易理解如何鉴定聚合物中的“对应的”残基(例如,使用可商购获得的多肽和核酸聚合物的序列比较软件;任选地手动地用于其它聚合物)。
设计的:如本文所使用的,术语“设计的”是指(i)其结构是人工选择的或已经由人工选择的药剂;(ii)通过需要人工过程产生的药剂;和/或(iii)与天然物质和其它已知药剂不同的药剂。
剂型:本领域的技术人员将了解,术语“剂型”可以用于指用于施用到受试者的药剂(例如,治疗剂、诊断剂或美容剂)的物理分立单位。通常,每个此类单位含有预定量的药剂。在一些实施例中,此类量是适合于根据已经确定在施用到相关群体(即,利用治疗给药方案)时与期望或有益(例如,治疗性和/或美容性)结果有关的给药方案施用的单位剂量(或其完整部分)。在一些实施例中,此类量是适合于根据已经确定在施用到相关群体时与期望或有益美容性结果(例如,对皮肤提供视觉和/或触觉改善)有关的方案施用的单位剂量(或其完整部分)。本领域的普通技术人员将了解,施用到特定受试者的组合物或药剂的总量由一或多个主治专业人员(例如,医师、护士或其它有许可证的专业人员)确定,并且可以涉及对多种剂型的施用。在一些实施例中,剂型可以以是或包括霜剂、凝胶、液体、洗剂、雾剂、面膜、基质、颗粒、糊剂、贴剂、粉末、血清、固体、喷雾剂(或其集合)或其组合的调配物的形式提供。
给药方案:本领域的技术人员将了解,术语“给药方案”可以用于指通常通过时间段分隔的单独施用到受试者的一组单位剂(通常多于一个)。在一些实施例中,给定药剂具有可能涉及一或多个剂的推荐给药方案。在一些实施例中,给药方案包括多个剂,所述多个剂中的每个剂在时间上与其它剂分隔。在一些实施例中,单独剂通过相同长度的时间段彼此分隔;在一些实施例中,给药方案包括多个剂和将单独剂分隔的至少两个不同时间段。在一些实施例中,给药方案内的所有剂具有相同的单位剂量。在一些实施例中,给药方案内的不同剂具有不同的量。在一些实施例中,给药方案包括第一剂量的第一剂,随后是不同于第一剂量的第二剂量的一或多个另外的剂。在一些实施例中,给药方案包括第一剂量的第一剂,随后是与第一剂量相同的第二剂量的一或多个另外的剂。在一些实施例中,给药方案在跨相关群体施用时与期望或有益结果有关。
赋形剂:如本文所使用的,术语“赋形剂”是指可以包含在药物组合物中例如以提供或有助于期望的稠度或稳定效果的非活性(例如,不是如美容性活性物等治疗性活性物)药剂。
卤素:术语“卤素”意指F、Cl、Br或I。
杂芳基:单独使用或作为较大部分,例如“杂芳烷基”或“杂芳烷氧基”的一部分使用的术语“杂芳基”和“杂芳-”是指具有5到10个环原子,优选地5个、6个或9个环原子的基团;在环阵列中共用6个、10个或14π个电子的基团;和/或除碳原子外,还具有一个到五个杂原子的基团,其中术语“杂原子”是指氮、氧或硫并且包含氮或硫的任何氧化形式以及碱性氮的任何季铵化形式。示范性杂芳基包含噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、中氮茚基、嘌呤基、二氮杂萘基和蝶啶基。本文所使用的术语“杂芳基”和“杂芳-”还包含杂芳香族环与一或多个芳基、脂环族或杂环基环融合的基团,其中基团或连接点处于杂芳香族环上。示范性基团包含吲哚基、异吲哚基、苯噻嗯基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。杂芳基可以是单环或双环的。术语“杂芳基(heteroaryl)”可以与术语“杂芳基环”、“杂芳基团(heteroaryl group)”或“杂芳香族”可互换使用,所述术语中的任何术语包含任选地经取代的环。术语“杂芳烷基”是指被杂芳基取代的烷基,其中烷基和杂芳基部分独立地是任选地经取代的。
杂环:本文所使用的术语“杂环(heterocycle)”、“杂环基”、“杂环基团”和“杂环(heterocyclic ring)”可互换使用,并且是指饱和或部分不饱和的并且除了碳原子外还具有一或多个,优选地一个到四个杂原子的稳定的5到7元单环或7到10元双环杂环部分,如上文所定义的。当关于杂环的环原子使用时,术语“氮”包含经取代的氮。作为实例,在具有0-3个选自氧、硫或氮的杂原子的饱和或部分不饱和环中,氮可以为N(如在3,4-二氢-2H-吡咯基中)、NH(如在吡咯烷基中)或+NR(如在N-取代的吡咯烷基中)。杂环可以在产生稳定结构的任何杂原子或碳原子处与其侧基连接,并且环原子中的任何环原子可以是任选地经取代的。此类饱和或部分不饱和杂环基团的实例包含四氢呋喃基、四氢噻吩基、吡咯烷基、哌啶基、吡咯啉基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、噁唑烷基、哌嗪基、二噁烷基、二氧戊环基、二氮杂环基、氧氮杂环基、硫氮杂环基、吗啉基和奎宁环基。术语“杂环”、“杂环基(heterocyclyl)”、“杂环基环”、“杂环基(heterocyclic group)”、“杂环部分”和“杂环基团”在本文中可互换使用并且还包含杂环基环与一或多个芳基环、杂芳基环或脂环族环稠合的基团,如二氢吲哚基、3H-吲哚基、苯并二氢吡喃基、菲啶基或四氢喹啉基,其中基团或连接点处于杂环基环上。杂环基可以是单环或双环的。术语“杂环烷基”是指被杂环基取代的烷基,其中烷基和杂环基部分独立地是任选地经取代的。
“改善”、“增加”、“抑制”或“减少”:如本文所使用的,术语“改善”、“增加”、“抑制”、“减少”或其语法等效物指示相对于基线或其它参考测量结果的值。在一些实施例中,适当的参考测量结果可以是或包括在不存在(例如,之前和/或之后)特定药剂或治疗的情况下,或者在存在适当的相当的参考药剂的情况下,在其它相当的条件下的特定***(例如,在单个个体中)中的测量结果。在一些实施例中,适当的参考测量结果可以是或包括在存在相关药剂或治疗的情况下已知或预期以特定方式响应的相当的***中的测量结果。
分离的:如本文所使用的,是指已经(1)从最初生产时(无论是在自然界和/或在实验环境中)与其缔合的组分中的至少一些组分中分离出的物质和/或实体,和/或(2)通过人工设计、生产、制备和/或制造的物质和/或实体。分离的物质和/或实体可以与其最初缔合的其它组分分离约10%、约20%、约30%、约40%、约50%、约60%、约70%、约80%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或超过约99%。在一些实施例中,分离的药剂是约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或大于约99%纯的。如本文所使用的,如果物质基本上不含其它组分,则所述物质是“纯的”。在一些实施例中,如本领域的技术人员将理解的,在与例如一或多种载剂或赋形剂(例如,缓冲液、溶剂、水等)等某些其它组分组合后,物质仍可以被认为是“分离的”或甚至是“纯的”;在此类实施例中,物质的分离或纯度百分比是在不包含此类载剂或赋形剂的情况下计算的。
连接子:如本文所使用的,用于指将不同元素彼此连接的多元素药剂的所述部分。
标志物:本文所使用的标志物是指其存在或水平是特定状态或事件的特性的实体或部分。在一些实施例中,特定标志物的存在或水平可以是疾病、病症或病状的存在、状态或阶段的特性。
任选地经取代的:如本文所使用的,化合物有时可以含有“任选地经取代的”部分。通常,无论前面是否有术语“任选地”,术语“经取代的”都意味着指定部分的一或多个氢被合适的取代基替代。“经取代的”适用于结构中明确或隐含的一或多个氢(例如,是指至少并且是指至少 除非另有指示,否则“任选地经取代的”基团可以在所述基团的每个可取代位置处具有合适的取代基,并且当任何给定结构中的多于一个位置可以被选自指定组的多于一个取代基取代时,在每个位置处,取代基可以相同或不同。本发明所设想的取代基组合优选地是使稳定或化学上可行的化合物形成的取代基组合。如本文所使用的,术语“稳定”是指其在经历允许其生产、检测并且在某些实施例中回收、纯化并且用于本文所公开的目的中的一或多个目的条件时基本上不会发生变化的化合物。“任选地经取代的”基团的可取代碳原子上的合适的单价取代基独立地是:卤素;-(CH2)0-4R°;-(CH2)0-4OR°;-(CH2)0-4R°、-O-(CH2)0-4C(O)OR°;-(CH2)0-4CH(OR°)2;-(CH2)0-4SR°;-(CH2)0- 4Ph,其可以被R°取代;-(CH2)0–4O(CH2)0–1Ph,其可以被R°取代;-CH=CHPh,其可以被R°取代;-(CH2)0–4O(CH2)0–1-吡啶基,其可以被R°取代;-NO2;-CN;-N3;-(CH2)0-4N(R°)2;-(CH2)0-4N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2)0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°;-C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4C(O)SR°;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR-、SC(S)SR°;-(CH2)0-4SC(O)R°;-(CH2)0-4C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°、-(CH2)0-4OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2)0-4SSR°;-(CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R°;-S(O)2NR°2;-(CH2)0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C1-4直链或支链亚烷基)O-N(R°)2;或-(C1-4直链或支链亚烷基)C(O)O-N(R°)2,其中每个R°可以如以下限定被取代并且独立地为卤素、C1-6脂肪族、-CH2Ph、-O(CH2)0-1Ph、-CH2-(5到6元杂芳基环)或具有0-4个独立地选自氮、氧或硫的杂原子的5到6元饱和环、部分不饱和环或芳基环,或者尽管上文进行了定义,但是两个独立出现的R°结合其介入原子形成具有0-4个独立地选自氮、氧或硫的杂原子的3到12元饱和环、部分不饱和环或芳基单环或双环,所述杂原子可以如以下限定被取代。R°上合适的单价取代基(或通过将两个独立出现的R°与其中间原子一起形成的环)独立地为卤素、-(CH2)0- 2R·、-(卤代R·)、-(CH2)0-2OH、-(CH2)0-2OR·、-(CH2)0-2CH(OR·)2;-O(卤代R·)、-CN、-N3、-(CH2)0-2C(O)R·、-(CH2)0-2C(O)OH、-(CH2)0-2C(O)OR·、-(CH2)0-2SR·、-(CH2)0-2SH、-(CH2)0- 2NH2、-(CH2)0-2NHR·、-(CH2)0-2NR· 2、-NO2、-SiR· 3、-OSiR· 3、-C(O)SR·、-(C1-4直链或支链亚烷基)C(O)OR·或-SSR·,其中每个R·是未经取代的或者在前面有“卤代”的情况下仅被一或多个卤素取代并且独立地选自C1-4脂肪族、-CH2Ph、-O(CH2)0-1Ph或具有0-4个独立地选自氮、氧或硫的杂原子的5到6元饱和环、部分不饱和环或芳基环。R°的饱和碳原子上的合适的二价取代基包含=O和=S。“任选地经取代的”基团的饱和碳原子上的合适的二价取代基包含以下:=O(“oxo”)、=S、=NNR*2、=NNHC(O)R*、=NNHC(O)OR*、=NNHS(O)2R*、=NR*、=NOR*、-O(C(R*2))2-3O-或-S(C(R*2))2-3S-,其中每个独立出现的R*选自氢、可以如以下限定别取代的C1-6脂肪族或具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的5到6元饱和环、部分不饱和环或芳基环。与“任选地经取代的”基团的邻位可取代碳结合的合适的二价取代基包含:-O(CR*2)2-3O-,其中每个独立出现的R*选自氢、可以如以下限定被取代的C1-6脂肪族或具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的5到6元饱和环、部分不饱和环或芳基环。R*的脂肪族基团上合适的取代基包含卤素、-R·、-(卤代R·)、-OH、-OR·、-O(卤代R·)、-CN、-C(O)OH、-C(O)OR·、-NH2、-NHR·、-NR· 2或-NO2,其中每个R·是未经取代的或者在前面有“卤代”的情况下仅被一或多个卤素取代,并且独立地是C1-4脂肪族、-CH2Ph、-O(CH2)0- 1Ph或具有0-4个独立地选自氮、氧或硫的杂原子的5到6元饱和环、部分不饱和环或芳基环。“任选地经取代的”基团的可取代氮上的合适的取代基包含 或其中每个独立地是氢、可以如下文所限定的被取代的C1-6脂肪族、未经取代的-OPh或具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的5到6元饱和环、部分不饱和环或芳基环,或者尽管上文进行了定义,但是两个独立出现的与其中间原子一起形成具有0-4个独立地选自氮、氧或硫的杂原子的3到12元饱和、部分不饱和或芳基单环或双环。的脂肪族基团上的合适的取代基独立地是卤素、R·、-(卤代R·)、-OH、-OR·、-O(卤代R·)、-CN、-C(O)OH、-C(O)OR·、-NH2、NHR·、-NR· 2或-NO2,其中每个R·是未经取代的或者在前面有“卤代”的情况下仅被一或多个卤素取代,并且独立地是C1-4脂肪族、-CH2Ph、-O(CH2)0-1Ph或具有0-4个独立地选自氮、氧或硫的杂原子的5到6元饱和环、部分不饱和环或芳基环。
生理条件:如本文所使用的,具有其在细胞或生物体生活和/或繁殖的条件下本领域理解的含义参考条件。在一些实施例中,所述术语是指生物体或细胞***在自然界中可能出现的外部或内部环境的条件。在一些实施例中,生理条件是存在于人或非人动物体内的那些条件,尤其是存在于所关注靶部分处和/或内的那些条件。生理条件通常包含例如,20-40℃范围内的温度(并且具体地约37℃)、大气压为1、pH为6-8、1-20mM葡萄糖浓度、大气水平下的氧气浓度以及其地球上遇到的重力中的一或多种。
参考:如本文所使用的,描述了相对于其执行比较的标准或对照。例如,在一些实施例中,将所关注药剂、动物、个体、群体、样品、序列或值与参考或对照药剂、动物、个体、群体、样品、序列或值进行比较。在一些实施例中,与所关注测试或确定基本上同时测试和/或确定参考或对照。在一些实施例中,参考或对照是任选地体现在有形介质中的历史参考或对照。通常,如本领域的技术人员所理解的,在与评估中的条件或环境相当的条件或环境下确定或表征参考或对照。本领域的技术人员将理解何时存在足够的相似性来证明对特定可能的参考或对照的依赖和/或比较。
样品:如本文所使用的,术语“样品”通常是指从所关注来源获得或来源于所述来源的材料的等分试样。在一些实施例中,所关注来源是生物或环境来源。在一些实施例中,所关注来源可以是或包括如微生物、植物或动物(例如,人)等细胞或生物体。在一些实施例中,所关注来源是或包括生物组织或液体。在一些实施例中,样品是通过任何适当的方式直接从所关注来源获得的“初级样品”。在一些实施例中,如根据上下文将清楚的,术语“样品”是指通过处理初级样品(例如,通过去除初级样品中的一或多种组分和/或通过向初级样品中添加一或多种药剂)而获得的制剂。此类“经过处理的样品”可以包括例如从样品中提取的或通过使初级样品经理如色谱、提取、沉淀等一或多种技术获得的材料。
受试者:如本文所使用的,术语“受试者”是指例如出于实验、诊断、预防、美容和/或治疗目的施用或可以施用所提供***的任何生物体、。典型的受试者包含动物(例如,如小鼠、大鼠、兔、非人灵长类动物和/或人等哺乳动物)。在一些实施例中,受试者是人。在一些实施例中,受试者患有和/或易患一或多种病症或病状。在一些实施例中,受试者表现出病症或病状的一或多种症状。在一些实施例中,受试者已经被诊断患有一或多种病症或病状。在一些实施例中,病症或病状是或包含癌症或一或多种肿瘤的存在。在一些实施例中,受试者正在接受或已经接受某些疗法来诊断和/或治疗疾病、病症或病状。在一些实施例中,受试者是指寻求如皮肤外观和/或触感的改善等美容性益处和/或改善的人。
实质性结构相似性:如本文所使用的,术语“实质性结构相似性”是指在特定位置处存在共享的结构特征。在一些实施例中,术语“实质性结构相似性”是指例如以下的结构元素的存在和/或同一性:环、片、螺旋、H键供体、H键受体、糖基化模式、盐桥、二硫键和其组合。在一些实施例中,术语“实质性结构相似性”是指原子或部分相对于彼此的三维布置和/或取向(例如:所关注药剂与参考药剂之间或其中的距离和/或角度)。
治疗剂:如本文所使用的,短语“治疗剂”总体上是指当施用于生物体时引起期望的药理学效果(在一些实施例中,其可以是或包括美容性效果)的任何药剂。在一些实施例中,如果药剂跨适当的群体表现出统计学显著的效果,则认为所述药剂表现出效果(即,为治疗剂)。在一些实施例中,适当的群体可以是模型生物体的群体。在一些实施例中,适当的群体可以由如某些年龄组、性别、遗传背景、预先存在的临床病状等或其组合等特定准则限定。在一些实施例中,治疗剂是可以用于使疾病、病症和/或病状的一或多种症状或特征减轻、改善、缓解、抑制、预防、延迟其发作、降低其严重程度和/或降低其发生率的物质。在一些实施例中,治疗剂是实现美容性效果的治疗剂(即,是美容剂)。在一些实施例中,治疗剂可以用于实现皮肤外观和/或触感的改善和/或另一种美容性益处。
治疗:如本文所使用的,术语“治疗(treat)”、“治疗(treatment)”或“治疗(treating)”是指疾病、病症和/或病状的一或多种症状或特征的发生率和/或严重程度的部分或完全减轻、改善、延迟发作、抑制、预防、缓解和/或降低,或实现另一种期望的生理效果(例如,如皮肤外观和/或触感的改善,如皮肤的视觉和/或触觉改善等期望的美容性效果)。在一些实施例中,治疗包括施用产生生理效果的药剂。在一些实施例中,治疗包括在施用时以本文所述的方式改善物理外观的美容治疗。在一些实施例中,可以向未表现出疾病、病症和/或病状的迹象或特征的受试者施用治疗(例如,可以是预防性的)。在一些实施例中,可以向仅表现出疾病、病症和/或病状的早期或轻微迹象或特征的受试者施用治疗,例如用于降低发展与疾病、病症和/或病状相关的病理的风险的目的。在一些实施例中,可以向表现出疾病、病症或病状的已确立、严重和/或晚期迹象的受试者施用治疗。
具体实施方式
如本文所描述的,本公开提供了与增强有效负载(例如,其可以是或包括活性剂)在靶部位处的渗透和/或保留有关的某些技术,所述靶部位例如可以是皮肤中或皮肤上的部位,例如在角质层、表皮、真皮或底层下皮组织上、处、中或下方。在一些实施例中,本公开提供了一种能够跨皮肤表面传输和/或增强传输有效负载并将有效负载传输和/或增强传输到靶部位中的***。在一些实施例中,本公开提供了渗透到靶部位中和/或保留在靶部位处的渗透剂。在一些实施例中,渗透剂可以包括任选地通过连接子彼此缔合的载剂部分和有效负载部分。在一些实施例中,渗透部分是或包括苯并噻唑。
例如,本公开表明,在重建的3维人皮肤组织(EpiDermTM)中,约75%的所应用的剂量的与CBT(gly-CBT)缀合的甘氨酸在6小时内渗透皮肤。然而,只有约1/3的渗透量出现在受体隔室中,而2/3保留在皮肤中。而且,令人惊讶的是,即使在用Triton-X、甲醇或二氯甲烷洗涤后,也无法去除大部分渗透到皮肤中的量。后两种是用于去除皮肤中的分子的常用有机溶剂。这些强溶剂甚至能从皮肤中提取脂质。所述强溶剂无法从皮肤中提取gly-CBT(例如,含有CBT的实体)表明CBT具有出人意料的在皮肤中的保留能力。在猪皮肤中也观察到无法从皮肤中提取gly-CBT(例如,含有CBT的实体)。本公开教导了CBT渗透到皮肤中并保留在皮肤中的能力可以用于各种皮肤病应用和美容性应用。在一些实施例中,以供根据本公开使用的载剂部分是或包括CBT或其类似物。
在一些实施例中,此类载剂部分(例如,CBT或其类似物)可以与有效负载部分连接或以其它方式缔合,使得有效负载部分(和/或其活性剂组分)渗透到皮肤中和/或保留在皮肤内(例如,渗透和/或保留的程度和/或时间大于在不存在CBT的相当条件的情况下的程度和/或时间)。
在一些实施例中,如本文所述的渗透剂可以包含例如纳米颗粒、脂质体、胶束等与活性剂缔合的包封组分。在一些实施例中,此类包封组分可以被认为是“连接部分”,其程度使得其促进载剂部分与有效负载部分(例如,与活性剂)的缔合。可替代地,在一些实施例中,此类包封组分可以被认为是有效负载部分的一部分(例如,其可以是或包括包封组分和活性剂)。在一些实施例中,包封组分(例如,纳米颗粒)可以由生物相容性材料制备和/或可以是生物相容性材料。在一些实施例中,包封组分可以促进有效负载部分和/或活性剂与如本文所述的载剂部分的缔合,和/或可以以其它方式改善或有助于改善有效负载部分、活性剂和/或渗透剂的一或多个特征(例如,稳定性)。在一些实施例中,包封组分(例如,纳米颗粒)具有可以用载剂部分(例如,CBT)改性的表面。
在一些实施例中,渗透剂是式(I):
或其药学上可接受的盐,
其中
A为有效负载部分;
B为载剂部分;
L为连接子;
并且n为1-100。
在一些实施例中,n为1。在一些实施例中,n为2。在一些实施例中,n为3。在一些实施例中,n为5。在一些实施例中,n为10。在一些实施例中,n为20。在一些实施例中,n为50。在一些实施例中,n为1-2。在一些实施例中,n为1-5。在一些实施例中,n为1-50。
在一些实施例中,渗透剂是式(I-a):
或其药学上可接受的盐,
其中
A为有效负载部分;
L为连接子;
R1在每次出现时独立地为-H、卤素、-CN、任选地经取代的C1-6脂肪族、任选地经取代的5到10元杂环基、任选地经取代的6到10元芳基或任选地经取代的5到10元杂芳基;
R2为-H、卤素、-CN、任选地经取代的C1-6脂肪族、任选地经取代的5到10元杂环基、任选地经取代的6到10元芳基或任选地经取代的5到10元杂芳基;并且
m为1-4。
在一些实施例中,渗透剂是式(I-a):
或其药学上可接受的盐,
其中A、L、R1、R2和m如本文中所限定的。
在一些实施例中,渗透剂是式(I-b):
或其药学上可接受的盐,
其中A是本文所限定的。
在一些实施例中,渗透剂是式(I-c):
或其药学上可接受的盐,
其中A是本文所限定的。
在一些实施例中,渗透剂是式(I-d):
或其药学上可接受的盐,
其中A是本文所限定的。
在一些实施例中,渗透剂是式(II):
或其药学上可接受的盐,
其中
A为有效负载部分;
B为载剂部分;
L为连接子;
并且n为1-100。
载剂部分
在一些实施例中,根据本公开提供和/或利用的***可以包括任选地通过连接子彼此缔合的一或多种载剂和有效负载部分。
在一些实施例中,本公开提供了以下见解:某些载剂部分可以出人意料地赋予如本文所述的渗透剂表现出渗透到皮肤中达到期望程度(例如,进入皮肤的所施用药剂的分数和/或所施用药剂渗透的深度——例如,所施用药剂渗透到所关注靶部分的程度)和/或保留在皮肤中(例如,渗透剂在皮肤中例如在所关注靶部位处持续的时间)的能力。
在那些可以包括多个载剂部分的实施例中,此类载剂部分在一些实施例中可以全部相同;在其它实施例中,所提供的***可以包括多个不同的载剂部分。
例如,在一些实施例中,根据本公开有用的载剂部分通过例如当与特定有效负载部分缔合(例如,连接)时特定的亲脂性程度表征。在一些实施例中,CBT表示在如本文所述的有用渗透剂中可以与有效负载部分连接的载剂部分。阅读本公开的本领域的技术人员将理解,在一些实施例中,可以例如通过多个疏水部分(例如,疏水载剂部分)的连接来调节包括特定有效负载部分的渗透剂的亲脂性,所述疏水部分可以相同或不同并且单独或一起可以被认是为或构成本文所述的载剂部分。
在一些实施例中,载剂部分可以是或包括任选地经取代的苯并噻唑。在一些实施例中,载剂部分可以是或包括氰基苯并噻唑(CBT)。在一些实施例中,载剂部分可以是或包括2-氰基-6-羟基苯并噻唑。在一些实施例中,载剂部分可以是或包括D-荧光素、L-荧光素、D-氨基荧光素或L-氨基荧光素。在一些实施例中,载剂部分可以是或包括除苯并噻唑以外的分子。
在一些实施例中,载剂部分可以是或包括式(III)的部分:
其中R1、R2和m如本文中所限定的。
在一些实施例中,载剂部分可以是或包括式(III-a)的部分
其中R1和m如本文中所限定的。
在一些实施例中,载剂部分可以是或包括式(III-b)的部分:
其中R1和m如本文中所限定的。
不希望受任何特定理论束缚的情况下,本公开提出如本文所述的载剂部分(例如,CBT和/或其类似物,或其它适当的亲脂性实体)可以以足够的强度与皮肤或粘膜中发现的一或多种细胞外基质蛋白(例如,角蛋白、弹性蛋白、胶原蛋白等)相互作用(例如,其可以通过例如测量Ka和/或Kd和/或评估对如Triton-X、甲醇和/或二氯甲烷等溶剂的存在等预期破坏条件的稳定性来表征)。本领域的技术人员在阅读本公开后将理解,载剂部分可以通过疏水相互作用与例如皮肤或粘膜的靶区域相互作用。另外,还应当理解,在一些实施例中,载剂部分可以通过共价缀合或离子相互作用与靶区域相互作用。
在一些实施例中,如本文所述的载剂部分可以用于例如在一或多个身体组织中保留和靶向活性物,所述活性物可以通过皮肤中发现的那些高水平的ECM蛋白来表征。在一些实施例中,在皮肤中发现的ECM蛋白包含但不限于角蛋白、弹性蛋白或胶原蛋白。阅读本公开的本领域技术人员将会理解,在一些实施例中,身体组织可以包括粘膜。
苯并噻唑的其它化学结构包含但不限于欧洲药物化学杂志(European Journalof Medicinal Chemistry),2015年6月5日,第97卷,第911-927页、医药化学当前论题(CurrTop Med Chem.)2017;17(2):208-237、植物土壤环境(PLANT SOIL ENVIRON),51,2005(11):496-505、药物化学研究(Medicinal Chemistry Research),2012年9月,第21卷,第9期,第2644-2651页中所描述的。
连接子
在一些实施例中,可以渗透皮肤的***包括缀合载剂部分和有效负载(其通常是或包括活性剂)的连接子。在一些实施例中,连接子部分被称为“L”。在一些实施例中,连接子可以在生物学条件下是可降解的。在一些实施例中,连接子可以在生物学条件下是不可降解的。在一些实施例中,连接子可以通过水解或酶促反应降解。在一些实施例中,连接子可以通过应用切割启动子(例如,电、化学和/或酶促刺激)是可切割的。在一些实施例中,连接子在***施用后降解(例如,在如数小时、数天、数周或数月内等指定时间段中和/或内)。
在一些实施例中,可以通过与胺基团的化学反应来介导载剂部分与有效负载部分的缀合。在一些实施例中,连接子可以包括胺基团。在一些实施例中,连接子可以包括酰胺基团。在一些实施例中,连接子可以是键。
在一些实施例中,如本文所述的渗透剂可以包含包封组分;在一些此类实施例中,可以通过此类包封组分实现如本文所述的载剂部分与有效负载部分的缔合。多种技术可用于将载剂与例如脂质体、纳米颗粒、胶束等包封组分缀合或缔合。
在一些实施例中,如本文所述的载剂部分与有效负载部分之间的缔合可以涉及化学缀合;在一些实施例中,化学缀合可以是或包括点击化学。在一些实施例中,有效负载部分可以是或包括多肽;在一些此类实施例中,与多肽的连接可以是或包括与含有例如苏氨酸、半胱氨酸或赖氨酸等残基的杂原子的缀合。在一些实施例中,可以通过与半胱氨酸残基的化学缀合进行与多肽的连接。在一些特定实施例中,如CBT等载剂部分可以与肽或蛋白质的半胱氨酸部分(例如,通过点击化学)缀合。
在一些实施例中,L为任选地经取代的C1-6亚烷基链,其中L的一个、两个或三个亚甲基单元任选地并且独立地被-NH-、-O-、-S-、-S(O)-、-S(O)2-或-C(O)-替代。多种技术可以用于将载剂与活性剂缀合或缔合。
在一些实施例中,L选自由以下组成的组:-NH-、-O-、-S-、-S(O)-、-S(O)2-和-C(O)-。在一些实施例中,L为-NH-。在一些实施例中,L为-O-。在一些实施例中,L为-S-。在一些实施例中,L为-S(O)-。在一些实施例中,L为-S(O)2-。在一些实施例中,L为-C(O)NH-。在一些实施例中,L为-NHC(O)-。在一些实施例中,L为-C(O)-。
在一些实施例中,L为聚乙二醇(PEG)。在一些实施例中,L可以为乙二胺,例如聚乙二醇二胺等。
在一些实施例中,L包括由“点击”反应产生的部分。在一些实施例中,L包括***。在一些实施例中,L包括亚胺。在一些实施例中,L包括肟。在一些实施例中,L包括肼。在一些实施例中,L包括由亲核加成产生的部分。在一些实施例中,L包括由迈克尔加成(Michaeladdition)产生的部分。在一些实施例中,L包括硫巯基(thiol-ene)。
在一些实施例中,有效负载部分或活性剂可以是低分子量化合物或小分子;本领域的技术人员了解可以利用各种技术将低分子量化合物或小分子与载剂部分缀合。
如本文所述,本领域的技术人员了解如本文所述的用于将载剂部分与包封组分缀合的各种技术。
有效负载部分
在一些实施例中,根据本公开提供和/或利用的***可以包括任选地通过连接子彼此缔合的一或多种载剂和有效负载部分。
在一些实施例中,有效负载部分可以是或包括治疗剂。在一些实施例中,治疗剂是或包括多肽、蛋白质、氨基酸、抗体、拟肽、脂质、小分子、糖胺聚糖、核酸或其组合。在一些实施例中,合适的治疗剂可以选自皮肤病剂、抗肿瘤剂、免疫剂和神经剂等。在一些实施例中,合适的皮肤病活性剂可以包含例如局部麻醉剂、抗炎剂、抗增殖剂、抗感染剂(如抗病毒剂、抗真菌剂或抗菌剂)和用于治疗皮肤的医学病状的活性剂。
合适的糖胺聚糖的实例包含但不限于硫酸乙酰肝素、肝素、硫酸软骨素、硫酸皮肤素和硫酸角质素。在一些实施例中,糖胺聚糖可以成基于糖胺聚糖的蛋白聚糖的形式,包含例如多能蛋白聚糖、基底膜聚糖、磷脂酰肌醇聚糖、多配体聚糖、核心蛋白聚糖。本领域的技术人员在阅读本公开后将会理解,当与载剂部分(例如CBT)掺入时,如糖胺聚糖部分等某些有效负载部分将与离子和水分子缔合以形成水合复合物。此类实施例的施用可以结合粘膜,例如眼、唇、口、***、上呼吸道(即鼻和鼻道、副鼻窦、咽和声襞(带)上方的喉部分)、肺、GI道、尿道口和***的粘膜。本领域的技术人员应当理解,此类实施例将形成病原体进入的屏障,同时用于募集蛋白质,例如细胞因子和生长因子。
在那些可以包括多个有效负载部分的实施例中,此类有效负载部分在一些实施例中可以全部相同;在其它实施例中,所提供的***可以包括多个不同的有效负载部分。
在一些实施例中,在美国专利第8,791,062号中描述了一种治疗剂,所述美国专利通过引用并入本文。
在一些实施例中,合适的皮肤病剂选自:16-17A-环氧***(CAS登记号:1097-51-4)、对甲氧基肉桂酸/4-甲氧基肉桂酸(CAS登记号:830-09-1)、甲氧基肉桂酸辛酯(CAS登记号:5466-77-3)、甲氧基肉桂酸辛酯(CAS登记号:5466-77-3)、对甲氧基肉桂酸甲酯(CAS登记号:832-01-9)、4-雌甾烯-17β-醇-3-酮(4-ESTREN-17β-OL-3-ONE)(CAS登记号:62-90-8)、对甲氧基苯甲酰乙酸乙酯(CAS登记号:2881-83-6)、二氢尿嘧啶(CAS登记号:1904-98-9)、洛匹那韦(Lopinavir)(CAS登记号:192725-17-0)、利坦色林(RITANSERIN)(CAS登记号:87051-43-2)、尼洛替尼(Nilotinib)(CAS登记号:641571-10-0);罗库溴铵(Rocuronium bromide)(CAS登记号:119302-91-9)、对硝基苄基-6-(1-羟乙基)-1-氮杂双环(3.2.0)庚烷-3,7-二酮-2-羧酸酯(CAS登记号:74288-40-7)、阿维菌素(Abamectin)(CAS登记号:71751-41-2)、帕利哌酮(Paliperidone)(CAS登记号:144598-75-4)、吉米沙星(Gemifioxacin)(CAS登记号:175463-14-6)、戊柔比星(Valrubicin)(CAS登记号:56124-62-0)、咪唑立宾(Mizoribine)(CAS登记号:50924-49-7)、琥珀酸索非那新(Solifenacinsuccinate)(CAS登记号:242478-38-2)、拉帕替尼(Lapatinib)(CAS登记号:231277-92-2)、地屈孕酮(Dydrogesterone)(CAS登记号:152-62-5)、2,2-二氯-N-[(1R,2S)-3-氟-1-羟基-1-(4-甲基磺酰基苯基)丙烷-2-基]乙酰胺(CAS登记号:73231-34-2)、替米考星(Tilmicosin)(CAS登记号:108050-54-0)、依法韦仑(Efavirenz)(CAS登记号:154598-52-4)、吡柔比星(Pirarubicin)(CAS登记号:72496-41-4)、那格列奈(Nateglinide)(CAS登记号:105816-04-4)、表阿霉素(Epirubicin)(CAS登记号:56420-45-2)、恩替卡韦(Entecavir)(CAS登记号:142217-69-4)、依托考昔(Etoricoxib)(CAS登记号:202409-33-4)、西尼地平(Cilnidipine)(CAS登记号:132203-70-4)、盐酸多柔比星(Doxorubicinhydrochloride)(CAS登记号:25316-40-9)、艾司西酞普兰(Escitalopram)(CAS登记号:128196-01-0)、磷酸西格列汀一水合物(Sitagliptin phosphate monohydrate)(CAS登记号:654671-77-9)、阿维A酸(CAS登记号:55079-83-9)、苯甲酸利扎曲坦(Rizatriptanbenzoate)(CAS登记号:145202-66-0)、多尼培南(Doripenem)(CAS登记号:148016-81-3)、苯磺酸阿曲库铵(Atracurium besylate)(CAS登记号:64228-81-5)、尼鲁米特(Nilutamide)(CAS登记号:63612-50-0)、3,4-二羟基苯乙醇(CAS登记号:10597-60-1)、酒石酸酮色林(KETANSERIN TARTRATE)(CAS登记号:83846-83-7)、奥扎格雷(Ozagrel)(CAS登记号:82571-53-7)、甲磺酸依普沙坦(Eprosartan mesylate)(CAS登记号:144143-96-4)、盐酸雷尼替丁(Ranitidine hydrochloride)(CAS登记号:66357-35-5)、6,7-二氢-6-巯基-5H-吡唑并[l,2-a][1,2,4]***鎓氯化物(CAS登记号:153851-71-9)、磺胺吡啶(Sulfapyridine)(CAS登记号:144-83-2)、替考拉宁(Teicoplanin)(CAS登记号:61036-62-2)、他克莫司(Tacrolimus)(CAS登记号:104987-11-3)、罗美昔布(LUMIRACOXIB)(CAS登记号:220991-20-8)、丙烯醇(CAS登记号:107-18-6)、保护美罗培南(Protected meropenem)(CAS登记号:96036-02-1)、奈拉滨(Nelarabine)(CAS登记号:121032-29-9)、吡美莫司(Pimecrolimus)(CAS登记号:137071-32-0)、4-[6-甲氧基-7-(3-哌啶-1-基丙氧基)喹唑啉-4-基]-N-(4-丙烷-2-基氧基苯基)哌嗪-1-甲酰胺(CAS登记号:387867-13-2)、利托那韦(Ritonavir)(CAS登记号:155213-67-5)、阿达帕林(Adapalene)(CAS登记号:106685-40-9)、阿瑞匹坦(Aprepitant)(CAS登记号:170729-80-3)、依普利酮(Eplerenone)(CAS登记号:107724-20-9)、甲磺酸雷沙吉兰(Rasagiline mesylate)(CAS登记号:161735-79-1)、米替福新(Miltefosine)(CAS登记号:58066-85-6)、拉替拉韦钾(Raltegravir potassium)(CAS登记号:871038-72-1)、达沙替尼一水合物(Dasatinib monohydrate)(CAS登记号:863127-77-9)、奥索马嗪(OXOMEMAZINE)(CAS登记号:3689-50-7)、普拉克索(Pramipexole)(CAS登记号:104632-26-0)、帕瑞昔布钠(PARECOXIB SODIUM)(CAS登记号:198470-85-8)、替加环素(Tigecycline)(CAS登记号:220620-09-7)、托曲珠利(Toltrazuril)(CAS登记号:69004-03-1)、长春氟宁(Vinflunine)(CAS登记号:162652-95-1)、屈螺酮(Drospirenone)(CAS登记号:67392-87-4)、达托霉素(Daptomycin)(CAS登记号:103060-53-3)、孟鲁司特钠(Montelukast sodium)(CAS登记号:151767-02-1)、布林佐胺(Brinzolamide)(CAS登记号:138890-62-7)、马拉韦罗(Maraviroc)(CAS登记号:376348-65-1)、度骨化醇(Doxercalciferol)(CAS登记号:54573-75-0)、噁喹酸(Oxolinic acid)(CAS登记号:14698-29-4)、盐酸柔红霉素(Daunorubicin hydrochloride)(CAS登记号:23541-50-6)、尼扎替丁(Nizatidine)(CAS登记号:76963-41-2)、伊达比星(Idarubicin)(CAS登记号:58957-92-9)、盐酸氟西汀(FLUOXETINE HYDROCHLORIDE)(CAS登记号:59333-67-4)、子囊霉素(Ascomycin)(CAS登记号:11011-38-4)、β-甲基乙烯基磷酸酯(MAP)(CAS登记号:90776-59-3)、阿莫罗芬(Amorolfine)(CAS登记号:67467-83-8)、盐酸非索非那定(FexofenadineHCl)(CAS登记号:83799-24-0)、酮康唑(Ketoconazole)(CAS登记号:65277-42-1)、9,10-二氟-2,3-二氢-3-甲基-7-氧代-7H-吡啶并-1(CAS登记号:82419-35-0)、酮康唑(CAS登记号:65277-42-1)、盐酸特比萘芬(Terbinafine HCl)(CAS登记号:78628-80-5)、阿莫罗芬(CAS登记号:78613-35-1)、甲氧沙林(Methoxsalen)(CAS登记号:298-81-7)、盐酸奥洛他定(Olopatadine HCl)(CAS登记号:113806-05-6)、吡啶硫酮锌(Zinc Pyrithione)(CAS登记号:13463-41-7)、盐酸奥洛他定(CAS登记号:140462-76-6)、环孢菌素(Cyclosporine)(CAS登记号:59865-13-3)以及肉毒杆菌(Botulinum)毒素和其类似物和疫苗组分。
蛋白质、多肽和肽活性物
在一些实施例中,在所公开的***中有用的蛋白质可以包含例如,如细胞因子和其受体等分子以及包含细胞因子或其受体的嵌合蛋白,包含例如肿瘤坏死因子α和β、其受体和其衍生物;肾素;生长激素,包含人生长激素、牛生长激素、甲硫氨酸-人生长激素、去苯丙氨酸人生长激素(des-phenylalanine human growth hormone)和猪生长激素;生长激素释放因子(GRF);甲状旁腺和垂体激素;甲状腺刺激素;人胰腺激素释放因子;脂蛋白;秋水仙碱;催乳素;促肾上腺皮质激素;促甲状腺激素;催产素;加压素;生长抑素;赖氨加压素;肠促胰酶素;亮丙瑞林(leuprolide);α-1-抗胰蛋白酶;胰岛素A链;胰岛素B链;胰岛素原;***;降钙素;黄体化激素;黄体化激素释放激素(LHRH);LHRH激动剂和拮抗剂;胰高血糖素;如因子VIIIC、因子IX、组织因子和维勒布兰德(von Willebrands)因子等凝血因子;如蛋白质C等抗凝血因子;心房利钠因子;肺表面活性剂;除组织型纤溶酶原激活剂(t-PA)之外的纤溶酶原激活剂,例如尿激酶;蛙皮素;凝血酶;造血生长因子;脑啡肽酶;RANTES(regulated on activation normally T-cell expressed and secreted,活化正常T细胞表达和分泌的调节因子);人巨噬细胞炎性蛋白(MIP-1-α);如人血清白蛋白等血清白蛋白;副中肾管抑制物质;松弛素A链;松弛素B链;松弛素原;小鼠***关联肽;绒毛膜***;***释放激素;牛生长激素;猪生长激素;如β-内酰胺酶等微生物蛋白;DNase;抑制素;激活素;血管内皮生长因子(VEGF);激素或生长因子的受体;整合素;蛋白质A或D;类风湿因子;如骨源性神经营养因子(BDNF)等神经营养因子、神经营养素-3、4、-5或-6(NT-3、NT-4、NT-5或NT-6),或如NGF-β等神经生长因子;血小板源性生长因子(PDGF);如酸性FGF和碱性FGF等成纤维细胞生长因子;表皮生长因子(EGF);如TGF-α和TGF-β等包含TGF-β1、TGF-β2、TGF-β3、TGF-β4或TGF-β5的转化生长因子(TGF);***-I和-II(IGF-I和IGF-II);des(1-3)-IGF-I(脑IGF-I)、***结合蛋白;如CD-3、CD-4、CD-8和CD-19等CD蛋白;***;骨诱导因子;免疫毒素;骨形态发生蛋白(BMP);如干扰素-α(例如,干扰素α2A)、干扰素-β、干扰素-γ、干扰素-λ和复合干扰素等干扰素;集落刺激因子(CSF),例如,M-CSF、GM-CSF和G-CSF;白介素(IL),例如,IL-1到IL-10;超氧化物歧化酶;T-细胞受体;表面膜蛋白;衰变加速因子;病毒抗原,例如HIV-1包膜糖蛋白gp120、gp160的一部分或其片段;转运蛋白;归巢受体;地址素;如***素等生育抑制剂;生育促进剂;调节蛋白;如免疫粘附素等抗体(包含其片段)和嵌合蛋白;这些化合物的前体、衍生物、前药和类似物,以及这些化合物的药学上可接受的盐,或其前体、衍生物、前药和类似物。在一些实施例中,蛋白质或肽可以是天然的或重组的并且包含例如融合蛋白。
在一些实施例中,有效负载是或包括生长激素。在一些实施例中,生长激素是人生长激素(hGH)、重组人生长激素(rhGH)、牛生长激素、甲硫氨酸-人生长激素、去苯丙氨酸人生长激素和猪生长激素;胰岛素、胰岛素A链、胰岛素B链和胰岛素原;或生长因子,例如血管内皮生长因子(VEGF)、神经生长因子(NGF)、血小板源性生长因子(PDGF)、成纤维细胞生长因子(FGF)、表皮生长因子(EGF)、转化生长因子(TGF)或***-I和-II(IGF-I和IGF-II)。
在一些实施例中,以供在本文公开的可注射的、可生物降解的递送贮库中使用的肽包含但不限于胰高血糖素样肽-1(GLP-1)和其前体、衍生物、前药和类似物。
核酸
在一些实施例中,有效负载部分(和/或活性剂)是或包括核酸药剂。在一些实施例中,根据本公开有用的核酸药剂可以是或包括核酸;在一些实施例中,根据本公开有用的核酸药剂可以是或包括核酸前体、衍生物、前药、类似物等。在一些实施例中,根据本公开有用的核酸药剂可以选自由以下组成的组:治疗性核苷酸、核苷和其类似物;治疗性寡核苷酸;以及治疗性多核苷酸。
本领域的普通技术人员将了解各种治疗性核酸药剂,其中许多治疗性核酸药剂可能特别有用,例如用作抗癌剂、抗微生物剂和/或抗病毒剂。
在一些实施例中,合适的核酸药剂可以包含例如核酶、反义寡脱氧核苷酸、适体和siRNA。在一些实施例中,合适的核苷类似物包含但不限于阿糖胞苷(araCTP)、吉西他滨(gemcitabine)(dFdCTP)和氟尿苷(floxuridine)(FdUTP)。在一些实施例中,合适的核酸活性剂是干扰RNA,例如shRNA、miRNA或siRNA。在一些实施例中,合适的siRNA包含例如IL-7(白介素-7)siRNA、IL-10(白介素-10)siRNA、IL-22(白介素-22)siRNA、IL-23(白介素23)siRNA、CD86 siRNA、KRT6a(角蛋白6A)siRNA、K6a N171K(角蛋白6a N171K)siRNA、TNFα(肿瘤坏死因子α)siRNA、TNFR1(肿瘤坏死因子受体-1)siRNA、TACE(肿瘤坏死因子(TNF)-α转换酶)siRNA、RRM2(核糖核苷酸还原酶亚基-2)siRNA和VEGF(血管内皮生长因子)siRNA。这些siRNA的人基因靶标的mRNA序列是本领域已知的。对于IL-7,参见例如GenBank登录号:NM-000880.3、GenBank登录号:NM-001199886.1、GenBank登录号:NM-001199887.1和GenBank登录号:NM-001199888.1;对于IL-10,参见例如GenBank登录号:NM-000572.2;对于IL-22,参见例如GenBank登录号:NM-020525.4;对于IL-23,参见例如GenBank登录号:NM-016584.2和GenBank登录号:AF301620.1;对于CD86,参见例如GenBank登录号:NM-175862.4、GenBank登录号:NM-006889.4、GenBank登录号:NM-176892.1、GenBank登录号:NM-001206924.1和GenBank登录号:NM-001206925.1;对于KRT6a,参见例如GenBank登录号:NM-005554.3;对于TNFα,参见例如GenBank登录号:NM-000594.2;对于TNFR1,参见例如GenBank登录号:NM-001065.3;对于TACE,参见例如GenBank登录号:NM-003183.4;对于RRM2,参见例如GenBank登录号:NM-001165931.1和GenBank登录号:NM-001034.3;对于VEGF,参见例如GenBank登录号:NM-001025366.2、GenBank登录号:NM-001025367.2、GenBank登录号:NM-001025368.2、GenBank登录号:NM-001025369.2、GenBank登录号:NM-001025370.2、NM-001033756.2、GenBank登录号:NM-001171622.1和GenBank登录号:NM-003376.5。
某些示范性治疗剂和/或其它活性剂
在一些实施例中,除了其它方面外,本公开提供了包括治疗剂的渗透剂。在一些实施例中,可以将治疗剂或活性剂引导到以下药物靶标中的一或多个:Kringle结构域、羧肽酶、羧酸酯水解酶、糖基化酶、视紫红质样多巴胺受体、视紫红质样肾上腺受体、视紫红质样组胺受体、视紫红质样血清素受体、视紫红质样短肽受体、视紫红质样乙酰胆碱受体、视紫红质样核苷酸样受体、视紫红质样脂质样配体受体、视紫红质样褪黑激素受体、金属蛋白酶、转运体ATP酶、羧酸酯水解酶、过氧化物酶、脂氧合酶、DOPA脱羧酶、A/G环化酶、甲基转移酶、磺脲受体、其它转运体(例如,多巴胺转运体、GABA转运体1、去甲肾上腺素转运体、钾转运ATP酶α-链1、钠-(钾)-氯共转运体2、血清素转运体、突触囊泡胺转运体和噻嗪敏感性钠-氯共转运体)、电化学核苷转运体、电压门控离子通道、GABA受体(Cys-环)、乙酰胆碱受体(Cys-环)、NMDA受体、5-HT3受体(Cys-环)、配体门控离子通道Glu:钾盐镁矾、AMPA Glu受体、酸敏感离子通道醛固酮、利阿诺定(Ryanodine)受体、维生素K环氧化物还原酶、MetGluR样GABAB受体、内向整流K+通道、NPC1L1、MetGluR样钙敏感受体、醛脱氢酶、酪氨酸3-羟化酶、醛糖还原酶、黄嘌呤脱氢酶、核糖核苷还原酶、二氢叶酸还原酶、IMP脱氢酶、硫氧还蛋白还原酶、双加氧酶、肌醇单磷酸酶、磷酸二酯酶、腺苷脱氨酶、肽基脯氨酰异构酶、胸苷酸合酶、氨基转移酶、法尼基二磷酸合酶、蛋白激酶、碳酸酐酶、微管蛋白、肌钙蛋白、IKB激酶-β抑制剂、胺氧化酶、环氧酶、细胞色素P450、甲状腺素5-脱碘酶、类固醇脱氢酶、HMG-CoA还原酶、类固醇还原酶、二氢乳清酸氧化酶、环氧化物水解酶、转运体ATP酶、转运蛋白、糖基转移酶、核受体NR3受体、核受体:NR1受体或拓扑异构酶。
在一些实施例中,治疗剂或活性剂靶向视紫红质样GPCR、核受体、配体门控离子通道、电压门控离子通道、盘尼西林结合蛋白、髓过氧化物酶样、钠:神经递质同向转运体家族、II型DNA拓扑异构酶、纤连蛋白III型或细胞色素P450中的一种。
在一些实施例中,治疗剂是或包括抗癌剂。合适的抗癌剂包含但不限于放线菌素D、阿仑单抗(Alemtuzumab)、别嘌醇钠(Allopurinol sodium)、氨磷汀(Amifostine)、安吖啶(Amsacrine)、阿那曲唑(Anastrozole)、Ara-CMP、天冬酰胺酶、氮杂胞苷(Azacytadine)、苯达莫司汀(Bendamustine)、贝伐单抗(Bevacizumab)、比卡鲁胺(Bicalutimide)、博来霉素(Bleomycin)(例如,博来霉素A2和B2)、硼替佐米(Bortezomib)、白消安(Busulfan)、喜树碱钠盐(Camptothecin sodium salt)、卡培他滨(Capecitabine)、卡铂(Carboplatin)、卡莫司汀(Carmustine)、西妥昔单抗(Cetuximab)、苯丁酸氮芥(Chlorambucil)、顺铂(Cisplatin)、克拉屈滨(Cladribine)、氯法拉滨(Clofarabine)、环磷酰胺(Cyclophosphamide)、阿糖胞苷、达卡巴嗪(Dacarbazine)、更生霉素(Dactinomycin)、柔红霉素、柔红霉素脂质体、达卡巴嗪、地西他滨(Decitabine)、多西他赛(Docetaxel)、多柔比星、多柔比星脂质体、表阿霉素、雌氮芥(Estramustine)、依托泊苷(Etoposide)、磷酸依托泊苷、依西美坦(Exemestane)、氟尿苷、氟达拉滨(Fludarabine)、磷酸氟达拉滨、5-氟尿嘧啶、福莫司汀(Fotemustine)、氟维司群(Fulvestrant)、吉西他滨、戈舍瑞林(Goserelin)、六甲基三聚氰胺、羟基脲、伊达比星、异环磷酰胺、伊马替尼(Imatinib)、伊立替康(Irinotecan)、伊沙匹隆(Ixabepilone)、拉帕替尼、来曲唑(Letrozole)、醋酸亮丙瑞林、洛莫司汀(Lomustine)、二氯甲基二乙胺、美法仑(Melphalan)、6-巯基嘌呤、甲氨蝶呤(Methotrexate)、光辉霉素(Mithramycin)、丝裂霉素C(Mitomycin C)、米托坦(Mitotane)、米托蒽醌(Mitoxantrone)、尼莫司汀(Nimustine)、奥法木单抗(Ofatumumab)、奥沙利铂(Oxaliplatin)、紫杉醇(Paclitaxel)、帕尼单抗(Panitumumab)、培门冬酶(Pegaspargase)、培美曲塞(Pemetrexed)、喷司他丁(Pentostatin)、帕妥珠单抗(Pertuzumab)、吡铂(Picoplatin)、哌泊溴烷(Pipobroman)、普乐沙福(Plerixafor)、丙卡巴肼(Procarbazine)、雷替曲塞(Raltitrexed)、利妥昔单抗(Rituximab)、链脲霉素(Streptozocin)、替莫唑胺(Temozolomide)、替尼泊苷(Teniposide)、6-硫鸟嘌呤、噻替哌(Thiotepa)、托泊替康(Topotecan)、曲妥单抗(Trastuzumab)、曲奥舒凡(Treosulfan)、三亚乙基密胺(Triethylenemelamine)、三甲曲沙(Trimetrexate)、尿嘧啶氮芥(UracilNitrogen Mustard)、戊柔比星、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)、长春瑞滨(Vinorelbine)和其类似物、前体、衍生物和前药。应当注意的是,如本文所述,上述化合物中的两种或两种以上化合物可以组合地用于渗透剂中或包括渗透剂的组合物中。
在一些实施例中,治疗剂可以是或包括***样物质或其衍生物,和/或***样物质受体激动剂或拮抗剂,例如,纳曲酮(naltrexone)、纳洛酮(naloxone)、纳布啡(nalbuphine)、芬太尼(fentanyl)、舒芬太尼(sufentanil)、羟考酮(oxycodone)或其药学上可接受的盐或衍生物中的任何一种。
在一些实实施例中,治疗剂或活性剂是小分子或低分子量化合物,例如,分子量小于或等于约1000道尔顿,例如小于或等于约800道尔顿的分子或化合物。
在一些实施例中,治疗剂或活性剂是或包括标记。合适的标记包含例如放射性同位素、荧光剂、化学发光剂、发色团、酶、酶底物、酶辅因子、酶抑制剂、发色团、染料、金属离子、磁性颗粒、纳米颗粒和量子点。
在一些实施例中,治疗剂或活性剂可以以任何合适的浓度存在于本文公开的组合物中。合适的浓度可以根据相关药剂的效力、其半衰期等而变化。另外,在一些实施例中,根据本公开的渗透剂组合物可以包含一或多种活性剂,例如,上述活性剂中的两种或两种以上活性剂的组合。
纳米颗粒
在一些实施例中,药剂是或包括纳米颗粒。在一些实施例中,药剂包封在纳米颗粒内。在一些实施例中,用于制作纳米颗粒的材料的实例包含如聚乳酸共乙醇酸、聚酐、透明质酸等有机聚合物以及如金、二氧化硅和氧化铁等无机材料。在一些实施例中,纳米颗粒也可以由形成脂质体或固体脂质纳米颗粒的脂质制成。在一些实施例中,纳米颗粒可以包封美容性活性物,包含但不限于维生素、抗氧化剂、着色剂、芳香剂和防晒剂。在一个实施例中,选择纳米颗粒的大小、形状或弹性,以便优先诱导所述纳米颗粒在表层皮肤层中的定位。
在一些实施例中,使用连接子将载剂部分(例如,CBT)与纳米颗粒缀合。在一些实施例中,将载剂部分与纳米颗粒缀合的连接子可以选自甘氨酸、其它氨基酸、聚乙二醇、琥珀酸、己二酸二酰肼等。
美容性活性物
在一些实施例中,所提供的渗透剂包含有效负载或作为美容剂的活性剂。本领域的技术人员了解各种美容剂,包含例如在并入本文的US 2006/0008428A1中所描述的那些美容剂。在一些实施例中,美容剂可以是或包括呈纯化形式或复合形式的,尤其是基于矿物或植物的化合物或化合物的混合物,所述化合物或化合物的混合物在体外或体内表现出内在活性并且能够在美容性产品中进行调配。
如本领域的技术人员所了解,被认为是“美容性产品”的组合物是旨在与人体的各个表面部分(表皮、体毛和头发***、指甲、嘴唇和外生殖器官)或牙齿和口腔粘膜接触的任何物质或制剂,其唯一或主要目的是清洁、增香、改变其外观和/或掩盖体味和/或提供保护或保持处于良好状况(化妆品指令(Cosmetics Directive)76/768/EEC,已修订)。
在一些实施例中,包含在如本文所述的渗透剂中的有效负载部分或活性物是或包括一或多种美容性活性物。可替代地或另外,在一些实施例中,如本文所述的渗透剂的调配物可以包含一或多种此类美容性活性物。在一些实施例中,美容性活性物可以包含但不限于安全且有效量的选自由以下组成的组的护肤剂:糖胺聚糖、氨基酸、肽和其衍生物、脱皮活性物、维生素和其衍生物、类视黄醇和其衍生物、羟基酸、抗痤疮活性剂、自由基清除剂、螯合剂、抗炎剂、局部麻醉剂、保湿剂、润肤剂、皮肤调理剂、止汗剂、抗氧化剂、抗皱产品、表面活性剂、除臭剂、着色剂、颜料、防晒剂或其它光保护剂、美黑活性剂、皮肤美白剂、抗脂肪团剂、益生菌/益生元、类黄酮、抗微生物活性物、皮肤愈合剂、香料或香水、***素。在一些实施例中,所提供的***包括在OTC专论中鉴定的化合物。在一些实施例中,OTC专论中鉴定的化合物包含例如其它抗痤疮产品、局部抗真菌剂、抗微生物产品、止汗剂、收敛剂、鸡眼和老茧去除剂、头皮屑产品、毛发生长/脱发、咬甲癖产品、银屑病、湿疹、红斑痤疮、皮肤漂白、皮肤美白产品、防晒剂、局部镇痛剂、去疣剂、杀虫剂、药物以及如法尼醇、植烷三醇、尿囊素、葡萄糖胺等其它药剂和任何其它旨在或以其它方式在皮肤病学上可接受的载剂中适合于局部应用于其皮肤混合物的惰性或活性材料。
在本文所述的渗透剂的一些特定实施例中,CBT直接(有或没有中间连接子)与选自颜料或防晒剂的美容性纳米颗粒缀合。
所提供的***的施用
本文描述的技术对于在靶部位处提供***是有用的。在一些实施例中,靶部位是或包括身体组织(例如,在身体组织上或内)。本文描述了用于将材料应用于应用部位的技术,使得在靶部位处提供***。
例如,在一些实施例中,身体组织是或包括上皮组织。在一些实施例中,身体组织是或包括***。在一些实施例中,身体组织是或包括神经组织。在一些实施例中,身体组织是或包括肌肉组织。在一些实施例中,身体组织是或包括眼睛组织、皮肤组织或皮下组织。在一些实施例中,身体组织是或包括皮下脂肪、角膜上皮或粘膜。
在许多实施例中,靶部位是在应用到例如组织表面的表面之后到达的部位。在一些实施例中,组织表面是暴露在生物体表面上的组织(例如,皮肤、眼睛或某些粘膜)表面。在一些实施例中,组织表面是内部组织的表面,所述表面可以例如通过执行程序(例如,如外科手术程序等医疗程序,包含例如无畸变程序)或应用于生物体的过程来接近或暴露。
在一些实施例中,本公开提供了可以施用于皮肤、口腔粘膜、***粘膜、眼睛、膀胱、鼻粘膜、耳道或***粘膜的***。
如本文所述,本公开提供了可以施用于皮肤的***。在一些实施例中,所提供的***是局部施用的(例如,应用到皮肤表面)。在一些实施例中,所提供的***作为透皮贴剂施用。
在一些实施例中,向受试者的面部(例如,受试者面部的整个面部和/或具体部位,如嘴唇、下唇、上唇、泪沟、鱼尾纹、鼻唇沟、前额、脸颊或其组合)施用所提供的***。在一些实施例中,向非面部部位(例如,膝盖、颈部、胸部、腿、手臂、躯干、臀部或脚)施用所提供的***。在一些实施例中,向手(例如,手背)施用所提供的***。在一些实施例中,向耳垂施用所提供的***。
在一些实施例中,在施用所提供的***之前准备施用部位。在一些实施例中,通过用温水和肥皂洗涤部位来准备施用部位。在一些实施例中,用商用微针滚轮准备施用部位。在一些实施例中,通过胶带剥离准备施用部位。在一些实施例中,胶带剥离包括将苏格兰透明半透明胶带(Scotch semitransparent tape)应用于施用部位。在一些实施例中,胶带剥离进一步包括从施用部位去除先前应用的苏格兰半透明胶带。在一些实施例中,重复胶带剥离,直到施用部位闪光。在一些实施例中,重复胶带剥离至少40次。
在一些实施例中,在应用所提供的***之后覆盖应用部位。在一些实施例中,在应用所提供的***之后用TegadermTM型膜覆盖应用部位。
在一些实施例中,在***施用后用水处理皮肤。
在一些实施例中,每日施用***。在一些实施例中,至少每日一次施用***。在一些实施例中,至少每日两次施用***。在一些实施例中,至少每日1-5次施用***。在一些实施例中,至少每日3-5次施用***。在一些实施例中,每3日施用***。在一些实施例中,每7日施用***。在一些实施例中,约每15日施用***。在一些实施例中,约每30日施用***。在一些实施例中,约每60日施用***。在一些实施例中,约每90日施用***。
在一些实施例中,所提供的***作为持续释放调配物的形式或在持续释放调配物中施用。在一些实施例中,渗透剂作为乳液或分散体的形式或在乳液或分散体中提供。
在一些实施例中,所提供的***可以在特定调配物中以在下边界与上边界(包含上边界和下边界)之间的范围内的重量(例如,w/w)%存在,所述上边界大于所述下边界,其中上边界可以为约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%或约5%,并且下边界可以为约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约1%。在一些实施例中,调配物包括***的约0.001%w/w到约5.00%w/w。在一些实施例中,调配物包括***的约0.01%w/w到约5.00%w/w。在一些实施例中,调配物包括***的约0.1%w/w到约5.00%w/w。在一些实施例中,调配物包括***的约1%w/w到约5.00%w/w。在一些实施例中,调配物包括***的约1%w/w到约3%w/w。在一些实施例中,调配物包括***的约2%w/w。在一些实施例中,调配物包括PBS和***的约2%w/w。
在一些实施例中,调配物包括所提供的***和美容性材料。在一些实施例中,调配物包括***的约1%w/w到约50%w/w。在一些实施例中,调配物包括***的约10%w/w到约50%w/w。在一些实施例中,调配物包括***的约20%w/w到约50%w/w。在一些实施例中,调配物包括***的约30%w/w到约50%w/w。在一些实施例中,调配物包括***的约40%w/w到约50%w/w。在一些实施例中,调配物包括***的约45%w/w到约50%w/w。
各种形式的调配物可以用于施用如本文所述的渗透剂和/或向患者递送相关的有效负载部分或活性剂。药学上可接受的赋形剂也是本领域的普通技术人员熟知的并且容易获得。本领域的技术人员将意识到,对赋形剂的选择通常至少部分地由所涉及的特定有效负载部分或活性剂和/或用于施用组合物的特定方法决定。因此,本领域的技术人员将理解,可以在各种调配物中的任何调配物中包含和/或施用如本文所述的渗透剂。在一些实施例中,适合于局部施用的调配物可以呈现为霜剂、洗剂、液体、血清、凝胶、糊剂、贴剂、粉末、喷雾剂或泡沫。
在一些实施例中,所提供的***可以用于治疗疾病、病症或病状。在一些实施例中,所提供的***可以用于治疗皮肤疾病、病症或病状(例如,“皮肤病状”)。在一些实施例中,皮肤病状可以选自由以下组成的组:例如,黑棘皮病(Acanthosis nigrican)、痤疮、痤疮疤痕、光化性角化病(Actinic keratosis)、斑秃、特应性皮炎(Atopic dermatitis)、基底细胞癌(Basal cell carcinoma)、蜂窝组织炎、唇疱疹接触性皮炎、头皮屑、尿布疹、皮肤干燥、隆突性皮肤纤维肉瘤(Dermatofibrosarcoma protuberan)、汗疱疹、湿疹、生殖器疱疹、生殖器疣、脱发、单纯疱疹感染、化脓性汗腺炎、荨麻疹、多汗症、脓疱病、寻常性鱼鳞病(Ichthyosis vulgaris)、瘢痕瘤和其它疤痕、毛发角化病、扁平苔藓、黑色素瘤、肝斑、默克尔细胞癌、黑痣、***、甲癣、瘙痒、神经性皮炎、皮肤过敏(如镍过敏)、钱币状皮炎、疼痛天疱疮、玫瑰糠疹、毒藤、毒橡树和毒漆树、银屑病、银屑病关节炎、癣、酒渣鼻、疥疮、头皮银屑病、硬皮病、皮脂腺癌、脂溢性皮炎、脂溢性角化病、带状疱疹、皮肤癌、鳞状细胞癌、瘀滞性皮炎、花斑癣、白癜风、疣和伤口愈合。
在一些实施例中,所提供的***可以用于治疗如粘膜等身体组织的疾病、病症或病状。在一些实施例中,所提供的***可以用于治疗与眼睛、鼻子、嘴、喉咙和***干燥相关的疾病、病症或病状。在一些实施例中,身体组织的病状可以选自由肛裂、肛瘘、细菌性***病、口臭、视力模糊、口腔溃疡、白内障、***、结肠炎、结肠息肉、色盲、结膜炎、憩室病、***困难、眼痛、青光眼、牙龈和牙齿问题、痔疮、人***瘤病毒(HPV)、肠易激综合征、喉炎、白斑、黄斑变性、鼻和鼻窦息肉、肛周或肛周脓肿、肛周或肛周感染、咽炎、绝经后粘膜干燥、眼睛发红、鼻窦炎、干燥综合征(syndrome)、喉咙痛、鹅口疮、扁桃体炎、滴虫病、葡萄膜炎和酵母菌感染。
在一些实施例中,所提供的***可以用于改善或保持皮肤的如色素沉着(包含老年斑、肝斑、白癜风、雀斑、炎症后色素沉淀)、毛发生长、毛发颜色、瘢痕、干燥、光泽、细纹和皱纹、光滑度、弹性、弹性组织变性、红斑、指甲外观或结构的变化、不想要的纹身、皮肤变薄、由于萎缩(包含萎缩性瘢痕)导致的皮肤体积损失、紫癜、与UV线暴露或化学暴露相关的损伤、头皮屑、结垢、出汗、突出的毛孔、老茧以及与时间老化和光老化相关的其它变化等一或多种美容性质。
例示
除了其它方面外,本发明实例还描述了可以用于表征和/或评估如本文所述的渗透剂(和/或组分和/或组合物或其组合)的某些策略。此类策略(或如阅读本公开的本领域的技术人员将理解的所述策略的等效物)可以用于评估渗透剂、组分(例如,部分)、组合物或其组合根据本公开使用的适合性。因此,在一些实施例中,本公开提供了用于表征和/或选择有用的部分、连接子、渗透剂和/或组分、组合物和/或其组合的技术。
实例1:CBT改性的分子的皮肤渗透
将CBT与甘氨酸(gly-CBT)和透明质酸(HA-CBT)两者缀合,以研究用CBT官能化的小分子活性物和用CBT官能化的高分子量活性物的皮肤渗透。利用分子量为约250kDA的透明质酸和用1H NMR测量的分站度为大约10%的作为中间间隔物的甘氨酸合成HA-CBT。
将冷冻的猪皮肤平衡到室温,并且然后切成约2×2cm的方块并置入6孔板中的0.9mL PBS中。用金属抹刀将25μL HA-CBT(10mg/mL于PBS中)、gly-CBT(1mg/mL于PBS中)和PBS轻轻涂抹在猪皮肤上形成1cm的圆圈。在涂抹调配物后,将6孔板置于37℃的加湿培养箱中,持续18小时。
然后使用外科手术刀切除应用区域中心中的小区域并将其置入活检模具中的OCT中。通过将活检模具直接置入甲基戊烷干冰浆料中使组织快速冷冻。然后将组织在恒冷箱切片机上切片至20μm的切片。在成像之前,将一滴ProLong Gold放置在每个切片上并用盖玻片覆盖。使用10x物镜和DAPI滤波器在ZeissAxioPlan2上拍摄图像,以可视化CBT的位置。
在角质层和表皮内观察到gly-CBT和HA-CBT两者的高荧光,并且观察到两种分子在真皮中的较低信号。这些结果表明,如分子量为250kDa的HA等大的聚合物和如甘氨酸等小的亲水分子可以在用CBT官能化后渗透皮肤。
实例2:gly-CBT的皮肤渗透和组织相互作用
使用3D人皮肤模型(Mattek EpiDermTM)评估gly-CBT在人皮肤中的渗透和相互作用。在使皮肤组织与培养基在6孔板中于37℃下平衡1小时后,将培养基替换为PBS,并将100μL的PBS和gly-CBT(1mg/mL)各自应用到4个皮肤组织的顶部。温育6小时后,将来自每组的单个组织在OCT中快速冷冻,以进行冷冻切片和显微镜检查。对于剩余样品,收集保留在组织***物顶部的液体(约100μL)和受体溶液中的液体(900μL)。然后用PBS将组织***物的顶部洗涤2x,并且然后将***物浸入2mL 1:1的PBS:MeOH溶液中,以提取渗透皮肤的分子。在37℃下提取2小时后,通过用读板器读取326nm处的吸光度来测量供体、受体和提取液中的gly-CBT的浓度。如实例1中所述,使用荧光显微镜检查对剩余组织***物进行冷冻切片和成像。
如图4的小图A所示,温育6小时后,仅保留约25%的应用于表皮组织表面上的gly-CBT,这表明显著的渗透。令人惊讶的是,在提取程序之后并且在供体溶液和受体溶液中,仅检测到总gly-CBT的约50%。只能够从表皮组织中提取约10%的所应用的gly-CBT;然而,用显微镜检查在组织内观察到显著的荧光信号(图4,小图C-D)。
为了进一步研究gly-CBT在人皮肤组织中的渗透,在将gly-CBT和gly-氨基荧光素(gly-Luc)应用到EpiDermTM组织中之后,使用HPLC对不同化学物种的分布进行定量。如上所述,将100μL的gly-CBT和gly-Luc应用于皮肤组织的顶部。在温育6小时后,收集供体溶液和受体溶液,并尝试用1:1的MeOH:PBS提取渗透皮肤的化学物种。在第一提取方案之后,用PBS冲洗组织***物并通过用UV254灯曝光在暗室中成像。成像后,依次用1.0%Triton X-100、酸化MeOH(0.1%TFA)和DCM进行另外的提取。之后的提取都未成功提取出任何另外的CBT物种。
如图5的小图A-B所示,<20%的应用的gly-CBT和gly-荧光素在暴露于组织6小时后保留在供体溶液中。此外并且与图2所示的先前研究一致,gly-CBT和gly-Luc的总回收率<60%(图3,小图C)。在第一次提取过程和洗涤步骤之后,暴露于gly-CBT的组织***物具有极强的荧光(图3,小图D)。这表明由于与表皮组织的相互作用,很大一部分渗透表皮组织的gly-CBT无法提取。令人惊讶的是,表面活性剂(0.1%Triton X-100溶液)、酸化甲醇或二氯甲烷均无法提取出更多的CBT物种,这表明与皮肤组织有很强的相互作用。
实例3:局部应用的CBT官能化分子的生物相容性。
为了评估CBT官能化分子的生物相容性,使用由马泰克公司(Mattek)供应的3D重建表皮模型进行皮肤刺激研究。以OECD TG 439方案为基础进行皮肤刺激测试。在从马泰克公司获得EpidermTM(Epi-200)后,将组织***物从琼脂糖中去除并在6孔板的0.9mL培养基中于37℃下温育1小时。然后将组织***物转移到含有0.9mL的新鲜培养基的新孔中并在37℃下温育过夜18小时。将30μL的PBS、HA-CBT(20mg/mL和2mg/mL于PBS中)、gly-CBT(1mg/mL和0.1mg/mL)和SDS(5wt%)各自应用并涂抹在3个独立组织***物的顶部。在37℃下温育1小时后,移出调配物并用PBS洗涤组织***物三次。然后将组织***物在新鲜培养基中于37℃下温育24小时。然后将培养基与新鲜培养基交换,并将***物在37℃下再温育另外18小时。温育后,使用MTT测定评估组织的活力,所述MTT测定在马泰克公司制定的方案(EPI-200-SIT)中详细讨论。
虽然阳性对照(5%SDS)显示皮肤组织中细胞活力几乎100%降低的显著刺激,但gly-CBT和HA-CBT均未显示细胞活力的任何降低。这表明两种CBT改性的分子均是非刺激物并且与人皮肤组织相容。
实例4:HA-CBT在人皮肤上的保留。
为了评估HA-CBT相对于天然HA的保留时间,用IR标签标记HA。通过将CF-647胺与HA(约50kDa)缀合合成IR标记的HA(IR-HA)。将CBT与IR-HA缀合以产生IR-HA-CBT,其中CBT的取代度为10mol%。
将冷冻的人皮肤解冻,并且用肥皂轻轻洗涤角质层(SC),然后进行胶带剥离20次以减少SC厚度。将胶带剥离的皮肤片置入Franz扩散池中并在37℃下用PBS平衡1小时。在平衡后,在37℃的加湿烘箱中的供体隔室中,将皮肤片暴露于IR-HA(10mg/mL于PBS中)或IR-HA-CBT(10mg/mL于PBS中)中持续5小时。5小时后,去除IR-HA和IR-HA-CBT溶液,并且用PBS洗涤皮肤表面三次。然后将皮肤在37℃的供体隔室中暴露于PBS过夜。在Franz扩散池中温育后,将皮肤片快速冷冻并在低温恒温器上切片。将含有冷冻切片的载玻片在室温下在PBS中进一步洗涤30分钟。在这最后一个洗涤步骤之后,用90%甘油固定载玻片并在具有Cy5过滤器的荧光显微镜上成像,以可视化所选IR染料的位置。
在用IR-HA-CBT处理的皮肤的上表皮/SC中观察到强IR信号,而在用IR-HA处理的皮肤中未观察到IR信号(图7)。因为皮肤被胶带剥离以减少SC的厚度,所以IR-HA和IR-HA-CBT两者均渗透皮肤。然而,在由在Franz池中用PBS洗涤皮肤过夜和在PBS中洗涤载玻片上的冷冻切片两者组成的剧烈的洗涤步骤后,皮肤样品仅保留了IR-HA-CBT,这表明通过与CBT缀合,IR-HA在人皮肤中,具体地在表皮和SC的上层的保留增加。
Claims (14)
5.根据权利要求1所述的渗透剂,其中L为通过基团中的任何一个基团的化学键。
6.根据权利要求1所述的渗透剂,其中L为任选地经取代的C1-6亚烷基链,其中L的一个、两个或三个亚甲基单元任选地并且独立地被-NH-、-O-、-S-或-C(O)-替代。
7.根据权利要求1所述的***,其中A为纳米颗粒,其中所述纳米颗粒包封一或多种治疗剂。
8.根据权利要求1所述的***,其中m大于1。
9.根据权利要求1所述的***,其中A选自用于治疗美容性病状的药剂。
10.根据权利要求1所述的***,其中A选自用于治疗皮肤病学病状的药剂。
11.根据权利要求1所述的***,其中L能在生物学条件下降解。
12.根据权利要求1所述的***,其中A为防晒剂。
13.根据权利要求1所述的***,其中活性剂是维生素、视黄酸衍生物、着色剂或剥离素。
14.一种通过向有需要的受试者施用根据权利要求1所述的***来治疗所述受试者的方法。
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