CN107849083A - 用于治疗皮肤病症的烟酰胺核苷和紫檀芪组合物和方法 - Google Patents
用于治疗皮肤病症的烟酰胺核苷和紫檀芪组合物和方法 Download PDFInfo
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- CN107849083A CN107849083A CN201680046668.7A CN201680046668A CN107849083A CN 107849083 A CN107849083 A CN 107849083A CN 201680046668 A CN201680046668 A CN 201680046668A CN 107849083 A CN107849083 A CN 107849083A
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Abstract
描述了用于治疗皮肤病症的含有烟酰胺核苷和紫檀芪的组合的组合物,以及使用这些组合物及其等效物来治疗皮肤病症的方法。使用这些组合物或方法治疗的皮肤病症包括日光暴露相关性皮肤病症、炎性皮肤病症、自身免疫疾病相关性皮肤病症和癌症相关性皮肤病症。在一个实施方案中,将含有烟酰胺核苷和紫檀芪的组合的组合物制备为口服制剂。
Description
相关申请引用
本申请要求美国临时申请号62/173,733的权益,该申请通过引用以其全部并入本文。
发明领域
本发明领域大体上涉及用于治疗皮肤病症的组合物和方法。特别地,本发明涉及用于治疗皮肤病症的烟酰胺核苷和紫檀芪组合物和方法。
发明背景
皮肤病症属于最常见人体疾病。它们影响约30%至约70%的个体,并且在全球水平上被排列为非致命疾病负担的第四大主要原因(Hay等人,J.Invest.Dermatol.2014,134,1527-1534)。根据国际疾病分类的最新研究,10类人体疾病中存在一千多种皮肤病症,其中几种病状导致大多数的皮肤疾病负担(Hay等人,J.Invest.Dermatol.2014,134,1527-1534)。总地来说,在2010年皮肤病症是表示为因伤残所致年数损失的非致命负担的第四大主要原因。皮肤病症对个体造成若干有害影响,例如损害健康相关的生活质量、畏惧他人的负面评价、身体无能和死亡。尽管如此,皮肤病症持续受到极少的关注(Hay等人,J.Invest.Dermatol.2014,134,1527-1534)。
标准治疗包括避免引发物例如日光暴露。治疗或预防性药剂的组合物可全身递送,例如经由口服施用、局部施加或注入真皮层。多年以来已使用了各种各样的治疗和方法,包括局部施加皮质类固醇、维生素D3类似物例如卡泊三烯、煤焦油等。一些患者已利用了沐浴液(bath solution)和通用保湿剂。还已使用了阳光和紫外光治疗。有时需要利用维甲类、甲氨蝶呤、环孢霉素、羟基脲和抗生素的全身治疗。最近,已开发出新的生物药剂和生物免疫应答调节剂,例如阿来西普、依法珠单抗和依那西普。
这些治疗的每一种具有其益处和缺点。在许多情况下,患者产生了对治疗的耐性,从而导致有效性降低。另外,这些治疗往往是麻烦的(messy),具有令人不悦的气味,并且对患者而言是重复和乏味的。
Suave等人的美国专利号9,00,147描述了用于治疗皮肤病症的烟酰核苷和烟酰胺核苷衍生物的口服和局部组合物。欧洲专利号2,493,462描述了含有紫檀芪和任选栎精或其任何可接受的盐的组合物,经由局部施用用于皮肤疾病和损伤的预防、治疗或两者。WO2015/066382描述了口服和局部皮肤护理组合物,其含有烟酰胺核苷或其盐,任选地与以下化合物组合:例如芪类化合物(例如,紫檀芪)、姜黄素、肽、视黄醇、水杨酸、过氧化苯甲酰、维生素C(L-抗坏血酸)、花色素苷或其组合。
鉴于所述多种有害影响和对皮肤病症的很少关注,对不涉及抗生素和免疫抑制剂的用于皮肤病症的全身治疗的制剂和方法存在需要。
发明详述
一种组合物,其包含治疗有效量的烟酰胺核苷和治疗有效量的紫檀芪的组合,以及药学上可接受的赋形剂,其中所述组合为治疗皮肤病症的治疗有效量。
一种方法,其包括施用治疗有效量的烟酰胺核苷和治疗有效量的紫檀芪的组合以治疗需要治疗皮肤病症的患者中的皮肤病症。
描述了治疗皮肤病症的口服制剂和方法。在某些实施方案中,组合物可含有治疗有效量的烟酰胺核苷、治疗有效量的紫檀芪或两者。在某些实施方案中,组合物可含有烟酰胺核苷和紫檀芪。在某些实施方案中,方法可包括施用治疗有效量的烟酰胺核苷和/或紫檀芪。在某些实施方案中,方法可包括口服施用治疗有效量的烟酰胺核苷和紫檀芪的组合。在某些实施方案中,方法可包括口服施用治疗有效量的烟酰胺核苷和紫檀芪的组合来治疗皮肤病症。
在某些实施方案中,组合物可含有治疗有效量的烟酰胺核苷、治疗有效量的紫檀芪或两者。在某些实施方案中,组合物可含有烟酰胺核苷和紫檀芪。在某些实施方案中,方法可包括施用治疗有效量的烟酰胺核苷和/或紫檀芪。在某些实施方案中,方法可包括局部施用治疗有效量的烟酰胺核苷和紫檀芪的组合。在某些实施方案中,方法可包括局部施用治疗有效量的烟酰胺核苷和紫檀芪的组合来治疗皮肤病症。
在某些实施方案中,可以每天约100mg至约1000mg的量来施用烟酰胺核苷。烟酰胺核苷可与紫檀芪组合施用,可以每天约25mg至约500mg的量来施用紫檀芪。
在某些实施方案中,可以每天约200mg至约700mg的量来施用烟酰胺核苷。烟酰胺核苷可与紫檀芪组合施用,可以每天约25mg至约250mg的量来施用紫檀芪。
在某些实施方案中,可以每天约250mg的量来施用烟酰胺核苷。烟酰胺核苷可与紫檀芪组合施用,可以每天约25mg至约250mg的量来施用紫檀芪。在某些实施方案中,可以每天约250mg的量来施用烟酰胺核苷。烟酰胺核苷可与紫檀芪组合施用,可以每天约50mg的量来施用紫檀芪。
一种组合物,其包含治疗有效量的烟酰胺单核苷酸和治疗有效量的ε-葡萄素(viniferin)的组合以及药学上可接受的赋形剂,其中所述组合为治疗皮肤病症的治疗有效量。
一种方法,其包括施用治疗有效量的烟酰胺单核苷酸和治疗有效量的ε-葡萄素的组合以治疗需要治疗皮肤病症的患者中的皮肤病症。
一种组合物,其包含治疗有效量的烟酰胺单核苷酸和治疗有效量的烟酸的组合以及药学上可接受的赋形剂,其中所述组合为治疗皮肤病症的治疗有效量。
一种方法,其包括施用治疗有效量的烟酰胺单核苷酸和治疗有效量的烟酸的组合以治疗需要治疗皮肤病症的患者中的皮肤病症。
一种组合物,其包含治疗有效量的烟酰胺核苷和治疗有效量的ε-葡萄素的组合以及药学上可接受的赋形剂,其中所述组合为治疗皮肤病症的治疗有效量。
一种方法,其包括施用治疗有效量的烟酰胺核苷和治疗有效量的ε-葡萄素的组合以治疗需要治疗皮肤病症的患者中的皮肤病症。
一种组合物,其包含治疗有效量的烟酰胺核苷和治疗有效量的白藜芦醇的组合以及药学上可接受的赋形剂,其中所述组合为治疗皮肤病症的治疗有效量。
一种方法,其包括施用治疗有效量的烟酰胺核苷和治疗有效量的白藜芦醇的组合以治疗需要治疗皮肤病症的患者中的皮肤病症。
本文描述了用于治疗皮肤病症的含有烟酰胺核糖、紫檀芪或其组合的药物组合物。在某些实施方案中,组合物可含有治疗有效量的烟酰胺核糖。在某些实施方案中,组合物可含有治疗有效量的紫檀芪。
在某些实施方案中,组合物可含有治疗有效量的烟酰胺核糖和紫檀芪的组合。药物组合物可呈软凝胶胶囊或硬壳胶囊的形式,或其它固体形式例如片剂。在某些实施方案中,药物组合物可含有约250mg的烟酰胺核苷和约50mg的紫檀芪。药物组合物可每日施用一次或更多次。在某些实施方案中,组合物可每日施用两次。在每日施用两次药物组合物的实施方案中,组合物可含有约125mg的烟酰胺核苷和约25mg的紫檀芪。在某些实施方案中,含有烟酰胺核苷和紫檀芪的化合物、组合物或药物组合物可制备为口服制剂。在某些实施方案中,含有烟酰胺核苷和紫檀芪的化合物、组合物或药物组合物可制备为局部制剂。
本发明的其它特征、优点和实施方案经阐述或从考虑以下详细描述和权利要求书中显而易见。此外,应理解前文的发明内容和下文的详述是示例性的,并且旨在提供进一步解释而不限制如所要求保护的本发明的范围。
I.定义
术语“患者”、“对象”、“个体”或“宿主”指的是人或非人动物。
术语“治疗”和“改善”意指皮肤病症的视觉指标在施用后被治愈、减弱、减少、改善、减轻、缓和、预防和/或逆转。皮肤病症的视觉指标可为脸红、红斑、丘疹、脓疱、毛细血管扩张、面部水肿、肥大性酒渣鼻、牛皮癣、发红、光滑、粗糙、血管过多和/或面部瑕疵。
如本文所使用的,术语“治疗有效的”指的是产生期望治疗结果所需的烟酰胺核苷和紫檀芪的量。在某些实施方案中,烟酰胺单核苷酸、烟酰胺(niacinamide、nicotinamide)和/或烟酸(nicotinic acid、niacin)可代替烟酰胺核苷。在某些实施方案中,可使用烟酰胺核苷、烟酰胺单核苷酸和/或烟酸的组合。在某些实施方案中,ε-葡萄素和/或白藜芦醇可代替紫檀芪。在某些实施方案中,可使用紫檀芪、ε-葡萄素和/或白藜芦醇的组合。
如本文所使用的,术语“药学上可接受的载体”指的是药学上可接受的物质、组合物或载体,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包胶材料,参与运载或运输任何主题组合物或其组分。
如本文通常所使用的,“药学上可接受的”指的是在合理医学判断的范围内,与合理的收益/风险比相称的适合于与人类和动物的组织、器官和/或体液接触使用而不具有过量毒性、刺激性、过敏性响应或其它问题或并发症的那些化合物、材料、组合物和/或剂型。
如本文所使用的,“立体异构体”指的是具有相同分子式和键合原子顺序(构造),但其原子在空间中的三维定向上有差异的异构分子。立体异构体的实例包括对映体和非对映体。如本文所使用的,对映体指的是旋光性或手性分子的两种镜像形式之一。外消旋混合物含有旋光性或手性分子的两种形式。非对映体(或非对映异构体)是不为对映体的立体异构体(彼此为非可重叠镜像)。手性分子含有手性中心,也称为立构中心或立体中心,所述中心是在携带基团的分子中的任何点,但不一定是原子,其使得任两个基团的互换导致立体异构体。在有机化合物中,手性中心通常是碳、磷或硫原子,但其它原子也可能是有机和无机化合物中的立构中心。一分子可具有多个立构中心,从而赋予其多种立体异构体。在其立体异构现象归因于四面体立体中心(例如,四面体碳)的化合物中,假设可能的立体异构体的总数将不超过2n,其中n是四面体立构中心的数量。具有对称性的分子常常具有少于最大可能立体异构体数的立体异构体数。对映体的50∶50混合物被称为外消旋混合物。对映体的混合物可富集对映体,使得一种对映体以大于50%的量存在。对映体和/或非对映体可使用本领域已知的技术来拆分或分离。
如本文所使用的,“取代的”指的是本文所述的化合物或官能团的所有可允许的取代基。可允许的取代基可包括有机化合物的无环和环状、支链和非支链、碳环和杂环、芳族和非芳族的取代基。示例性取代基包括但不限于:卤素、羟基或含有任意碳原子数(其可为1-14个碳原子),并且在直链、支链或环状结构形式(format)中任选地包括例如氧、硫或氮基团的一个或更多个杂原子的任何其它有机基团。代表性的取代基包括烷基、取代烷基、烯基、取代烯基、炔基、取代炔基、苯基、取代苯基、芳基、取代芳基、杂芳基、取代杂芳基、卤素、羟基、烷氧基、取代烷氧基、苯氧基、取代苯氧基、芳氧基、取代芳氧基、烷基硫基、取代烷基硫基、苯基硫基、取代苯基硫基、芳基硫基、取代芳基硫基、氰基、异氰基、取代异氰基、羰基、取代羰基、羧基、取代羧基、氨基、取代氨基、酰氨基、取代酰氨基、磺酰基、取代磺酰基、磺酸、磷酰基、取代磷酰基、膦酰基、取代膦酰基、多芳基、取代多芳基、C3-C20环状基团、取代C3-C20环状基团、杂环基团、取代杂环基团、氨基酸、聚(乳酸-共-乙醇酸)、肽和多肽基团。这类烷基、取代烷基、烯基、取代烯基、炔基、取代炔基、苯基、取代苯基、芳基、取代芳基、杂芳基、取代杂芳基、卤素、羟基、烷氧基、取代烷氧基、苯氧基、取代苯氧基、芳氧基、取代芳氧基、烷基硫基、取代烷基硫基、苯基硫基、取代苯基硫基、芳基硫基、取代芳基硫基、氰基、异氰基、取代异氰基、羰基、取代羰基、羧基、取代羧基、氨基、取代氨基、酰氨基、取代酰氨基、磺酰基、取代磺酰基、磺酸、磷酰基、取代磷酰基、膦酰基、取代膦酰基、多芳基、取代多芳基、C3-C20环状基团、取代C3-C20环状基团、杂环基团、取代杂环基团、氨基酸、聚(乳酸-共-乙醇酸)、肽和多肽基团可被进一步取代。
杂原子(例如氮)可具有氢取代基和/或满足杂原子价态的本文中所述的有机化合物的任何可允许的取代基。要理解,“取代”或“取代的”包括隐含条件:这种取代是根据被取代原子和取代基的允许价态,并且取代产生稳定化合物,即不自发经历例如通过重排、环化、消除等转化的化合物。
术语“烷基”指的是饱和脂族基的基团,包括直链烷基、支链烷基、环烷基(脂环族基)、烷基取代的环烷基和环烷基取代的烷基。
在一些实施方案中,直链或支链烷基在其骨架中具有30个或更少(例如,对于直链是C1-C30,对于支链是C3-C30)、20个或更少、15个或更少或10个或更少的碳原子。同样地,一些环烷基在其环结构中具有3-10个碳原子,并且可在环结构中具有5、6或7个碳。如在整个说明书、实施例和权利要求书中所使用的,术语“烷基”(或“低级烷基”)可包括“未取代烷基”和“取代烷基”,两者中的后者指的是具有取代烃骨架的一个或更多个碳上的氢的一个或更多个取代基的烷基部分。这类取代基包括但不限于:卤素(例如氟、氯、溴或碘)、羟基、羰基(例如羧基、烷氧基羰基、甲酰基或酰基)、硫代羰基(例如硫代酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、亚膦酸酯、氨基、酰氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷基硫基、硫酸酯、磺酸酯、氨磺酰基、亚磺酰氨基、磺酰基、杂环基、芳烷基、或者芳族或杂芳族部分、-NRR′,其中R和R′独立地为氢、烷基或芳基,并且其中氮原子任选地季铵化;-SR,其中R为氢、烷基或芳基;-CN;-NO2;-COOH;羧酸酯;-COR,-COOR或-CON(R)2,其中R为氢、烷基或芳基;叠氮、芳烷基、烷氧基、亚氨基、膦酸酯、亚膦酸酯、甲硅烷基、醚、磺酰基、亚磺酰氨基、杂环基、芳族或杂芳族部分、卤代烷基(例如-CF3、-CH2-CF3、-CCl3);-CN;-NCOCOCH2CH2;-NCOCOCHCH;-NCS;及其组合。
除非另外规定碳的数目,否则如本文中所使用的“低级烷基”意指如前定义的烷基,但在其骨架结构中具有一至十个碳原子或一至六个碳原子。同样地,“低级烯基”和“低级炔基”具有类似的链长。在整个本申请中,烷基可为低级烷基。在一些实施方案中,本文中称为烷基的取代基是低级烷基。
本领域技术人员将理解,适当时,在烃链上取代的部分自身可为取代的。例如,取代烷基的取代基可包括卤素、羟基、硝基、硫醇基、氨基、叠氮基、亚氨基、酰氨基、磷酰基(包括膦酸酯和亚膦酸酯)、磺酰基(包括硫酸酯、亚磺酰氨基、氨磺酰基和磺酸酯),和甲硅烷基,以及醚、烷基硫基、羰基(包括酮、醛、羧酸酯和酯)、-CF3、-CN等等。环烷基可以相同方式被取代。
术语“烯基”和“炔基”指的是在长度上类似并且可能代替上述烷基但分别含有至少一个双键或三键的不饱和脂族基团。
术语“取代烯基”指的是具有取代烃骨架的一个或更多个碳上的一个或更多个氢原子的一个或更多个取代基的烯基部分。这类取代基包括但不限于:卤素、叠氮、烷基、芳烷基、烯基、炔基、环烷基、羟基、羰基(例如羧基、烷氧基羰基、甲酰基或酰基)、甲硅烷基、醚、酯、硫代羰基(例如硫代酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、亚膦酸酯、氨基(或季铵化氨基)、酰氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷基硫基、硫酸酯、磺酸酯、氨磺酰基、亚磺酰氨基、磺酰基、杂环基、烷芳基、卤代烷基、-CN、芳基、杂芳基及其组合。
术语“取代炔基”指的是具有取代烃骨架的一个或更多个碳上的一个或更多个氢原子的一个或更多个取代基的炔基部分。这类取代基包括但不限于:卤素、叠氮、烷基、芳烷基、烯基、炔基、环烷基、羟基、羰基(例如羧基、烷氧基羰基、甲酰基或酰基)、甲硅烷基、醚、酯、硫代羰基(例如硫代酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、亚膦酸酯、氨基(或季铵化氨基)、酰氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷基硫基、硫酸酯、磺酸酯、氨磺酰基、亚磺酰氨基、磺酰基、杂环基、烷芳基、卤代烷基、-CN、芳基、杂芳基及其组合。
如本文所使用的,“芳基”指的是C5-C26元芳族、稠合芳族、稠合杂环或二芳族环体系。如本文所使用的,“芳基”可包括5-、6-、7-、8-、9-、10-、14-、18-和24元单环芳族基团,例如苯、萘、蒽、菲、芘、碗烯(corannulene)、晕苯等。“芳基”进一步包括具有两个或更多个环状环的多环环体系,其中两个或更多个碳为两个毗连环(即,“稠合环”)所共有,其中至少一个环是芳族的,例如,其它一个或更多个环状环可为环烷基、环烯基、环炔基、芳基和/或杂环。
术语“取代芳基”指的是其中一个或更多个芳族环上的一个或更多个氢原子被一个或更多个取代基取代的芳基,所述取代基包括但不限于:卤素、叠氮、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、羰基(例如酮、醛、羧基、烷氧基羰基、甲酰基或酰基)、甲硅烷基、醚、酯、硫代羰基(例如硫代酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、亚膦酸酯、氨基(或季铵化氨基)、酰氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、亚氨基、烷基硫基、硫酸酯、磺酸酯、氨磺酰基、亚磺酰氨基、磺酰基、杂环基、烷芳基、卤代烷基(例如CF3、-CH2-CF3、-CCl3)、-CN、芳基、杂芳基及其组合。
“杂环”、“杂环的”和“杂环基”可互换使用,并且指的是经由含有3-10个环原子的单环或双环环的环碳或氮原子连接的环状基团,并且可具有5-6个环原子,包括碳和一至四个杂原子,所述杂原子各自选自非过氧化氧、硫和N(Y),其中Y不存在或为H、O、C1-C10烷基、苯基或苄基,并且任选地含有1-3个双键且任选被一个或更多个取代基取代。杂环基在定义上有别于杂芳基。杂环的实例包括但不限于哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、二氢呋喃并[2,3-b]四氢呋喃、吗啉基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、吡喃基、2H-吡咯基、4H-喹嗪基、奎宁环基、四氢呋喃基、6H-1,2,5-噻二嗪基。杂环基团可任选地被如上文针对烷基和芳基所定义的一个或更多个取代基取代。
术语“杂芳基”指的是C5-C26元芳族、稠合芳族、二芳族环体系或其组合,其中一个或更多个芳族环结构上的一个或更多个碳原子已被杂原子取代。合适的杂原子包括但不限于氧、硫和氮。广义上定义,如本文所使用的“杂芳基”包括5-、6-、7-、8-、9-、10-、14-、18-和24-元单环芳族基团,所述芳族基团可包括一至四个杂原子,例如吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、三唑、四唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等等。杂芳基还可被称为“芳基杂环”或“杂芳族基(heteroaromatics)”。“杂芳基”进一步包括具有两个或更多个环的多环环体系,其中两个或更多个碳为两个毗连环(即,“稠合环”)所共有,其中至少一个环是杂芳族的,例如,其它一个或更多个环状环可为环烷基、环烯基、环炔基、芳基、杂环或其组合。杂芳基环的实例包括但不限于:苯并咪唑基、苯并呋喃基、苯并噻吩基(benzothiofuranyl)、苯并噻吩基(benzothiophenyl)、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、吲哚啉基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲基二氧基苯基、萘啶基、八氢异喹啉基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、酚黄素基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基(pyridinyl,pyridyl)、嘧啶基、吡咯烷基、吡咯啉基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四氢异喹啉基、四氢喹啉基、四唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基和呫吨基。环中的一个或更多个可如下文针对“取代杂芳基”所定义般被取代。
术语“取代杂芳基”指的是其中一个或更多个杂芳族环上的一个或更多个氢原子被一个或更多个取代基取代的杂芳基,所述取代基包括但不限于:卤素、叠氮、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、羰基(例如酮、醛、羧基、烷氧基羰基、甲酰基或酰基)、甲硅烷基、醚、酯、硫代羰基(例如硫代酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯、膦酸酯、亚膦酸酯、氨基(或季铵化氨基)、酰氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、亚氨基、烷基硫基、硫酸酯、磺酸酯、氨磺酰基、亚磺酰氨基、磺酰基、杂环基、烷芳基、卤代烷基(例如CF3、-CH2-CF3、-CCl3)、-CN、芳基、杂芳基及其组合。
如本文中所使用的术语“杂原子”意指不同于碳或氢的任何元素的原子。示例性杂原子包括氮、氧和硫。
“类似物”和“衍生物”可互换使用,并且指的是具有与母体化合物相同的核,但在键级、一个或更多个原子和/或原子团的缺乏或存在及其组合上不同于母体化合物的化合物。衍生物可例如在核上存在的一个或更多个取代基上不同于母体化合物,其可包括一个或更多个原子、官能团或子结构。一般地,可想象(至少在理论上)经由化学和/或物理过程由母体化合物形成衍生物。
II.组合物
A.活性剂
i.烟酰胺核苷
如上文所讨论的,在某些实施方案中,所述方法和组合物含有烟酰胺核苷,其为辅酶NAD+的前体,其参与代谢过程例如能量产生、DNA修复、细胞解毒、炎症响应和蛋白质折叠。烟酰胺核苷的化学结构提供于下方。
烟酰胺核苷具有四个不对称中心,并且可使用任何旋光异构体,如分离的、纯的或部分纯化的旋光异构体及其任何混合物,包括外消旋混合物。对映体形式可为对映体过量,例如,基本上呈纯的形式。因此,一些实施方案涉及具有至少60%、至少70%、至少80%、至少85%、至少90%、至少96%、至少98%和其间范围的对映体过量的烟酰胺核苷。
外消旋形式可通过已知方法拆分成旋光对映体,例如通过用旋光性酸分离其非对映盐,和通过用碱处理来释放旋光性胺化合物。用于将外消旋物拆分成旋光对映体的另一种方法是基于在旋光性基质上的层析。还可通过形成非对映衍生物来拆分本发明的化合物。可使用本领域技术人员已知的用于拆分旋光异构体的另外的方法。这类方法包括由J.Jacques、A.Collet和S.Wilen在“Enantiomers,Racemates,and Resolutions”,JohnWiley and Sons,New York (1981)中讨论的那些。旋光性化合物还可由旋光性起始材料制备。
烟酰胺核苷是一种季铵盐,并且与抗衡阴离子形成离子键。抗衡阴离子的实例包括例如以下的合适有机酸的阴离子:甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、乙醇酸、衣康酸、乳酸、甲磺酸、马来酸、苹果酸、丙二酸、扁桃酸、草酸、苦味酸、丙酮酸、水杨酸、丁二酸、甲磺酸、乙磺酸、酒石酸、抗坏血酸、扑酸、二亚甲基水杨酸、乙二磺酸、葡糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、乙醇酸、对氨基苯甲酸、谷氨酸、苯磺酸、对甲苯磺酸、茶碱乙酸以及8-卤代茶碱,例如8-溴茶碱等等。药学上可接受的无机或有机酸抗衡阴离子的其它实例包括J.Pharm.Sci.66,2(1977)中所列出的药学上可接受的盐。在某些其它实施方案中,活性剂是烟酰胺核苷的衍生物、盐、溶剂合物或前药。在一些实施方案中,烟酰胺核苷中的核糖是β-D-核糖。在某些实施方案中,烟酰胺核苷可被以下代替或与以下组合:烟酰胺单核苷酸、烟酰胺(niacinamide、nicotinamide)和/或烟酸(nicotinic acid、niacin)。
在一些实施方案中,活性剂具有根据式I的化学结构:
或为其药学上的盐,其中:
X是O、S或NR;
R1和R2可为氢、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的非芳族杂环基团或取代或未取代的芳基;
R3、R4、R5和R6可选自:氢、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的非芳族杂环基团、卤素、-OR、-CN、-CO2R、-OCOR、-OCO2R、-C(O)NRR′、-OC(O)NRR′、-C(O)R、-COR、-SR、-OSO3H、-S(O)nR、-S(O)nOR、-S(O)nNRR′、-NRR′、-NRC(O)OR′、-NO2和-NRC(O)R′;
R7、R9和R10可选自:氢、取代或未取代的烷基、取代或未取代的芳基、-C(O)R、-C(O)OR、-C(O)NHR、-C(O)NRR′、-S(O)nR、-S(O)nOR、-S(O)nNRR′、-C(S)R、-C(S)OR和-C(O)SR;以及
R8、R11和R12可选自:氢、取代或未取代的烷基、取代或未取代的芳基、取代或未取代的非芳族杂环基团、卤素、-CN、-CO2R、-OCOR、-OCO2R、-C(O)NRR′、-OC(O)NRR′、-C(O)R、-COR、-OSO3H、-S(O)nR、-S(O)nOR、-S(O)nNRR′、-NRR′、-NRC(O)OR′、-NO2和-NRC(O)R′;
其中R和R′可为氢、取代或未取代的烷基、取代或未取代的芳基或取代或未取代的非芳族杂环基团;并且n为1或2。式I的化合物可包括其异构体、对映体和立体异构体。
ii.紫檀芪
紫檀芪是白藜芦醇的基于多元酚的衍生物,并且像NAD+前体般促进代谢健康。紫檀芪的化学结构提供于下方:
在一些实施方案中,活性剂是紫檀芪的衍生物、盐、溶剂合物或前药。在某些实施方案中,紫檀芪可被以下代替和/或与以下组合:ε-葡萄素和/或白藜芦醇。
在某些其它实施方案中,活性剂是具有根据式II的化学结构的芪:
或为其药学上可接受的盐,其中:
R′1、R′2和R′3可为氢、取代或未取代的烷基、取代或未取代的芳基、-C(O)R、-C(O)OR、-C(O)NHR、-C(O)NRR′、-S(O)nR、-S(O)nOR、-S(O)nNRR′、-C(S)R、-C(S)OR和-C(O)SR;
其中R和R′可为氢、取代或未取代的烷基、取代或未取代的芳基或取代或未取代的非芳族杂环基团;并且n为1或2。式II和式III的化合物可包括其异构体、对映体和立体异构体。
B.施用途径
在一个实施方案中,将化合物、组合物或药物组合物配制用于口服递送,即,呈口服制剂形式。口服固体剂型大体上描述于Remington’s Pharmaceutical Sciences,第18版,1990(Mack Publishing Co.Easton Pa.18042),第89章中。固体剂型包括片剂、胶囊、丸剂、片剂(troche)或锭剂、扁囊剂、弹丸剂、散剂或颗粒剂,或者将该材料掺合至例如聚乳酸、聚乙醇酸等的聚合物的粒状制剂中或脂质体中。这类组合物可影响所公开的物理状态、稳定性、体内释放速率和体内清除速率。参见,例如,Remington’s PharmaceuticalSciences,第18版(1990,Mack Publishing Co.,Easton,Pa.18042),第1435-1712页。组合物可以液体形式制备,或可呈干燥粉末(例如,冻干)形式。可使用脂质体或类蛋白包胶来配制组合物。可使用脂质体包胶并且可利用各种聚合物来衍生脂质体(例如,美国专利号5,013,556)。还参见,Marshall,K.在由G.S.Banker和C.T.Rhodes编辑的ModernPharmaceutics,第10章,1979。制剂可包括肽(或其化学改性形式)和惰性成分,所述惰性成分在胃环境中保护化合物并在肠中释放生物活性物质。
可将烟酰胺核苷、烟酰胺(niacinamide、nicotinamide)、烟酸(nicotinic acid)、紫檀芪、烟酰胺单核苷酸、烟酸(niacin)、ε-葡萄素、白藜芦醇或其衍生物化学改性,以使得化合物的口服和/或局部递送有效。考虑的化学改性是将至少一个部分连接至组分分子自身,其中所述部分允许从胃或肠吸收至血流中或直接吸收至肠粘膜中。还考虑的是提高一种或更多种组分的总体稳定性并增加体内循环时间。某些实施方案可为药物组合物。某些实施方案可为营养补充剂。
某些实施方案提供用于口服施用的液体剂型,包括药学上可接受的乳剂、溶液剂、混悬剂和糖浆剂,所述剂型可含有其它组分,包括:惰性稀释剂;辅剂例如润湿剂;乳化和悬浮剂以及甜味剂和矫味剂。
可提供控释口服制剂。控释可包括但不限于延迟释放和pH依赖型释放。在某些实施方案中,可通过使用包衣将烟酰胺核苷和紫檀芪或其衍生物掺合至微胶囊、微粒、纳米颗粒等中,以影响活性成分的释放。在某些实施方案中,可将烟酰胺核苷和紫檀芪或其衍生物掺合至允许通过扩散或沥滤机制来释放的惰性基质(例如胶)中。还可将缓慢变性的基质掺合至制剂中。
可提供改进释放的口服制剂。改进释放可允许特定的释放曲线。
可提供缓释口服制剂。缓释可允许在期望时间段内释放活性成分。
对不同释放制剂和相关术语的其它讨论可在Lesczek Krowczynski,Extended-Release Dosage Forms,1987(CRC Press,Inc.)中找到。
在某些方面,控释、改进释放或缓释口服制剂的形式是用于口服施用的片剂、胶囊或微珠。在其它方面,包含合适和有效治疗量的期望组分的控释、改进释放或缓释制剂可为丸剂、散剂、颗粒剂、无菌肠外溶液剂或混悬剂、口服溶液剂或混悬剂、油水乳剂以及植入物和微胶囊递送系统。
其它制剂可提供控释、改进释放或缓释曲线。本发明的组合物可包含常规药物粘合剂、赋形剂和添加剂,当以充足的量使用时其可用于控释、改进释放或缓释。可使用包衣剂(例如增塑剂)来增强本发明的组合物的控释、改进释放或缓释特征。
对于口服制剂而言,释放位置可为胃、小肠(十二指肠、空肠或回肠)或大肠。通过保护药剂(或衍生物)或通过在胃环境之外(例如在肠中)释放药剂(或衍生物),释放可避免胃环境的有害效应。为了确保完全的抗胃液性(gastric resistance),对至少pH 5.0暂时不透的包衣是有用的。用作肠溶包衣的更常见的惰性成分的实例是醋酸偏苯三酸纤维素(CAT)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、聚醋酸乙烯邻苯二甲酸酯(PVAP)、聚(甲基丙烯酸-共-丙烯酸乙酯)1∶1、乙酸邻苯二甲酸纤维素(CAP)、聚(甲基丙烯酸-共-甲基丙烯酸甲酯)1:1、聚(甲基丙烯酸-共-甲基丙烯酸甲酯)1∶2和天然虫胶树脂。这些包衣可用作混合膜。
i.软或硬凝胶胶囊
所述方法利用含有烟酰胺核苷和紫檀芪或其等效物的软胶囊的口服施用。可使用本领域中众所周知的技术来制备软胶囊。例如,通常使用转模包胶方法来生产软胶囊。通过重力将活性剂制剂进料至包胶机中。在一个实施方案中,制剂包含药用赋形剂,例如橄榄油、明胶、甘油、净化水、蜂蜡黄、葵花卵磷脂、二氧化硅、二氧化钛、F.D.&C Blue 1和F.D.&CRed 4、微晶纤维素、羟丙甲纤维素、植物硬脂酸镁和/或硅石。
胶囊壳可包含一种或更多种增塑剂,例如甘油、山梨醇、脱水山梨醇、麦芽糖醇、丙三醇、聚乙二醇、具有3至6个碳原子的多元醇、柠檬酸、柠檬酸酯、柠檬酸三乙酯及其组合。在一个实施方案中,增塑剂是甘油。
除增塑剂以外,胶囊壳可包括其它合适的壳添加剂,例如遮光剂、着色剂、湿润剂、防腐剂、矫味剂以及缓冲盐和酸。
当胶囊化的活性剂感光时,使用遮光剂来使胶囊壳不透明。合适的遮光剂包括但不限于二氧化钛、氧化锌、碳酸钙及其组合。在一个实施方案中,遮光剂是二氧化钛。
着色剂可用于销售和产品鉴别和/或区分的目的。合适的着色剂包括合成和天然的染料及其组合。
湿润剂可用于抑制软凝胶的水活性。合适的湿润剂包括甘油和山梨醇,其往往是增塑剂组合物的组分。由于已干燥、适当存储的软凝胶的低水活性,来自微生物的最大风险来自霉菌和酵母。出于这个理由,可将防腐剂掺合至胶囊壳中。合适的防腐剂包括对羟基苯甲酸的烷基酯,例如对羟基苯甲酸甲酯、乙酯、丙酯、丁酯和庚酯(统称为“对羟基苯甲酸酯类”)或其组合。
一种被称为的组合物包括烟酰胺核糖和紫檀芪作为活性成分。这种组合物可在由微晶纤维素、羟丙甲纤维素、植物硬脂酸镁、橄榄油、明胶、甘油、净化水、蜂蜡黄、葵花卵磷脂、二氧化硅、二氧化钛、F.D.&C Blue 1和F.D.&C Red 4形成的胶囊中,或在仅由植物材料制成的素硬胶囊中。任何实施方案可包括微晶纤维素、羟丙甲纤维素、植物硬脂酸镁和/或硅石。
可包括在所公开制剂中的其它药用赋形剂包括乙酰左旋肉碱、N-乙酰基半胱氨酸、α-硫辛酸、生物素、维生素B6、维生素B12、叶酸、白藜芦醇、长春西汀、吡啶甲酸铬、维生素D3、柚皮苷、栎精和肌酸。
ii.溶液剂和混悬剂
所述方法可涉及使用作为液体施用的组合物,其中活性剂溶解(例如,溶液剂)或分散(例如,混悬剂)于组合物中。可使用一种或更多种药学上可接受的赋形剂来制备溶液剂或混悬剂。合适的赋形剂包括但不限于:表面活性剂、湿润剂、增塑剂、结晶抑制剂、润湿剂、填充剂(bulk filling agent)、增溶剂、生物利用度增强剂、pH调节剂、矫味剂和组合。
iii.控制递送聚合物基质
可制备控释聚合物设备(device)来用于在聚合物设备(棒、圆筒、膜、盘)的植入、注射或口服摄入(微粒)之后全身长期释放。基质可呈例如微球的微粒形式,其中肽分散于固体聚合物基质或微胶囊内,其中核具有不同于聚合物壳的材料,并且肽分散或悬浮于核中,所述核在性质上可为液体或固体。除非在本文中明确定义,否则微粒、微球和微胶囊可互换使用。可将聚合物铸造为纳米至四厘米范围的薄片(slab)或膜、通过研磨或其它标准技术产生的粉末、或甚至凝胶例如水凝胶。
可将非生物可降解或生物可降解的基质用于递送所公开的化合物,尽管某些实施方案中存在生物可降解的基质。这些可为天然或合成的聚合物,尽管在某些实施方案中可使用合成聚合物来表征降解和释放曲线。基于期望释放的时间段来选择聚合物。在一些情况下,线性释放可能是最有用的,尽管在其它情况下脉冲释放或“整体释放(bulkrelease)”可提供更有效的结果。聚合物可呈水凝胶的形式(通常吸收多达约90重量%的水),并且可任选地与多价离子或聚合物交联。
可通过溶剂蒸发、喷雾干燥、溶剂提取和本领域技术人员已知的其它方法来形成基质。可使用针对制造用于药物递送的微球所开发的任何方法来制备生物溶蚀性微球,例如,如由Mathiowitz和Langer,J.Controlled Release 5:13-22(1987);Mathiowitz等人,Reactive Polymers 6:275-283(1987);和Mathiowitz等人,J.Appl.Polymer Sci.35:755-774(1988)所描述的。
可配制设备以局部释放来治疗植入或注射的区域,这将通常递送远少于用于治疗全身或全身递送的剂量的剂量。可将这些皮下植入或注射至肌肉、脂肪中或者吞咽。
C.剂量和剂量方案
可基于本领域普通技术人员将知晓的若干因素的考虑,由普通技术人员确定(例如,经由临床试验)特定治疗有效剂量的选择。这类因素包括待治疗或预防的疾病、所涉及症状、对象的体重、对象的免疫状况和技术人员所知的其它因素。在制剂中采用的确切剂量还将取决于施用途径和疾病相关浪费的严重性,并且应根据医师的判断和每个对象的情况来决定。可由来源于体外或动物模型试验系统的剂量-响应曲线推断有效剂量。
待施用于例如人的对象的活性化合物的剂量相当广泛地可变并且可经独立判断。实际上往往在一天的不同时间施用活性化合物的每日剂量。所施用的活性化合物的量可取决于例如活性组分的溶解度、所用制剂、对象状况(例如重量)和/或施用途径等因素。
单独或者与紫檀芪或其等效物组合的口服施用的烟酰胺核苷或其等效物的治疗有效量的大体范围是约50mg至约1500mg、约100mg至约1500mg、约100mg至约1000mg每天、约125mg至约900mg每天、约150mg至约850mg每天、约200mg至700mg每天、约200mg至约500mg每天、约250mg每天、约1000mg至约1500mg、或250mg每天的量。
单独或与烟酰胺核苷或其等效物组合的口服施用的紫檀芪或其等效物的治疗有效量的大体范围是约25mg至约1000mg、约100mg至约1000mg、约25mg至约500mg每天、约25mg至约250mg每天、约30mg至约225mg每天、约40mg至约200mg每天、约45mg至约250mg每天、约50mg每天、或50mg每天的量。在一个实施方案中,含有烟酰胺核苷和紫檀芪的化合物、组合物或药物组合物被制备为口服制剂。
在某些实施方案中,可以经数天、数周或数月的剂量方案施用组合物。剂量可为每天多次或每天单次剂量。当在多天、多周或多月内施用剂量时,每次剂量可为不等量。在剂量方案期间剂量可根据本文所公开的量和范围而变化。
III.使用方法
本文所述的某些组合物和方法可对皮肤具有有益效果。本文所述的某些组合物和方法可治疗和/或预防皮肤病症。本文所述的某些组合物可为口服组合物,以提供用于治疗和/或预防皮肤病症的口服制剂。本文所述的某些组合物和方法可改善和/或维持皮肤的美学外观。在任何实施方案中,组合物可治疗和/或预防皮肤病症,但可治疗或可不治疗红斑痤疮,如权利要求书中所指出的。
治疗的皮肤病症包括但不限于由日光暴露、炎症和自身免疫疾病引起的那些。治疗的皮肤病症可排除或可不排除红斑痤疮,如权利要求书中所指出的。治疗的皮肤病症可包括或可不包括红斑毛细血管扩张性玫瑰痤疮、毛细血管扩张、丘疹脓疱性玫瑰痤疮和/或肿块性玫瑰痤疮,如权利要求书中所指出的。
i.日光暴露相关性皮肤病症
用所述组合物和方法治疗的日光暴露相关性皮肤病症包括但不限于:光化性角化病、着色斑或老年斑、脂溢性角化病、晒伤、光过敏、痣、多形性日光疹、日光性弹性组织变性或皱纹、皮肤癌(例如黑素瘤、鳞状细胞癌、基底细胞癌)和雀斑。
ii.炎性皮肤病症
用所述组合物和方法治疗的炎性皮肤病症包括但不限于:牛皮癣、接触性皮炎、特应性皮炎、脂溢性皮炎、缺皮脂性湿疹、盘状湿疹、手部湿疹、引力性/静脉曲张性湿疹、湿疹性药疹、单纯性苔藓、痤疮,扁平苔藓、苔癣样糠疹、慢性苔癣样角化病、光泽苔藓、条纹状苔藓、蕈状肉芽肿病、红皮病、多形性红斑、史-约(Stevens-Johnson)综合征、血管炎和中毒性表皮坏死溶解症。
iii.自身免疫性皮肤病症
用所述组合物和方法治疗的自身免疫性皮肤病症包括但不限于:坏疽性脓皮病、系统性红斑狼疮、嗜酸性筋膜炎、硬皮病、寻常天疱疮、大疱性类天疱疮、局限性脱发、白癜风、牛皮癣、皮肌炎和营养不良性大疱性表皮松解症。
将参考以下非限制性实施例来进一步理解本发明。
实施例
实施例1:示例性组合物
材料:一种组合物是由Elysium Health以销售的产品。
表1.的活性组分
还含有以下药用赋形剂:微晶纤维素、羟丙甲纤维素、植物硬脂酸镁、橄榄油、明胶、甘油、净化水、蜂蜡黄、葵花卵磷脂、二氧化硅、二氧化钛、F.D.&C Blue 1和F.D.&C Red 4。任何实施方案可包括微晶纤维素、羟丙甲纤维素、植物硬脂酸镁和/或硅石。
除非另外定义,否则本文中使用的所有技术和科学术语都具有与本公开发明所属领域技术人员所通常理解的相同的含义。本文中引述的出版物和为其而引述它们的材料明确地通过引用并入。
本领域技术人员将认识到,或能够使用不超过常规的实验来确定本文所述发明的特定实施方案的许多等同内容。这类等同内容旨在被以下权利要求书所涵盖。
虽然前文描述涉及本发明的优选实施方案,但要注意,其它变化和改进将对本领域技术人员显而易见,并且可在不偏离本发明的精神或范围的情况下作出。此外,关于本发明的一个实施方案所描述的特征可与其它实施方案结合使用,即使上文未明确叙述。
Claims (23)
1.一种组合物,其包含:
(i)治疗有效量的烟酰胺核苷和治疗有效量的紫檀芪的组合;以及
(ii)药学上可接受的赋形剂,
其中所述组合为治疗皮肤病症的治疗有效量。
2.权利要求1所述的组合物,其中烟酰胺核苷的治疗有效量为约100mg至约1000mg每天,并且紫檀芪的治疗有效量为约25mg至约500mg每天。
3.权利要求1或2所述的制剂,其中烟酰胺核苷的治疗有效量为约200mg至700mg每天。
4.权利要求1至3中任一项所述的制剂,其中烟酰胺核苷的治疗有效量为约50至250mg每天。
5.权利要求1至4中任一项所述的制剂,其中紫檀芪的治疗有效量为约50mg每天。
6.权利要求1至5中任一项所述的制剂,其中所述皮肤病症由炎症、暴露于日光、自身免疫疾病或其组合引起。
7.权利要求6所述的制剂,其中由暴露于日光引起的皮肤病症选自光化性角化病、着色斑或老年斑、脂溢性角化病、晒伤、光过敏、痣、多形性日光疹、日光性弹性组织变性或皱纹、皮肤癌(例如黑素瘤、鳞状细胞癌、基底细胞癌)和雀斑。
8.权利要求6所述的制剂,其中由炎症引起的皮肤病症选自牛皮癣、接触性皮炎、特应性皮炎、脂溢性皮炎、缺皮脂性湿疹、盘状湿疹、手部湿疹、引力性/静脉曲张性湿疹、湿疹性药疹、单纯性苔藓、痤疮、扁平苔藓、苔癣样糠疹、慢性苔癣样角化病、光泽苔藓、条纹状苔藓、蕈状肉芽肿病、红皮病、多形性红斑、史-约综合征、血管炎和中毒性表皮坏死溶解症。
9.权利要求6所述的制剂,其中由自身免疫疾病引起的皮肤病症选自坏疽性脓皮病、系统性红斑狼疮、嗜酸性筋膜炎、硬皮病、寻常天疱疮、大疱性类天疱疮、局限性脱发、白癜风、牛皮癣、皮肌炎和营养不良性大疱性表皮松解症。
10.权利要求1至9中任一项所述的制剂,其中所述药学上可接受的赋形剂选自微晶纤维素、羟丙甲纤维素、植物硬脂酸镁、橄榄油、明胶、甘油、净化水、蜂蜡黄、葵花卵磷脂、二氧化硅、二氧化钛、F.D.&C Blue 1和F.D.&C Red 4。
11.前述权利要求中任一项所述的组合物,其中所述组合物是口服施用的。
12.前述权利要求中任一项所述的组合物,其中所述组合物作为每日一次剂量施用。
13.权利要求1-11中任一项所述的组合物,其中所述组合物作为每天两次剂量施用。
14.一种方法,其包括施用治疗有效量的烟酰胺核苷和治疗有效量的紫檀芪的组合以治疗需要治疗皮肤病症的患者中的皮肤病症。
15.权利要求14所述的方法,其中烟酰胺核苷的治疗有效量为约100mg至约1000mg每天,并且紫檀芪的治疗有效量为约25mg至约250mg每天。
16.权利要求14或15所述的方法,其中烟酰胺核苷的治疗有效量为约200mg至700mg每天。
17.权利要求14至16中任一项所述的方法,其中烟酰胺核苷的治疗有效量为约250mg每天。
18.权利要求14至17中任一项所述的方法,其中紫檀芪的治疗有效量为约50mg每天。
19.权利要求14至18中任一项所述的方法,其中所述皮肤病症由暴露于日光、炎症、自身免疫疾病或其组合引起。
20.权利要求19所述的方法,其中由暴露于日光引起的皮肤病症选自光化性角化病、着色斑或老年斑、脂溢性角化病、晒伤、光过敏、痣、多形性日光疹、日光性弹性组织变性或皱纹、皮肤癌(例如黑素瘤、鳞状细胞癌、基底细胞癌)和雀斑。
21.权利要求19所述的方法,其中由炎症引起的皮肤病症选自牛皮癣、接触性皮炎、特应性皮炎、脂溢性皮炎、缺皮脂性湿疹、盘状湿疹、手部湿疹、引力性/静脉曲张性湿疹、湿疹性药疹、单纯性苔藓、痤疮、扁平苔藓、苔癣样糠疹、慢性苔癣样角化病、光泽苔藓、条纹状苔藓、蕈状肉芽肿病、红皮病、多形性红斑、史-约综合征、血管炎和中毒性表皮坏死溶解症。
22.权利要求19所述的方法,其中由自身免疫疾病引起的皮肤病症选自坏疽性脓皮病、系统性红斑狼疮、嗜酸性筋膜炎、硬皮病、寻常天疱疮、大疱性类天疱疮、局限性脱发、白癜风、牛皮癣、皮肌炎和营养不良性大疱性表皮松解症。
23.权利要求14至22中任一项所述的方法,其中所述药学上可接受的赋形剂选自微晶纤维素、羟丙甲纤维素、植物硬脂酸镁、橄榄油、明胶、甘油、净化水、蜂蜡黄、葵花卵磷脂、二氧化硅、二氧化钛、F.D.&C Bluel和F.D.&C Red 4。
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