CN114632019A - 用于治疗或改善皮肤的状况和外观的组合物和使用方法 - Google Patents
用于治疗或改善皮肤的状况和外观的组合物和使用方法 Download PDFInfo
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- CN114632019A CN114632019A CN202011375990.9A CN202011375990A CN114632019A CN 114632019 A CN114632019 A CN 114632019A CN 202011375990 A CN202011375990 A CN 202011375990A CN 114632019 A CN114632019 A CN 114632019A
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- skin
- formulation
- peptide
- wrinkles
- improving
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Abstract
本发明涉及用于治疗、预防和改善皮肤的状况和外观美感的组合物、制剂及其使用方法。本发明具体涉及一种改善有需要的受试者上皮肤的状况或外观美感的方法,所述方法包括以有效改善所述皮肤的所述状况或外观美感的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。本发明还具体涉及在有需要的受试者的皮肤区域中再生胶原蛋白的方法、在有需要的受试者中预防或减少皱纹的方法以及在有需要的受试者中减少皮肤发红的方法。
Description
技术领域
本发明涉及用于治疗、预防和改善皮肤的状况和外观美感的组合物、制剂及其使用方法。
序列表的引用并入
在2020年11月6日创建且大小为5KB的命名为“QUTH-005_SequenceListing_ST25”的文件的内容据此通过引用以其整体并入。
背景技术
在化妆品工业中对研发可以局部应用于皮肤以改善皮肤状况和外观的产品的需求正在增加。受试者关注的是减轻或延缓时间性老化、激素性老化或光老化的皮肤的皮肤病学迹象,诸如细纹、皱纹和松垂的皮肤以及其他状况。在老化过程中,皮肤的肤色(即,皮肤的颜色和外观)由于老化和/或暴露于日光缓慢变差。已经研发了大量化妆品和医学治疗方法来尝试治疗正在老化或已经老化的皮肤。此类化妆品或治疗方法通常含有有机酸作为其活性成分或组分。这些活性成分经常与受试者不适感,诸如烧灼、瘙痒和发红相关。
因此,仍然存在对延缓或对抗皮肤的老化效应的产品,并且更具体地,对产生此类效应而无不良副作用的产品的需求。具体地,仍然存在使用肽组分的具有抗老化和皮肤肌理益处的局部应用性化妆品组合物的需求。
发明内容
本公开提供了改善有需要的受试者上皮肤的状况或外观美感的方法,所述方法包括以有效改善所述皮肤的所述状况或外观美感的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
在一些实施方案中,所述皮肤的状况或外观美感的改善选自由以下项组成的组:减轻时间性老化、光老化、激素老化和/或光化性老化的皮肤病学迹象;预防和/或减轻细纹和/或皱纹的外观;减轻面部细纹和皱纹、面颊、前额上的面部皱纹、两眼之间的垂直皱纹、眼上方和口周围的水平皱纹、木偶纹且特别是深度皱纹或皱褶的引人注目性;预防、减轻和/或减少细纹和/或皱纹的外观和/或深度;改善眼眶下细纹和/或眼眶周围细纹的外观;减轻鱼尾纹外观;使皮肤,特别是老化皮肤恢复年轻和/或恢复活力;减轻皮肤脆性;预防和/或逆转糖胺聚糖类和/或胶原蛋白丧失;改善雌激素失衡效应;预防皮肤萎缩;预防、减轻和/或治疗色素沉着过度;将皮肤色素减退减轻到最低限度;改善皮肤色调、光亮度(radiance)、清透度和/或紧致度(tautness);预防、减轻和/或改善皮肤松垂;改善皮肤紧实度(firmness)、丰满度、柔韧性和/或柔软性;改善前胶原蛋白和/或胶原蛋白产生;改善皮肤肌理和/或促进再肌理化(retexturization);改善皮肤屏障修复和/或功能;改善皮肤轮廓的外观;恢复皮肤光泽和/或亮度;将疲劳和/或紧张状态的皮肤病学迹象减轻到最低限度;抵抗环境压力;补充因衰老和/或更年期而减少的皮肤中的成分;改善皮肤细胞间通讯;增加细胞增殖和/或繁殖;增加因衰老和/或更年期而减少的皮肤细胞代谢;延缓细胞老化;改善皮肤保湿性;增加皮肤厚度;增加皮肤的弹性和/或回弹力;增强表皮脱落;改善微循环;减少和/或防止脂肪团形成;及其任何组合。
在一些实施方案中,时间性老化的皮肤病学迹象选自由以下项组成的组:皱缩、皱纹、垂肉、晒伤、皮肤的暗淡外观、皮肤紧致度的丧失、角化病、色素沉着过度、黑斑病、日光性着色斑、日光性角化病、皮肤日射病(dermatoheliosis)、皮肤色素减退及其任何组合。
本公开进一步提供了在有需要的受试者的皮肤区域中再生胶原蛋白的方法,所述方法包括以有效在所述皮肤区域中再生胶原蛋白的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
在一些实施方案中,所述受试者在所述皮肤区域中具有皱纹。在一些实施方案中,所述皮肤区域易于发展皱纹。在一些实施方案中,所述皮肤区域是在所述受试者的前额上、脸颊上、颈部上、眼睛周围或其任何组合。在一些实施方案中,所述受试者在所述皮肤区域中具有皮肤发红。
本公开进一步提供了在有需要的受试者中预防或减少皱纹的方法,所述方法包括以有效预防或减少皱纹的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
本公开进一步提供了在有需要的受试者中减少皮肤发红的方法,所述方法包括以有效减少皮肤发红的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
在一些实施方案中,所述皮肤发红起因于痤疮、接触刺激、皮肤敏感性、酒渣鼻、湿疹、手术、激光处理、过敏、微晶换肤术、擦皮术或其任何组合。
在一些实施方案中,本公开的制剂进一步包含局部施用可接受的媒介物。
在一些实施方案中,所述局部施用可接受的媒介物选自羟乙基纤维素、羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、透明质酸钠、透明质酸、卡波姆钠、芦荟凝胶、黄原胶、鲸蜡醇、鲸蜡硬脂醇、丙二醇1,3甘油、玫瑰果油、乳木果油、荷荷巴油、蓖麻油、澳洲坚果油、摩洛哥坚果油、夏威夷核果油、凡士林、矿物油、月见草油、硬脂酸甘油酯、聚山梨酯60、橄榄油酸鲸蜡硬脂酯、橄榄油酸脱水山梨醇酯(Sorbitan Olivate)、硬脂酰乳酸钠(SodiumStearyl Lactylate)、硬脂酸、PEG 100硬脂酸酯、苄醇、乙基己基甘油、苯甲酸、山梨酸、葡糖酸内酯、苯甲酸钠、葡糖酸钙及其任何组合。
在一些实施方案中,本公开的制剂进一步包含载体。在一些实施方案中,所述肽缀合至载体。
在一些实施方案中,所述载体选自由以下项组成的组:水凝胶、甘油、丙二醇、聚乙二醇、壳聚糖、藻酸盐、琼脂糖、聚醚、聚酯、甲基纤维素、透明质酸、胶原蛋白、层粘连蛋白、基质胶、纤连蛋白、玻连蛋白、聚-l-赖氨酸、蛋白聚糖、纤维蛋白胶、通过脱细胞化工程化和天然组织制得的凝胶、聚乙醇酸(PGA)、聚乳酸(PLA)以及PGA和PLA的组合如PLGA、聚ε-己内酯、聚乙烯醇(PVA)、聚乙二醇(PEG)、甲基丙烯酸甲酯、聚(甲基丙烯酸甲酯)(PMMA)、聚(甲基丙烯酸2-羟乙酯)(聚HEMA)、聚(癸二酸甘油酯)、自组装肽水凝胶AcN-RARADADARARADADA-CNH(SEQ ID NO.2)、聚氨酯、聚(异丙基丙烯酰胺)、聚(N-异丙基丙烯酰胺)[聚(NIPAM)]及其任何组合。在一些实施方案中,所述载体包括水凝胶。在一些实施方案中,所述载体进一步包括壳聚糖。
在一些实施方案中,所述制剂包含0.5重量%-50重量%载体。在一些实施方案中,所述制剂包含0.001重量%-1重量%肽。在一些实施方案中,所述制剂进一步包含胶原蛋白。在一些实施方案中,所述制剂包含0.02重量%-2重量%胶原蛋白。
在一些实施方案中,所述制剂呈凝胶、酊剂、霜剂、软膏、洗剂或气溶胶喷雾剂的形式。
在一些实施方案中,所述制剂在贴剂或绷带上递送。
在一些实施方案中,所述受试者是哺乳动物。在一些实施方案中,所述哺乳动物选自人、马、狗、猫、猪和牛。在一些实施方案中,所述受试者是非哺乳动物。
附图说明
图1A-1D示出了描绘受试者受访总结的一系列饼图。图1A–在北美洲的受访者的年龄分布。图1B-在北美洲的受访者的皮肤类型。允许受访者选择多于一个选项。图1C–在中国的受访者的年龄分布。图1D-–在中国的受访者的皮肤类型。
图2A-2E示出了描绘大多数北美洲用户在使用Kerra时报告积极效果的一系列饼图。要求参与者对以下陈述回答是/否。图2A–Q1:我感觉到Kerra使我的皮肤看起来受更少刺激。图2B–Q2:我感觉到Kerra使我的皮肤感觉到更水润。图2C–Q3:我感觉到Kerra使我的皮肤看起来更健康。图2D–Q4:我感觉到Kerra使我的皮肤感觉到更光滑。图2E–Q5:我感觉到Kerra改善了我的皮肤的总体外观。
图3A-3F示出了描绘中国参与者在干性和油性皮肤上使用Kerra时报告了良好的反应的一系列图表。图3A–Kerra与您当前的产品相比如何?图3B–您用Kerra的体验如何?图3C–当询问“评价您在将Kerra应用于皮肤时的体验”时,来自具有油性皮肤的用户的李克特量表反应。图3D–当询问“评价您在使用Kerra 7天后的体验”时,来自具有油性皮肤的用户的李克特量表反应。图3E–当询问“评价您在将Kerra应用于皮肤时的体验”时,来自具有干性皮肤的用户的李克特量表反应。图3F–当询问“评价您在使用Kerra 7天后的体验”时,来自具有干性皮肤的用户的李克特量表反应(N=14)。
图4A-4C示出了显示易长痤疮皮肤的受访者在使用Kerra后注意到了积极效果的一系列图表。图4A–在用Kerra处理之前的基线痤疮症状(疼痛和发红)。图4B–参与者评价了Kerra应用5天后对痤疮的作用。图4C–总体报告的Kerra对易长痤疮皮肤的作用表明Kerra具有积极益处。N=8名参与者。
具体实施方式
本公开提供了组合物及其使用方法。在一个实施方案中,组合物提供了在改善皮肤的状况和外观方面的用途。
I.定义
除非另外定义,否则本文所用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常所理解相同的含义。本说明书中使用的术语仅用于描述特定实施方案,而不旨在限制本公开。
在提供取值范围时,应理解在所述范围的上限与下限之间的每个插入值(到下限的十分之一单位,除非上下文清楚地另外指明)以及在所陈述范围内的任何其他所陈述的值或插入值均被涵盖在本公开之内。这些更小范围的上限和下限可以独立地被包括在更小范围之内,也被涵盖在本公开之内,服从于在所陈述范围内任何确切排除的限制。在所述的范围包括限值中的一个或两个时,排除了那些所包括的限值中的任一个或两个的范围也被包括在本公开内。
以下术语用于描述本公开。在术语并未在本文中具体定义的情况下,所述术语由在上下文中将所述术语应用于描述本公开的普通技术人员以本领域中所公认的含义给出。
除非上下文另外指明,否则如本文所用且在所附权利要求中的冠词“一个(种)(a/an)”在本文中用于指代冠词的一个(种)或多于一个(种)(即,至少一个(种))语法对象。举例来说,“一个(种)要素”意指一个(种)要素或多于一个(种)要素。
如本文在说明书和权利要求书中使用的短语“和/或”应理解为意指如此联合的要素,即在一些情况下结合存在以及在其他情况下分离存在的要素中的“任一个(种)或两个(种)”。由“和/或”列出的多个(种)要素应以相同方式解释,即如此联合的要素中的“一个(种)或多个(种)”。除了由“和/或”子句具体鉴定的要素外,还可以任选地存在其他要素,无论与具体鉴定的那些要素有关还是无关。因此,作为非限制性实例,当与开放式语言诸如“包含”结合使用时,提及“A和/或B”在一个(种)实施方案中可以是指仅A(任选地包括除B外的要素);在另一个(种)实施方案中,是指仅B(任选地包括除A外的要素);在又另一个(种)实施方案中,是指A和B(任选地包括其他要素);等。
如本文在说明书和权利要求中使用的,“或”应理解为具有与如上文定义的“和/或”相同的含义。例如,当在列表中分开项目时,“或”或“和/或”应解释为包括性的,即包括许多要素或要素列表中的至少一个(种),还包括其中的多于一个(种),并且任选地包括另外未列出的项目。只有明确相反指示的术语,如“……中仅一个(种)”或“……中恰好一个(种)”或当在权利要求中使用时,“由……组成”是指包括许多要素或要素列表中的恰好一个(种)要素。一般来讲,当前面为排他性术语诸如“任一个(种)”、“一个(种)”、“仅一个(种)”或“恰好一个(种)”时,如本文使用的术语“或”应仅解释为指示唯一的可替代方案(即,“一个(种)或另一个(种)而不是两者”)。
在权利要求以及上文说明书中,所有过渡短语,诸如“包含”、“包括”、“携带”、“具有”、“含有”、“涉及”、“持有”、“由……构成”等应理解为开放式的,即意指包括但不限于。仅过渡短语“由……组成”和“基本上由……组成”应分别是闭合的或半闭合的过渡短语,如美国专利局专利审查程序手册(United States Patent Office Manual of PatentExamining Procedures),第2111.03节所述。
如本文在说明书和权利要求中使用的,提及一个(种)或多个(种)要素的列表的短语“至少一个(种)”应理解为意指选自要素列表中的要素的任何一个(种)或多个(种)的至少一个(种)要素,但不一定包括在要素列表内具体列出的每一个(种)要素的至少一个(种),并且不排除要素列表中的要素的任何组合。该定义还允许可以任选地存在除了短语“至少一个(种)”所提及的要素列表内具体鉴定的要素外的要素,无论与具体鉴定的那些要素有关还是无关。因此,作为非限制性实例,“A和B中的至少一个(种)”(或等效地,“A或B中的至少一个(种)”,或等价地,“A和/或B中的至少一个(种)”)在一个(种)实施方案中可以是指至少一个(种)、任选地包括多于一个(种)A,其中B不存在(且任选地包括除B外的要素);在另一个(种)实施方案中,是指至少一个(种)、任选地包括多于一个(种)B,其中A不存在(且任选地包括除A外的要素);在另外一个(种)实施方案中,是指至少一个(种)、任选包括多于一个(种)A和至少一个(种)、任选包括多于一个(种)B(且任选地包括其他要素);等。
还应理解,除非上下文另外指明,否则在本文所述的包括多于一个步骤或动作的某些方法中,所述方法的步骤或动作的次序不一定限于在其中叙述所述方法的步骤或动作的次序。
术语“共同施用(co-administration/co-administering)”或“组合疗法”是指并行施用(同时施用两种或更多种治疗剂)和时变施用(在不同于施用一种或多种另外治疗剂的时间的某时施用一种或多种治疗剂)两者,只要所述治疗剂在一定程度上(优选在有效量下)同时存在于患者中即可。
如本文所用,除非另外指明,否则术语“化合物”在上下文适用时是指本文公开的任何特定化学化合物并且包括其互变异构体、位置异构体、几何异构体和适用时立体异构体(包括光学异构体(对映异构体)和其它立体异构体(非对映异构体))以及其药学上可接受的盐和衍生物(包括前药和/或氘代形式)。所设想的氘代小分子是其中药物分子中含有的一个或多个氢分子已经被氘置换的那些。
在其用于上下文时,术语化合物通常是指单一化合物,而且还可以包括其他化合物,诸如所公开化合物的立体异构体、位置异构体和/或光学异构体(包括外消旋混合物)以及特定对映异构体或对映异构富集的混合物。在上下文中所述术语还是指化合物的已经被修饰以有利于将化合物施用和传递至活性位点的前药形式。应注意,在描述本发明化合物时,尤其描述了众多取代基和与其相关的变量。普通技术人员应理解,本文所述的分子是基本上如下面描述的稳定化合物。当示出键时,在所示且熟知其化合价相互作用规则的化合物的上下文内表示或理解为双键和单键两者。
术语“患者”或“受试者”用于描述向其提供用根据本公开的组合物的治疗(包括预防性治疗)的动物,优选人类或驯养动物。对于对为特定动物(如人类患者)特有的那些状况或疾病状态的治疗,术语患者是指该特定动物,包括驯养动物,诸如狗或猫;哺乳动物,诸如小鼠、大鼠和非人灵长类动物;或农场动物,诸如马、奶牛、绵羊等。一般来讲,在本公开中,除非所述术语使用的上下文中另外陈述或暗示,否则术语患者是指人类患者。
术语“治疗(treat/treatment/treating)”是指(1)减少病症的严重程度或持续时间;(2)改善与病症相关的一种或多种症状,而不必治愈所述病症;或(3)预防病症。
术语“有效”用于描述化合物、组合物或组分当在其预期用途的上下文中使用时实现预期结果的量。术语有效的包括本申请中另外描述或使用的所有其他有效量或有效浓度术语。
术语“基本上”、“大约”和“约”通常意指所陈述值的±10%,例如约100将包括90至110。
II.本公开的组合物
本公开提供了包含以下氨基酸序列、基本上由其组成或由其组成的肽:X1X2X3X4X5X6X7(SEQ ID NO:21),其中
X1是选自谷氨酰胺、苏氨酸、丝氨酸或天冬酰胺的任选残基;
X2是选自组氨酸、精氨酸或赖氨酸的任选带正电残基;
X3是谷氨酸、苏氨酸、异亮氨酸、组氨酸、赖氨酸、谷氨酰胺、酪氨酸、缬氨酸或亮氨酸;
X4是甘氨酸或缬氨酸;
X5是选自丝氨酸、苏氨酸、天冬氨酸、异亮氨酸或甘氨酸的任选残基;
X6是选自亮氨酸、缬氨酸、谷氨酰胺、甘氨酸、异亮氨酸或丝氨酸的任选残基;并且X7是选自天冬氨酸、天冬酰胺、缬氨酸或赖氨酸的任选残基。
在一些实施方案中,肽包含氨基酸序列SEQ ID NO:22,其中X1是Q,其中X2是H,其中X3是R,其中X4是E,其中X5是D,其中X6是G并且其中X7是S。
在一些方面,肽包含QHREDGS(SEQ ID NO:1)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含REDG(SEQ ID NO:3)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含RLDG(SEQ ID NO:4)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含REDGS(SEQ ID NO:5)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含RLDGS(SEQ ID NO:6)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含HREDG(SEQ ID NO:7)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含HRLDG(SEQ ID NO:8)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含HREDGS(SEQ ID NO:9)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含HRLDGS(SEQ ID NO:10)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHREDG(SEQ ID NO:11)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHRLDG(SEQ ID NO:12)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHREDVS(SEQ ID NO:13)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHREDGS(SEQ ID NO:14)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHRLDGS(SEQ ID NO:15)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含KRLDGS(SEQ ID NO:16)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHREDGSL(SEQ ID NO:17)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHRLDGSL(SEQ ID NO:18)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHRLDGSLD(SEQ ID NO:19)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽包含QHREDGSLD(SEQ ID NO:20)的氨基酸序列、基本上由其组成或由其组成。在一些方面,肽由QHREDGS(SEQ ID NO:1)的氨基酸序列组成。
在一些实施方案中,本发明的组合物或肽包含如美国专利号9,096,643和美国公布号US20180296631A1和US20190328824A1中所述的非天然存在的肽、基本上由其组成或由其组成,将每一个所述专利通过引用以其整体并入本文。
在一些实施方案中,肽可以是线性的、环状的、交联或固定的,只要肽的细胞保护活性得以保留。此外,肽可以形成宽的U形,以呈现该肽在存在于血管生成素1中时的天然结构特征。
在还其他实施方案中,肽可以包括基本上不影响核心残基的U形的修饰,从而保留肽的细胞保护活性,例如整联蛋白结合活性。例如,可以对肽进行修饰以包括在C或N末端处的一个或多个另外的氨基酸残基,或包括可以起到稳定肽、保护肽免受不希望的降解或改善其活性的作用的末端保护基。可以使用用于保护肽端的任何化学基团。有用的N末端保护基包括例如具有式R—C(O)—的低级烷酰基,其中R是包含1-5个碳原子的直链或支链低级烷基链。N末端保护基的实例包括乙酰基和缺乏氨基功能的氨基酸类似物。合适的羧基末端保护基的实例包括例如形成酯的烷基,特别是低级烷基(如甲基、乙基和丙基),以及形成酰胺的氨基官能团,诸如伯胺(—NH2),以及单烷基氨基和二烷基氨基,诸如甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、甲基乙基氨基等。也可以使用脱羧化氨基酸类似物(诸如胍丁胺)实现C末端保护。当然,如果需要的话,也可以可替代地掺入具有甚至更大结构复杂性的N-和C-保护基团。
在又其他实施方案中,肽还可以在其核心氨基酸残基中的一个或多个处被修饰,例如以包括衍生化的R-基团。合适的修饰包括可以稳定肽的U形、优化其活性或起到保护肽免受降解的作用的那些修饰。
III.制剂
本公开提供了用于施用本文所述的组合物(例如QHREDGS(SEQ ID NO:1))的制剂、剂量和方法。
在一些实施方案中,QHREDGS(SEQ ID NO:1)肽是可溶的。
所公开的组合物以及药物组合物和制剂可以进一步包含任何合适的助剂中的至少一种,诸如但不限于稀释剂、粘合剂、稳定剂、缓冲剂、盐、亲脂性溶剂、防腐剂、佐剂等。优选药学上可接受的助剂。制备此类无菌溶液的非限制性实例和方法是本领域熟知的,诸如但不限于在Gennaro编辑,Remington's Pharmaceutical Sciences,第18版,MackPublishing Co.(Easton,Pa.)1990和在“Physician's Desk Reference”,第52版,MedicalEconomics(Montvale,N.J.)1998中。可以常规地选择适合于如本领域熟知的或如本文所述的蛋白质支架、片段或变体组合物的施用方式、溶解性和/或稳定性的药学上可接受的载体。
A.局部用制剂
本发明的组合物(例如QHREDGS(SEQ ID NO:1))可以在生理学上可接受的媒介物或载体中提供。媒介物可以是疏水性的或亲水性的。合适的疏水性载体包括例如通常用于化妆品中的蜡质非离子物质,诸如脂肪醇和脂肪酸的酯和醚,其碳链长度为从C8至C22,优选从C8至C15、或从C12至C15。
示例性脂肪疏水性载体包括但不限于肉豆蔻酸异丙酯、棕榈酸异丙酯、棕榈酸辛酯、羊毛脂酸异丙酯、乙酰化羊毛脂醇、C12-C15醇的苯甲酸酯、辛酸鲸蜡硬脂酯、棕榈酸鲸蜡酯、肉豆蔻酸肉豆蔻酯、乳酸肉豆蔻酯、乙酸鲸蜡酯、二辛酸丙二醇酯/癸酸丙二醇酯、油酸癸酯、乙酰化羊毛脂、庚酸硬脂酯、苹果酸二异硬脂酯、羟基硬脂酸辛酯、羟基硬脂酸辛酯、异硬脂酸异丙酯、乳木果油或玫瑰果油。
示例性合适的亲水性载体可以包括但不限于水、化妆品中常用的低级醇(C1-6)、二醇和烷氧基化二醇,包括乙二醇、二甘醇、三甘醇、丙二醇、二丙二醇等。
局部施用可接受的媒介物可以呈乳液的形式。合适乳液的非限制性实例包括油包水乳液、水包油乳液、水包硅树脂乳液、硅树脂包水乳液、水包蜡乳液、水包油包水三重乳液或具有霜剂、凝胶或微乳液外观的类似物。如本文所用,除非另外指明,否则术语“油”包括硅油和天然衍生的油,诸如玫瑰果油。乳液可以包括乳化剂,诸如非离子、阴离子或两性表面活性剂、硬脂酸甘油酯、聚山梨酯60、橄榄油酸鲸蜡硬脂酯、橄榄油酸脱水山梨醇酯、硬脂酰乳酸钠、硬脂酸、PEG 100硬脂酸酯或胶凝剂,其量典型地为按重量计从约0.001%至约5%。
局部施用可接受的媒介物可以包括但不限于水;植物油;矿物油;酯油,诸如棕榈酸辛酯,肉豆蔻酸异丙酯和棕榈酸异丙酯;醚,诸如二辛醚(dicapryl ether)和二甲基异山梨醇;醇,诸如乙醇和异丙醇;脂肪醇,诸如鲸蜡醇、鲸蜡硬脂醇、硬脂醇和山嵛醇;异链烷烃,诸如异辛烷、异十二烷(IDD)和异十六烷;硅油,诸如环聚甲基硅氧烷、聚二甲基硅氧烷、聚二甲基硅氧烷交联聚合物、聚硅氧烷及其衍生物,优选有机改性的衍生物,包括PDMS、聚二甲基硅氧烷共聚多元醇、聚二甲基硅氧烷醇和氨基封端的聚二甲基硅氧烷醇(amodimethiconol);烃油,诸如矿物油、凡士林、异二十烷和聚烯烃,例如(氢化)聚异丁烯;多元醇,诸如丙二醇、甘油、丁二醇、戊二醇、己二醇、辛二醇;蜡,诸如蜂蜡、巴西棕榈蜡、地蜡、微晶蜡、聚乙烯蜡和植物蜡;或前述的任何组合或混合物。水性媒介物可以包括一种或多种可与水混溶的溶剂,包括低级醇,诸如乙醇、异丙醇等。媒介物可以构成制剂的按重量计从约50%至约99%。
在一些实施方案中,将本发明的肽配制成用于使用靶向递送系统的递送。示例性靶向递送系统包括但不限于脂质体、微球体(参见例如授予Unger等人的美国专利号5,770,222),使得组分和/或活性成分可以更容易地到达并影响应用区域(例如脸部或颈部,或皮肤的其他区域)的皮下层。
也可以将本发明的肽配制成用于局部施用的制剂。局部用制剂的实例包括但不限于洗剂、霜剂、血清、喷雾剂、气溶胶、粉饼、软膏、香精、凝胶、糊剂、贴剂、笔状物、毛巾状物、面膜、棒状物、泡沫、酏剂、浓缩物等,特别是用于局部施用。优选地,将组合物配制为凝胶、酊剂、霜剂、软膏、洗剂或气溶胶喷雾剂。
局部用制剂包含制剂的从约0.000001重量%至约20重量%的本发明肽。在一些实施方案中,局部用制剂包含制剂的从约0.00001重量%至约10重量%的肽。在一些实施方案中,局部用制剂包含制剂的从约0.00001重量%至约5重量%的肽。在一些实施方案中,局部用制剂包含制剂的从约0.00001重量%至约0.0001重量%的肽。在一些实施方案中,局部用制剂包含制剂的从约0.00001重量%至约0.001重量%的肽。在一些实施方案中,局部用制剂包含制剂的从约0.001重量%至约1重量%的肽。
在一些实施方案中,局部用制剂具有从约1至约13的pH范围。在一些实施方案中,局部用制剂具有从约2至约12的pH范围。在一些实施方案中,局部用制剂具有从约3.5至约7的pH范围。在一些实施方案中,局部用制剂具有从约7至约10.5的pH范围。在一些实施方案中,局部用制剂具有从约3至约4、约4至约5、约5至约6、约6至约7、约7至约8、约8至约9、约9至约10、约10至约11或约11至约12的pH范围。可以添加合适的pH调节剂,诸如但不限于氢氧化钠、柠檬酸和三乙醇胺以使pH在期望的范围内。
本公开的药物组合物或局部用制剂可以进一步包含一种或多种另外的皮肤活性物质,包括但不限于抗老化组分、类视黄醇、植物性材料、角质层分离剂、脱屑剂、角化细胞增殖增强剂、胶原酶抑制剂、弹性蛋白酶抑制剂、脱色剂、消炎剂、类固醇、抗痤疮剂、抗氧化剂、抗瘢痕形成剂和晚期糖化终产物(AGE)抑制剂。这些各种成分的量是在化妆品领域中常规用于实现其预期用途的那些,并且单独或总共范围典型为制剂的从约0.001重量%至约20重量%。这些成分的性质及其量必须与本公开的组合物的生产和功能相容。
示例性抗老化组分包括但不限于植物性材料(例如紫铆(Butea frondosa)提取物;三蕊香料藤(Tiliacora triandra)提取物、马齿苋(Portulaca oleracea)、粉红蜜茱萸(Melicope elleryana)等)、植醇;植烷酸(phytonic acid);类视黄醇;羟基酸(包括α-羟基酸和β-羟基酸)、水杨酸和烷基水杨酸盐;表皮脱落剂(例如,乙醇酸、3,6,9-三噁十一烷二酸(3,6,9-trioxaundecanedioic acid)等)、雌激素合成酶刺激化合物(例如,咖啡因和衍生物);能够抑制5α-还原酶活性的化合物(例如,亚麻酸、亚油酸、非那雄胺及其混合物);和屏障功能增强剂(例如,神经酰胺、甘油酯、胆固醇及其酯、α-羟基和ω-羟基脂肪酸及其酯等)。
示例性类视黄醇包括但不限于视黄酸(例如,全反式、或9-顺式、或13-顺式)及其衍生物、视黄醛、视黄醇(维生素A)及其酯,诸如棕榈酸视黄酯、乙酸视黄酯和丙酸视黄酯及其盐。可以特别提及视黄醇。当存在时,包含的类视黄醇的量典型地为从约0.0001重量%至约5重量%、更典型地为从约0.01重量%至约2.5重量%,或从约0.1重量%至约1.0重量%。包含类视黄醇的制剂还可以以有效稳定类视黄醇的量(例如0.0001%-5%)包含抗氧化剂(诸如抗坏血酸和/或BHT)和/或螯合剂(诸如EDTA或其盐(例如,EDTA二钠))。
本公开的药物组合物或局部用制剂可以进一步包含以下项中的一种或多种:皮肤渗透增强剂;润肤剂,诸如肉豆蔻酸异丙酯、凡士林、挥发性或非挥发性硅油(例如聚甲基硅氧烷、聚二甲基硅氧烷)、酯油、矿物油、玫瑰果油、乳木果油、荷荷巴油、蓖麻油、澳洲坚果油、摩洛哥坚果油、夏威夷核果油、凡士林、矿物油、月见草油和脂肪酸酯;湿润剂,诸如甘油、己二醇或辛二醇;皮肤饱满剂(skin plumper),诸如棕榈酰寡肽、胶原蛋白、胶原蛋白和/或糖胺聚糖(GAG)增强剂;防晒剂,诸如阿伏苯宗或甲氧基肉桂酸辛酯;表皮脱落剂;或抗氧化剂。
示例性表皮脱落剂包括但不限于α-羟基酸、β-羟基酸、含氧酸(oxa-acid)、含氧二酸(oxadiacid)及其衍生物,诸如酯、酸酐或盐。示例性羟基酸包括但不限于乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、2-羟基链烷酸、扁桃酸、水杨酸或其衍生物。表皮脱落剂可以构成制剂的从约0.001重量%至约20重量%。
示例性抗氧化剂包括但不限于具有酚羟基官能团的化合物,诸如抗坏血酸及其衍生物/酯;β-胡萝卜素;儿茶素;姜黄素;阿魏酸衍生物(例如阿魏酸乙酯、阿魏酸钠);没食子酸衍生物(例如没食子酸丙酯);番茄红素;还原酸;迷迭香酸;鞣酸;四氢姜黄素;生育酚及其衍生物,包括乙酸生育酚;尿酸;或其任何混合物。其他合适的抗氧化剂是呈还原或非还原形式的一种或多种硫醇官能团(-SH)的那些,诸如谷胱甘肽、硫辛酸、巯基乙酸和其他巯基化合物。抗氧化剂可以是无机的,诸如亚硫酸氢盐、偏亚硫酸氢盐、亚硫酸盐或其他含硫的无机盐和酸。抗氧化剂可以单独地或总共地构成制剂的从约0.001重量%至约10重量%。抗氧化剂可以单独地或总共地构成制剂的总重量的从约0.01%至约5%(w/w)。
本公开的药物组合物或局部用制剂可以进一步包含一种或多种其他组分,包括但不限于:维生素,诸如生育酚和抗坏血酸;和维生素衍生物,诸如单棕榈酸抗坏血酸酯、乙酸生育酚和棕榈酸维生素E酯;增稠剂,诸如羟烷基纤维素、羧甲基纤维素、卡波姆、鲸蜡醇,鲸蜡硬脂醇和植物胶,诸如黄原胶;胶凝剂,诸如酯封端的聚酯酰胺、羟乙基纤维素、羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、透明质酸钠、透明质酸、卡波姆钠或芦荟凝胶;结构剂;金属螯合剂,诸如EDTA或其盐;颜料;着色剂;和pH调节剂。代表性的pH调节缓冲剂包括有机酸盐,诸如柠檬酸、抗坏血酸、葡萄糖酸、碳酸、酒石酸、琥珀酸、乙酸或邻苯二甲酸的盐;Tris、盐酸氨丁三醇或磷酸盐缓冲液。
本公开的药物组合物或局部用制剂可以进一步包含本领域技术人员已知的一种或多种其他组分,包括但不限于成膜剂、保湿剂、矿物质、粘度和/或流变改性剂、抗痤疮剂、驱虫剂、皮肤清凉化合物、皮肤保护剂、润滑剂、香料、防腐剂、稳定剂及其混合物。所述组分可以单独地或总共地构成制剂的从约0.0001重量%至约20重量%。
本公开的药物组合物或局部用制剂可以进一步包含一种或多种本领域常用且已知的相容的化妆品上可接受的佐剂,包括但不限于:着色剂、珠光剂(pearl)、chromalite、云母、颜料、染料、香料、润肤剂、湿润剂(诸如丙二醇1,3甘油)、防腐剂(诸如苄醇、乙基己基甘油、苯甲酸、山梨酸、葡糖酸内酯、苯甲酸钠或葡糖酸钙)、维生素、螯合剂、增稠剂、麻醉剂、抗过敏剂、抗真菌剂、抗微生物剂、其他抗炎剂、抗氧化剂、防腐剂、脱色剂、成膜剂、驱虫剂、药剂、光稳定剂、防晒剂、稳定剂、表面活性剂、增稠剂、粘度调节剂和植物性材料。
本公开的药物组合物或局部用制剂可以进一步包含化妆品成分,包括但不限于皮肤渗透增强剂、表面平滑剂、皮肤饱满剂、光学扩散剂、表皮脱落增强剂和抗氧化剂。有关这些和其他适合的化妆品成分的详细描述可以在由Cosmetic,Toiletry,and FragranceAssociation(CTFA)公布的"International Cosmetic Ingredient Dictionary andHandbook,"第10版(2004),在第2177-2299页中找到,将所述文献通过引用以其整体并入本文。化妆品成分以及在化妆品或药物领域中使用的那些化妆品成分的量可以构成制剂总重量的从约0.01%至约20%。
本公开的药物组合物或局部用制剂可以进一步包含防晒剂以保护皮肤免紫外线损伤。在一些实施方案中,防晒剂通过使用单一防晒剂或防晒剂的组合来提供UVA和UVB两者的保护。示例性防晒剂包括但不限于有阿伏苯宗、肉桂酸衍生物(诸如肉桂酸辛基甲氧基酯)、水杨酸辛酯、羟苯甲酮、氰双苯丙烯酸辛酯、二氧化钛、氧化锌、或其任何混合物。防晒剂可以构成制剂的总重量的从约1重量%至约30重量%。
B.包含载体的制剂
本发明的制剂可以包含本发明的肽和至少一种载体。在一些实施方案中,肽可以缀合至载体。在某些实施方案中,载体是水凝胶。在一些实施方案中,水凝胶包含壳聚糖、藻酸盐、琼脂糖、甲基纤维素、透明质酸、胶原蛋白、层粘连蛋白、基质胶、纤连蛋白、玻连蛋白、聚-l-赖氨酸、蛋白聚糖、纤维蛋白胶、通过脱细胞化工程化和天然组织制得的凝胶及其组合中的至少一种。在一些实施方案中,水凝胶包含壳聚糖。
制剂可以包含制剂的从约0.000001重量%至约20重量%的本发明肽。在一些实施方案中,制剂包含制剂的从约0.00001重量%至约10重量%的肽。在一些实施方案中,制剂包含制剂的从约0.00001重量%至约5重量%的肽。在一些实施方案中,制剂包含制剂的从约0.00001重量%至约0.0001重量%的肽。在一些实施方案中,制剂包含制剂的从约0.00001重量%至约0.001重量%的肽。在一些实施方案中,制剂包含制剂的从约0.001重量%至约1重量%的肽。
在一些实施方案中,制剂包含按重量计占制剂的约10%、约15%、约20%、约25%、约30%、约35%、约40%、约45%、约50%、约55%、约60%、约65%、约70%或约75%的载体。在一些实施方案中,制剂包含按重量计占制剂的从约10%至约40%的载体。在一些实施方案中,制剂包含按重量计占制剂的从约20%至约50%的载体。在一些实施方案中,制剂包含按重量计占制剂的从约30%至约60%的载体。在一些实施方案中,制剂包含按重量计占制剂的从约40%至约70%的载体。在一些实施方案中,制剂包含按重量计占制剂的从约20%至约50%的载体。
载体中如本文所述的肽或肽组合的量不受特别限制,并且可以由本领域的普通技术人员基于病症的严重程度和本领域技术人员通常考虑的其他因素来调整。在本发明的某些实施方案中,载体中存在的肽或肽组合的浓度为从约10μM至约1000μM。在仍其他实施方案中,载体中存在的肽或肽组合为从约50μM至约800μM;约75μM至约750μM;约100μM至约600μM;或约150μM至约500μM。
在一些实施方案中,制剂进一步包含胶原蛋白。在一些实施方案中,制剂包含按重量计占制剂的约0.01%、约0.02%、约0.03%、约0.04%、约0.05%、约0.06%、约0.07%、约0.08%、约0.09%、约1.0%、约1.1%、约1.2%、约1.3%、约1.4%、约1.5%、约1.6%、约1.7%、约1.8%、约1.9%、约2.0%、约2.1%、约2.2%、约2.3%、约2.4%、约2.5%、约2.6%、约2.7%、约2.8%、约2.9%或约3.0%的胶原蛋白。在一些实施方案中,制剂包含按重量计占制剂的从约0.02%至约2%的胶原蛋白。
在一个实施方案中,本发明提供了包含分散在载体中或固定在载体上的如本文所述的肽的制剂。
用于此目的的合适载体通常为以下中的至少一种:i)生物相容的(即,对受试者无毒的任何合成或天然存在的材料),ii)可生物降解的,和iii)足以耐受它们所施用到的环境的机械稳定性。合适的载体可以是预成形膜、或三维多孔或纤维支架。载体也可以是可注射的,使得它们可以以微创方式用注射器施加。合适载体的实例包括但不限于天然载体,诸如多糖,例如壳聚糖、藻酸盐、琼脂糖、甲基纤维素、透明质酸、胶原蛋白(例如胶原蛋白I、胶原蛋白II和胶原蛋白IV)、层粘连蛋白、基质胶、纤连蛋白、玻连蛋白、聚-1-赖氨酸、蛋白聚糖、纤维蛋白胶、通过脱细胞化工程化和天然组织制得的凝胶以及拟胚体。还包括作为合适载体的是合成载体,诸如聚乙醇酸(PGA)、聚乳酸(PLA)以及PGA和PLA的组合(诸如PLGA)、聚ε-己内酯、聚乙烯醇(PVA)、聚乙二醇(PEG)、甲基丙烯酸甲酯、聚(甲基丙烯酸甲酯)(PMMA)、聚(甲基丙烯酸2-羟乙酯)(聚HEMA)、聚(癸二酸甘油酯)、自组装肽水凝胶诸如AcN-RARADADARARADADA-CNH(SEQ ID NO.:2)、聚氨酯、聚(异丙基丙烯酰胺)和聚(N-异丙基丙烯酰胺)[聚(NIPAM)]。也可以使用这些材料中的任一种的组合及其化学改性形式,诸如羧化或胺化形式。
在特定的实施方案中,组合物包含QHREDGS(SEQ ID NO:1)肽和由至少一种载体和溶剂构成的至少一种水凝胶。作为合适载体的实例,非限制性地提及甘油、丙二醇、聚乙二醇、壳聚糖、藻酸盐、琼脂糖、聚醚、聚酯、甲基纤维素、透明质酸、胶原蛋白、层粘连蛋白、基质胶、纤连蛋白、玻连蛋白、聚-l-赖氨酸、蛋白聚糖、纤维蛋白胶、通过脱细胞化工程化和天然组织制得的凝胶或其组合。在某些实施方案中,水凝胶包含或是聚乙醇酸(PGA)、聚乳酸(PLA)以及PGA和PLA的组合(诸如PLGA)、聚ε-己内酯、聚乙烯醇(PVA)、聚乙二醇(PEG)、甲基丙烯酸甲酯、聚(甲基丙烯酸甲酯)(PMMA)、聚(甲基丙烯酸2-羟乙酯)(聚HEMA)、聚癸二酸甘油酯、自组装肽水凝胶AcN-RARADADARARADADA-CNH(SEQ ID NO.:2)、聚氨酯、聚(异丙基丙烯酰胺)、聚(N-异丙基丙烯酰胺)[聚(NIPAM)]、这些物质的衍生物、或其组合。
在某些实施方案中,载体是水凝胶。在另外的实施方案中,合适的溶剂是水。可以使用其他载体和溶剂。
在仍另外的实施方案中,组合物包含或分散在第二载体内,所述第二载体例如为聚合物或共聚物材料,诸如聚乙烯化合物(polyvinyl)、聚丙烯酸物(polyacrylic)、聚氨酯、聚乙烯(polyethylene)等。在某些实施方案中,第二载体是包含或包括如本文所述的肽-水凝胶的织造或非织造层或多层制品。
在一些实施方案中,组合物包括至少一种水基水凝胶。作为此类水凝胶的非限制性实例,提及由聚丙烯酸、聚维酮、纤维素和芦荟制备的水凝胶。在一些实施方案中,使用羧甲基纤维素水凝胶。也可以根据本公开使用其他水凝胶。
在特定的实施方案中,载体选自聚合物,诸如水溶性聚合物、中性电荷的聚合物或中性电荷的水溶性聚合物。载体也可以是被FDA认为是公认安全的(GRAS)。作为可以根据本公开使用的载体的实例,非限制性地提及水凝胶,包括含纤维素的水凝胶,诸如羧甲基纤维素(CMC)。在本公开的一些实施方案中,至少一种载体还包括水、甘油及其混合物中的至少一种。
水凝胶或载体的平均分子量可以在例如从约100道尔顿(Da)至约1,000,000Da,诸如从约500,000Da至约1,000,000Da的范围内。
还可以选择载体的粘度以适合期望的应用。例如,载体的粘度可以在从大于0至约10,000厘泊(cp)或更高,诸如从约100至约10,000cp、从约500至约5,000cp、或甚至从约1000至约3000cp的范围内。在一些实施方案中,载体是高粘度CMC,其表现出在从约1,500cp至约3,000cp范围内的粘度,如在25℃下从CMC在水中的1%溶液测量的。在许多情况下,载体的粘度是浓度和温度两者依赖性的。即,粘度可以随着温度升高而降低,并且反之亦然。即,粘度可以随着浓度降低而降低,并且反之亦然。
在一些实施方案中,本公开的组合物还包含至少一种稳定剂。此类稳定剂可以用于多种目的。例如,为了在各种金属盐的存在下缓冲载体(例如水凝胶)的pH和/或粘度而向本发明的组合物中添加稳定剂。稳定剂可以是天然的或合成的,并且任选地是可生物降解的和/或可生物侵蚀的。适合根据本公开使用的pH稳定剂的非限制性实例包括缓冲盐和有机化学化合物,诸如三乙醇胺(通常缩写为TEA),其既是叔胺又是三醇。柠檬酸也适合作为pH稳定剂用于本公开中。
可以通过本领域已知的任何手段将本公开的肽固定在水凝胶中或缀合至水凝胶,所述手段包括但不限于溶剂浇铸。在特定的实施方案中,使用1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)化学将水凝胶和肽缀合。在此类实施方案中,将水凝胶和肽溶解在溶剂中,所述溶剂诸如盐水,任选地含有磷酸盐缓冲剂。将溶解的材料与EDC和N-羟基磺基琥珀酰亚胺(S-NHS)混合并使其反应。缀合后,可以使用标准程序对材料进行后处理,并将所述材料用于制备用于施用的膜或其他组合物。
C.药物制剂和支架
在某些实施方案中,本发明提供了包含至少一种如本文所述的本发明组合物的药物制剂。
在一些实施方案中,药物制剂进一步包含至少一种赋形剂,诸如水溶性聚合物、表面活性剂和/或另一种增强剂,诸如药学上可接受的赋形剂。药学上可接受的赋形剂的非限制性实例描述于E.W.Martin的Remington's Pharmaceutical Sciences中,并且包括纤维素、淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、水稻、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂乳粉、甘油、丙烯、二醇、水、乙醇等。在一些实施方案中,药物制剂还含有pH缓冲试剂以及润湿剂或乳化剂。
本发明的药物制剂可以呈适合向患者施用的任何形式,诸如呈水性分散体或悬浮液的形式。药物制剂还可以含有各种另外成分,诸如悬浮剂、稳定剂和/或分散剂。
在一些实施方案中,药物制剂呈控制释放制剂的形式。
本公开的组合物还可以包含至少一种赋形剂。至少一种赋形剂可以选自例如表面活性剂(阳离子的、阴离子的或中性的)、表面稳定剂和其他增强剂(诸如防腐剂)。可以根据本公开使用的表面活性剂的非限制性实例包括非离子表面活性剂,诸如聚山梨酸酯表面活性剂(例如,聚山梨酸酯20(Tween 20TM)和聚山梨酸酯80(Tween 80TM))。在一些实施方案中,本公开的组合物含有多种pH稳定剂,以便在组合物中形成pH缓冲体系。作为可以添加至本公开的组合物中的防腐剂的实例,非限制性地提及甘油,其可以在一定浓度下充当防腐剂。
本公开的组合物还可以包含至少一种乳化剂。合适乳化剂的非限制性实例包括磷脂、丙二醇、聚山梨醇酯、泊洛沙姆和单硬脂酸甘油酯。当然,可以使用其他已知的药物乳化剂。
可以适当地用于配制用于其预期施用途径的组合物的常用药物成分包括:酸化剂(实例包括但不限于乙酸、柠檬酸、富马酸、盐酸、硝酸);碱化剂(实例包括但不限于氨溶液、碳酸铵、二乙醇胺、单乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺、三醇胺(trolamine));吸附剂(实例包括但不限于粉末状纤维素和活性炭);气溶胶推进剂(实例包括但不限于二氧化碳、CCl2F2、F2ClC-CClF2-CClF2和CClF3);空气置换剂(实例包括但不限于氮气和氩气);抗真菌防腐剂(实例包括但不限于苯甲酸、对羟基苯甲酸丁酯、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸钠);抗微生物剂(实例包括但不限于银、铋、氯己定、聚六亚甲基双胍(PHMB)、次氯酸/次氯酸钠、结晶紫、臭氧和抗生素(例如杆菌肽));抗微生物防腐剂(实例包括但不限于苯扎氯铵、苄索氯铵、苄醇、西吡氯铵、氯丁醇、苯酚、苯乙醇、硝酸苯汞和硫柳汞);抗氧化剂(实例包括但不限于抗坏血酸、棕榈酸抗坏血酸酯、丁羟茴香醚、丁羟甲苯、次磷酸、单硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛次硫酸氢钠、焦亚硫酸钠);结合材料(实例包括但不限于嵌段聚合物、天然和合成橡胶、聚丙烯酸酯、聚氨酯、硅树脂、聚硅氧烷和苯乙烯-丁二烯共聚物);缓冲剂(实例包括但不限于偏磷酸钾、磷酸氢二钾、乙酸钠、无水柠檬酸钠和二水合柠檬酸钠);载剂(实例包括但不限于阿拉伯胶糖浆、芳香糖浆、芳香酏剂、樱桃糖浆、可可糖浆、橙皮糖浆、糖浆、玉米油、矿物油、花生油、芝麻油、抑菌氯化钠注射液和抑菌注射用水);螯合剂(实例包括但不限于依地酸二钠和依地酸);着色剂(实例包括但不限于FD&C红色3号、FD&C红色20号、FD&C黄色6号、FD&C蓝色2号、D&C绿色5号、D&C橙色5号、D&C红色8号、焦糖和氧化铁红);澄清剂(实例包括但不限于膨润土);乳化剂(实例包括但不限于阿拉伯胶、聚西托醇(cetomacrogol)、鲸蜡醇、单硬脂酸甘油酯、卵磷脂、单油酸脱水山梨醇酯、聚氧乙烯50单硬脂酸酯);包封剂(实例包括但不限于明胶和邻苯二甲酸乙酸纤维素);调味剂(实例包括但不限于茴香油、肉桂油、可可、薄荷醇、橙油、薄荷油和香草醛);湿润剂(实例包括但不限于甘油、丙二醇和山梨醇);研合剂(实例包括但不限于矿物油和甘油);油(实例包括但不限于花生油(arachisoil)、矿物油、橄榄油、花生油(peanut oil)、芝麻油和植物油);软膏基质(实例包括但不限于羊毛脂、亲水性软膏、聚乙二醇软膏、凡士林、亲水性凡士林、白色软膏、黄色软膏和玫瑰水软膏);渗透增强剂(透皮递送)(实例包括但不限于单羟基或多羟基醇、单或多价醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酯、饱和或不饱和二羧酸、精油、磷脂酰衍生物、脑磷脂、萜烯、酰胺、醚、酮和脲);增塑剂(实例包括但不限于邻苯二甲酸二乙酯和甘油);溶剂(实例包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯净水、注射用水、注射用无菌水和冲洗用无菌水);硬化剂(实例包括但不限于鲸蜡醇、鲸蜡酯蜡、微晶蜡、石蜡、硬脂醇、白蜡和黄蜡);栓剂基质(实例包括但不限于可可脂和聚乙二醇(混合物));表面活性剂(实例包括但不限于苯扎氯铵、壬苯醇醚10、辛苯醇醚9(oxtoxynol 9)、聚山梨酸酯80、月桂硫酸钠和单棕榈酸脱水山梨醇酯);悬浮剂(实例包括但不限于琼脂、膨润土、卡波姆、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄芪胶和硅酸镁铝);甜味剂(实例包括但不限于阿斯巴甜、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨醇和蔗糖);增稠剂(实例包括但不限于蜂蜡、鲸蜡醇和石蜡);张度剂(实例包括但不限于葡萄糖和氯化钠);增粘剂(实例包括但不限于海藻酸、膨润土、卡波姆、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮、海藻酸钠和黄芪胶);润湿剂(实例包括但不限于十七乙烯氧基鲸蜡醇(heptadecaethylene oxycetanol)、卵磷脂、单油酸山梨醇酯、单油酸聚氧乙烯山梨醇酯和硬脂酸聚氧乙烯酯)。
在特定的实施方案中,将本发明的药物制剂粘附到背衬或敷料上以用作贴剂或绷带。在此类实施方案中,根据本发明的药物贴剂包括背衬层和药物层。用于递送药剂的透皮贴剂的构造和使用是本领域熟知的(参见例如,1991年6月11日授权的美国专利号5,023,252,将所述专利通过引用并入本文)。此类贴剂可以被构造成连续、脉冲式或按需递送药剂。
如本文所用,术语“药物层”是指包含本发明组合物的任何层或包含如本文所定义的肽和水凝胶的任何层。
如本文所用,术语“背衬层”是指代表在应用药物贴剂之后的表面层的任何层。该定义包括通常用于药物贴剂的永久性背衬层,以及典型地用于薄柔性贴剂中的不可移动的薄膜。
在一些实施方案中,背衬层包含一种或多种选自以下项的聚合物:聚氨酯、聚酯弹性体、聚醚嵌段酰胺、聚丙烯酸酯、乙烯乙酸乙烯酯、乙烯丙烯酸酯共聚物、离聚物树脂、聚氯乙烯、聚偏二氯乙烯、聚酯和聚烯烃,诸如聚乙烯;特别优选聚烯烃(特别是聚乙烯)、聚酯、乙烯乙酸乙烯酯共聚物和聚氨酯。可用于形成背衬的其他材料包括但不限于改性纤维素,诸如棉、人造丝、苎麻等;改性聚烯烃,诸如低密度聚乙烯和聚丙烯;改性聚酯和改性聚(丙烯腈)。这些类型的特定材料的实例包括氧化纤维素;磷酸化纤维素;羧甲基化纤维素;琥珀酰化纤维素;聚烯烃(诸如聚丙烯)与聚丙烯酸化物(诸如聚丙烯酸)、水解聚(丙烯酰胺)、聚丙烯酸酯和聚(丙烯腈)的接枝物;纤维素与聚丙烯酸化物(诸如聚丙烯酸)、水解聚(丙烯酰胺)、聚丙烯酸酯和聚(丙烯腈)的接枝物;磺化聚烯烃;部分水解的聚(丙烯腈)和部分水解的聚酯。
背衬层可以是非织造织物或层压材料。在某些实施方案中,背衬层包括聚合物膜(诸如聚酯膜)和热密封层。在一些实施方案中,可以通过应用胶水(诸如丙烯酸粘合剂)的薄层来使背衬层自粘。
背衬层的厚度不受特别限制。优选地,背衬层具有在从0.1至5000μm;从0.5至1000μm;从1至750μm;从5至500μm;或从10至250μm范围内的厚度。
根据本发明的药物贴剂任选地包含可移除保护层(剥离衬件)。
在某些实施方案中,可移除保护层包括聚合物膜和硅酮涂层或含氟聚合物涂层。在特定的实施方案中,聚合物膜是聚烯烃,特别是聚乙烯或聚丙烯膜或聚酯,特别是聚对苯二甲酸乙二醇酯膜。
在将载体与颗粒组合之前或之后,可以将至少一种稳定剂和/或至少一种赋形剂(先前所述的)添加至载体。例如,如果需要特定的pH,可以将pH稳定剂(诸如三乙醇胺)添加至载体以稳定最终产物和/或分散体/悬浮液的pH。将组分混合后,使最终产物冷却至室温。可以例如通过控制稳定剂和/或其他组分的量来控制最终产物的粘度。
在另外的方面,本说明书提供了组织支架,其包含含有至少一种如本文所述的肽、和载体的组合物,其中肽被固定至载体。在某些实施方案中,至少一种肽具有QHREDGS(SEQID NO:1)的氨基酸序列。在某些实施方案中,载体是水凝胶。在另外的实施方案中,水凝胶是聚丙烯酸水凝胶、聚维酮水凝胶或纤维素水凝胶;壳聚糖、藻酸盐、琼脂糖、甲基纤维素、透明质酸、胶原蛋白、层粘连蛋白、基质胶、纤连蛋白、玻连蛋白、聚-l-赖氨酸、工程化和天然组织的prozation、和蛋白聚糖、纤维蛋白胶、通过脱细胞化工程化和天然组织制得的凝胶、及其组合;聚乙醇酸(PGA)、聚乳酸(PLA)以及PGA和PLA的组合如PLGA、聚ε-己内酯、聚乙烯醇(PVA)、聚乙二醇(PEG)、甲基丙烯酸甲酯、聚(甲基丙烯酸甲酯)(PMMA)、聚(甲基丙烯酸2-羟乙酯)(聚HEMA)、聚(癸二酸甘油酯)、自组装肽水凝胶AcN-RARADADARARADADA-CNH、聚氨酯、聚(异丙基丙烯酰胺)、聚(N-异丙基丙烯酰胺)[聚(NIPAM)]或其组合。
在本文所述的任何方面或实施方案中,组合物进一步包含至少一种具有以下氨基酸序列的肽:REDG(SEQ ID NO:3)、RLDG(SEQ ID NO:4)、REDGS(SEQ ID NO:5)、RLDGS(SEQID NO:6)、HREDG(SEQ ID NO:7)、HRLDG(SEQ ID NO:8)、HREDGS(SEQ ID NO:9)、HRLDGS(SEQID NO:10)、QHREDG(SEQ ID NO:11)、QHRLDG(SEQ ID NO:12)、QHREDVS(SEQ ID NO:13)、QHREDGS(SEQ ID NO:14)、QHRLDGS(SEQ ID NO:15)、KRLDGS(SEQ ID NO:16)、QHREDGSL(SEQID NO:17)、QHRLDGSL(SEQ ID NO:18)、QHRLDGSLD(SEQ ID NO:19)、QHREDGSLD(SEQ ID NO:20)或其组合。
在某些实施方案中,将肽缀合至组织支架内的水凝胶。
在本文所述的任何方面或实施方案中,组织支架呈片材、移植物、珠、晶片、芯片、盘、管、圆柱体或锥体的形式。
在任何方面或实施方案中,组织支架进一步包含酸化剂、碱化剂、吸附剂、气溶胶推进剂、空气置换剂、抗真菌防腐剂、抗微生物剂、抗微生物防腐剂、抗氧化剂、结合材料、缓冲剂、载剂、螯合剂、着色剂、澄清剂、乳化剂、包封剂、调味剂、湿润剂、研合剂、油、软膏基质、渗透增强剂、增塑剂、硬化剂、表面活性剂、悬浮剂、增稠剂、张度剂、增粘剂、润湿剂或其组合。
在任何方面或实施方案中,组织支架进一步包含另外的活性剂。在任何方面或实施方案中,组织支架包括有效诱导细胞生长、细胞分化、组织修复或其组合中的至少一种的量的QHREDGS(SEQ ID NO:1)肽。
在本文所述的任何方面或实施方案中,组织支架被配置用于体外或用于体内的组织生长、移植、修复或其组合。
在一些实施方案中,本发明的组织支架进一步包含至少一种稳定剂。
在还其他实施方案中,本发明的组织支架呈片材、移植物、珠、晶片、芯片、盘、管、圆柱体或锥体的形式。
在某些实施方案中,本发明的组织支架进一步包含酸化剂、碱化剂、吸附剂、气溶胶推进剂、空气置换剂、抗真菌防腐剂、抗微生物剂、抗微生物防腐剂、抗氧化剂、结合材料、缓冲剂、载剂、螯合剂、着色剂、澄清剂、乳化剂、包封剂、调味剂、湿润剂、研合剂、油、软膏基质、渗透增强剂、增塑剂、硬化剂、表面活性剂、悬浮剂、增稠剂、张度剂、增粘剂、润湿剂或其组合。在还其他实施方案中,本发明的组织支架进一步包含另外的活性剂。
IV.组合疗法
在本文所述的任何方面或实施方案中,所述的组合物和制剂可以单独使用或与另一种治疗剂组合使用以治疗此类病症。应了解,本发明的组合物和制剂可以单独使用或与另外活性剂(例如治疗剂)组合使用,所述另外的剂由熟练技术人员根据其预期目的进行选择。例如,另外的剂可以是本领域公认为可用于治疗由本发明的组合物和制剂治疗的疾病或病症的治疗剂。另外的剂也可以是赋予治疗组合物有益属性的剂,例如影响组合物粘度的剂。
应进一步理解,将包括在本发明内的组合是可用于它们的预期目的的那些组合。以下阐述的剂是出于说明目的,而非旨在限制。作为本发明部分的组合可以是本发明的化合物和选自以下列表的至少一种另外的剂。组合也可以包括多于一种另外的剂,例如两种或三种另外的剂,只要所述组合使得所形成的组合物可执行它的预期功能即可。
优选的组合包括抗微生物剂。此类剂包括但不限于银、铋、氯己定、聚六亚甲基双胍(PHMB)、次氯酸/次氯酸钠、结晶紫、臭氧和抗生素(例如杆菌肽)。
优选的组合是一种或多种非甾体抗炎药(也称为NSAID),其包括像布洛芬的药物。其他优选的组合是皮质类固醇,包括泼尼松龙;当与本发明的S1P受体激动剂或拮抗剂组合治疗患者时,通过逐渐减少所需的类固醇剂量,可以减少或甚至消除类固醇使用的众所周知的副作用。可以与本发明的组合物组合用于类风湿性关节炎的治疗剂的非限制性实例包括以下:一种或多种细胞因子抑制性抗炎药(CSAID);针对其他人细胞因子或生长因子的抗体或拮抗剂,所述其他人细胞因子或生长因子例如TNF、LT、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-12、IL-15、IL-16、IL-21、IL-23、干扰素、EMAP-II、GM-CSF、FGF和PDGF。本发明的S/T激酶抑制剂可以与针对细胞表面分子的抗体组合,所述细胞表面分子诸如CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69、CD80(B7.1)、CD86(B7.2)、CD90、CTLA或其配体(包括CD154(gp39或CD40L))。
治疗剂的优选组合可以在自身免疫和后续炎症级联中的不同点上进行干扰;优选实例包括TNF拮抗剂,像嵌合的、人源化的或人的TNF抗体、D2E7(HUMIRATM)、(PCT公布号WO97/29131)、CA2(REMICADETM)、CDP 571和可溶性p55或p75 TNF受体、其衍生物(p75TNFR1gG(ENBRELTM)或p55TNFR1gG(来那西普(Lenercept)),以及TNFα转化酶(TACE)抑制剂;类似地,由于相同的原因,IL-1抑制剂(白介素1转化酶抑制剂,IL-1RA等)也可以是有效的。其他优选的组合包括白介素11。又其他优选的组合是自身免疫应答的其他关键参与者,所述关键参与物与IL-18功能平行作用,依赖于IL-18功能或与IL-18功能一致;特别是IL-12拮抗剂,包括IL-12抗体或可溶性IL-12受体,或IL-12结合蛋白。已经显示IL-12和IL-18具有重叠但不同的功能,并且针对两者的拮抗剂的组合可能是最有效的。又另一个优选的组合是非消耗性抗CD4抑制剂。又其他优选的组合包括共刺激途径CD80(B7.1)或CD86(B7.2)的拮抗剂,包括抗体、可溶性受体或拮抗性配体。
本发明的组合物和制剂还可以与诸如以下的剂组合:甲氨蝶呤、6-MP、硫唑嘌呤、柳氮磺吡啶、美沙拉秦、奥沙拉秦、氯喹/氢氯喹、青霉胺、金硫苹果酸盐(肌肉内和口服)、硫唑嘌呤、秋水仙碱、皮质类固醇(口服、吸入和局部注射)、β-2肾上腺素能受体激动剂(沙丁胺醇、特布他林、沙美特罗(salmeteral))、黄嘌呤(茶碱、氨茶碱)、色甘酸盐、奈多罗米、酮替芬、异丙托铵和氧托品、环孢素、FK506、雷帕霉素、麦考酚酸莫酯、来氟米特、NSAID(例如布洛芬)、皮质类固醇(诸如泼尼松龙)、磷酸二酯酶抑制剂、腺苷(adensosine)激动剂、抗血栓剂、补体抑制剂、肾上腺素能剂、干扰促炎细胞因子(诸如TNFα或IL-1)的信号传递的剂(例如IRAK、NIK、IKK、p38或MAP激酶抑制剂)、IL-1β转换酶抑制剂、T-细胞信号传递抑制剂(诸如激酶抑制剂)、金属蛋白酶抑制剂、柳氮磺吡啶、6-巯嘌呤、血管紧张素转换酶抑制剂、可溶性细胞因子受体及其衍生物(例如,可溶性p55或p75 TNF受体和衍生物p75TNFRIgG(EnbrelTM和p55TNFRIgG(来那西普))、sIL-1RI、sIL-1RII、sIL-6R)、抗炎细胞因子(例如,IL-4、IL-10、IL-11、IL-13和TGFβ)、塞来考昔(celecoxib)、叶酸、硫酸羟氯喹、罗非考昔、依那西普、英夫利昔单抗(infliximab)、萘普生、伐地考昔、柳氮磺吡啶、甲基泼尼松龙、美洛昔康、乙酸甲基泼尼松龙、硫代苹果酸金钠、阿司匹林、曲安奈德(triamcinoloneacetonide)、萘磺酸右丙氧芬/扑热息痛、叶酸盐、萘丁美酮、双氯芬酸、吡罗昔康、依托度酸、双氯芬酸钠、奥沙普秦、盐酸羟考酮、重酒石酸氢可酮/扑热息痛、双氯芬酸钠/米索前列醇、芬太尼、阿那白滞素、盐酸曲马多、双水杨酯、舒林酸、氰钴胺素/fa/吡多辛(pyridoxine)、对乙酰氨基酚、阿仑膦酸钠、泼尼松龙、硫酸吗啡、盐酸利多卡因、吲哚美辛、硫酸葡糖胺(glucosamine sulf)/软骨素、盐酸阿米替林、磺胺嘧啶、盐酸羟考酮/对乙酰氨基酚、盐酸奥洛他定、米索前列醇、萘普生钠、奥美拉唑、环磷酰胺、利妥昔单抗(rituximab)、IL-1TRAP、MRA、CTLA4-IG、IL-18BP、抗IL-12、抗IL15、BIRB-796、SCIO-469、VX-702、AMG-548、VX-740、罗氟司特、IC-485、CDC-801和Mesopram。优选的组合包括甲氨蝶呤或来氟米特,并且在中度或重度类风湿性关节炎的情况下,包括环孢菌素和如上所述的抗TNF抗体。
本发明的组合物和制剂也可以与诸如以下的剂组合:阿仑单抗(alemtuzumab)、屈大麻酚(dronabinol)、达克珠单抗(daclizumab)、米托蒽醌、盐酸扎利罗登(xaliprodenhydrochloride)、氨吡啶、乙酸格拉替雷(glatiramer acetate)、那他珠单抗(natalizumab)、辛纳必醇(sinnabidol)、a-免疫因子NNSO3、ABR-215062、AnergiX.MS、趋化因子受体拮抗剂、BBR-2778、卡拉古林(calagualine)、CPI-1189、LEM(脂质体包封的米托蒽醌)、THC.CBD(大麻素激动剂)、MBP-8298、美索普兰(mesopram)(PDE4抑制剂)、MNA-715、抗IL-6受体抗体、纽若瓦斯(neurovax)、吡非尼酮同种异型体1258(RDP-1258)、sTNF-R1、他仑帕奈(talampanel)、特立氟胺、TGF-β2、替利莫肽(tiplimotide)、VLA-4拮抗剂(例如TR-14035、VLA4 Ultrahaler、Antegran-ELAN/Biogen)、干扰素γ拮抗剂和IL-4激动剂。
可以与本发明的制剂的组合物组合用于银屑病的治疗剂的非限制性实例包括以下:卡泊三醇(calcipotriene)、丙酸氯倍他索(clobetasol propionate)、曲安奈德、丙酸卤倍他索(halobetasol propionate)、他佐罗汀(tazarotene)、甲氨蝶呤、氟轻松醋酸酯、增强型二丙酸倍他米松、醋酸氟轻松、阿昔曲丁(acitretin)、焦油(tar)洗发剂、戊酸倍他米松、糠酸莫米他松、酮康唑、丙吗卡因/氟轻松、戊酸氢化可的松、氟羟可舒松、尿素、倍他米松、丙酸氯倍他索/emoll、丙酸氟替卡松、阿奇霉素、氢化可的松、保湿配方、叶酸、地奈德(desonide)、吡美莫司(pimecrolimus)、煤焦油、二乙酸二氟拉松、叶酸依那西普、乳酸、甲氧沙林(methoxsalen)、hc/次五倍子酸铋(bismuth subgal)/znox/resor、乙酸甲基泼尼松龙、泼尼松、防晒剂、哈西奈德(halcinonide)、水杨酸、地蒽酚、氯可托龙特戊酸酯、煤提取物、煤焦油/水杨酸、煤焦油/水杨酸/硫、去羟米松、地西泮、润肤剂、氟轻松醋酸酯/润肤剂、矿物油/蓖麻油/花生油、矿物油/花生油、石油/肉豆蔻酸异丙酯、补骨脂素、水杨酸、皂/三溴沙仑、硫柳汞/硼酸、塞来考昔、英夫利昔单抗、环孢菌素、阿法赛特(alefacept)、依法利珠单抗(efalizumab)、他克莫司(tacrolimus)、吡美莫司、PUVA、UVB和柳氮磺吡啶。
可以与本发明的制剂的化合物组合用于银屑病性关节炎的治疗剂的非限制性实例包括以下:甲氨蝶呤、依那西普、罗非考昔、塞来考昔、叶酸、柳氮磺吡啶、萘普生、来氟米特、乙酸甲基泼尼松龙、吲哚美辛、硫酸羟氯喹、泼尼松、舒林酸、增强型二丙酸倍他米松、英夫利昔单抗、甲氨蝶呤、叶酸盐、曲安奈德、双氯芬酸、二甲亚砜、吡罗昔康(piroxicam)、双氯芬酸钠、酮洛芬、美洛昔康、甲基泼尼松龙、萘丁美酮、托美丁钠、卡泊三醇、环孢霉素、双氯芬酸钠/米索前列醇、氟轻松醋酸酯、硫酸葡糖胺、硫代苹果酸金钠、重酒石酸氢可酮/扑热息痛、布洛芬、利塞膦酸钠、磺胺嘧啶、硫鸟嘌呤、伐地考昔、阿法赛特和依法利珠单抗。
可以与本发明的制剂的化合物组合用于再狭窄的治疗剂的非限制性实例包括以下:西罗莫司、紫杉醇、依维莫司、他克莫司、ABT-578和对乙酰氨基酚。
可以与本发明的制剂的化合物组合用于SLE(狼疮)的治疗剂的非限制性实例包括以下:NSAID,例如双氯芬酸、萘普生、布洛芬、吡罗昔康、吲哚美辛;COX2抑制剂、例如塞来考昔、罗非考昔、伐地考昔;抗疟药、例如羟氯喹;类固醇、例如泼尼松、泼尼松龙、布替耐德(budenoside)、地塞米松;细胞毒素、例如硫唑嘌呤、环磷酰胺、麦考酚酸莫酯、甲氨蝶呤;PDE4抑制剂或嘌呤合成抑制剂,例如具有式(I)、(Ia)、(Ib)或(Ic)的化合物也可以与诸如以下的剂组合:柳氮磺胺吡啶、5-氨基水杨酸、奥沙拉嗪、和干扰促炎细胞因子(诸如IL-1)的合成、产生或作用的剂,诸如半胱天冬酶抑制剂(像IL-1β转化酶抑制剂和IL-1ra)。具有式(I)、(Ia)、(Ib)或(Ic)的化合物也可以与以下剂一起使用:T细胞信号传导抑制剂,例如酪氨酸激酶抑制剂;或靶向T细胞激活分子的分子,例如CTLA-4-IgG或抗B7家族抗体、抗PD-1家族抗体。具有式(I)、(Ia)、(Ib)或(Ic)的化合物可以与以下剂组合:IL-11或抗细胞因子抗体,例如,芬突利珠单抗(fonotolizumab)(抗IFNg抗体),或抗受体受体抗体,例如,抗IL-6受体抗体和针对B细胞表面分子的抗体。具有式(I)、(Ia)、(Ib)或(Ic)的化合物也可以与以下剂一起使用:LJP 394(阿贝莫司(abetimus))、耗尽或灭活B细胞的剂如利妥昔单抗(抗CD20抗体)、lymphostat-B(抗BlyS抗体)、TNF拮抗剂(例如抗TNF抗体)、D2E7(PCT公布号WO 97/29131;HUMIRATM)、CA2(REMICADETM)、CDP 571、TNFR-Ig构建体(p75TNFRIgG(ENBRELTM)和p55TNFRIgG(LenerceptTM))。
本发明的制剂的一种或多种化合物可以以其本身或以其与一种或多种药学上可接受的载体或赋形剂混合的药物组合物以治疗或改善如本文所述的疾病或病症的剂量施用于人类患者。这些化合物的混合物也可以作为简单的混合物或以合适的配制药物组合物施用至患者。治疗有效剂量是指足以导致如本文所述的疾病或病症的预防或减弱的一种或多种化合物的量。用于配制和施用本申请的组合物的技术可见于本领域的普通技术人员熟知的参考文献中,诸如最新版的“Remington's Pharmaceutical Sciences,”MackPublishing Co.,Easton,PA中。
V.使用方法
改善皮肤的状况或外观美感的方法
皮肤由多层细胞构成,所述细胞通过在反复的循环中每隔30天恒定地进行自我脱落和再生。可以将所述层大致分成两部分–顶部表皮和下部真皮。皮肤的组织学研究显示,皱纹在一系列主要的细胞改变后形成。在老化的早期(年龄35-45岁)过程中,存在细胞更新和再生的渐进性和进行性减缓。这导致皮肤变得更薄。作为结果,正常起伏的脊型真皮-表皮连接层(DEJ)变得更平坦。这种平坦性减少了底部上的下部真皮和顶部上的表皮之间的营养交换表面积。
因老化而对表皮提供的营养减少是导致细胞耗竭和弱化的一个因素。在没有对表皮提供适当营养的情况下,表皮细胞的细胞代谢减缓。此外,细胞代谢的某些不需要的副产物(诸如自由基)的转运减少。此类自由基在细胞内的累积可能导致细胞中不希望的突变性损伤并且最终导致癌症。
DEJ中的粘附性通常由胶原蛋白4(多片结构或基底层)和胶原蛋白7(锚定于片结构上)提供。对DEJ的营养物的进行性减少使用于促进这种胶原蛋白新合成过程的信使循环减缓。由于没有最佳量的胶原蛋白,所以皮肤甚至更松垂,从而散布营养物的缺乏。自相矛盾的情况是,成熟老化的皮肤含有更多的弹性蛋白,身体以此来填充因胶原蛋白缺乏而留下的空位。令人遗憾的是,这种弹性蛋白断裂成碎片、钙化并且含有过量脂质。除因缺乏胶原蛋白支持而导致皮肤厚度减小外,正在老化或已经老化的皮肤更加松弛并且缺乏弹性。这两种特性为皱纹的标志。这种老化过程和皱纹外观在衰老的后期(45岁和45岁以上)过程中加速。截止到50岁时,几乎没有人可以逃避皱纹。
虽然遗传学起着重要作用,但是出现的皱纹数量高度依赖于日光暴露的量。“饱经风霜的(lived-in)面部”上的细纹,尤其是大量时间在户外度过的那些人的细纹,部分地是氧化损伤造成的结果,而氧化损伤是因过度暴露于紫外线(UV)日光-UVA(导致晒黑、起皱纹和黑素瘤)和UVB(导致晒伤和基底和鳞状细胞癌)二者所致。UV光可能通过增加蛋白水解酶的产生进一步损伤皮肤,所述的蛋白水解酶分解胶原蛋白,即位于真皮下的结缔组织。
本公开提供了包含本公开的肽(例如QHREDGS(SEQ ID NO:1))的所公开的组合物、药物组合物或制剂用于改善动物或受试者的皮肤的外观美感或状况的用途,如本领域已知的或如本文所述的,使用所公开的组合物和药物组合物,例如将治疗有效量的组合物或药物组合物施用于动物或受试者的皮肤或使动物或受试者的皮肤与治疗有效量的组合物或药物组合物接触,持续足以改善皮肤的外观美感的时间。在一方面,受试者是哺乳动物。优选地,受试者是人类。术语“受试者”和“患者”在本文中可互换使用。
本公开提供了用于改善皮肤的外观美感的方法。改善皮肤的外观美感包括但不限于减轻时间性老化、光老化、激素老化和/或光化性老化的皮肤病学迹象;预防和/或减轻细纹和/或皱纹的外观;减轻面部细纹和皱纹、面颊、前额上的面部皱纹、两眼之间的垂直皱纹、眼上方和口周围的水平皱纹、木偶纹且特别是深度皱纹或皱褶的引人注目性;预防、减轻和/或减少细纹和/或皱纹的外观和/或深度;改善眼眶下细纹和/或眼眶周围细纹的外观;减轻鱼尾纹外观;使皮肤,特别是老化皮肤恢复年轻和/或恢复活力;减轻皮肤脆性;预防和/或逆转糖胺聚糖类和/或胶原蛋白丧失;改善雌激素失衡效应;预防皮肤萎缩;预防、减轻和/或治疗色素沉着过度;将皮肤色素减退减轻到最低限度;改善皮肤色调、光亮度、清透度和/或紧致度;预防、减轻和/或改善皮肤松垂;改善皮肤紧实度、丰满度、柔韧性和/或柔软性;改善前胶原蛋白和/或胶原蛋白产生;改善皮肤肌理和/或促进再肌理化;改善皮肤屏障修复和/或功能;改善皮肤轮廓的外观;恢复皮肤光泽和/或亮度;将疲劳和/或紧张状态的皮肤病学迹象减轻到最低限度;抵抗环境压力;补充因衰老和/或更年期而减少的皮肤中的成分;改善皮肤细胞间通讯;增加细胞增殖和/或繁殖;增加因衰老和/或更年期而减少的皮肤细胞代谢;延缓细胞老化;改善皮肤保湿性;增加皮肤厚度;增加皮肤的弹性和/或回弹力;增强表皮脱落;改善微循环;减少和/或防止脂肪团形成;及其任何组合。
时间性老化的症状包括:干性和薄皮肤、细皱纹、异常血管、老年斑以及良性和恶性皮肤肿瘤。年轻人的皮肤比老年人的皮肤更频繁地自我更新。由此顶层因老化过程而失去更多的水分,并且老年人的皮肤具有更干燥和更脱水的外观。胶原蛋白产生减少导致最初在眼部(常称作“鱼尾纹”)、前额和其他日光暴露区周围观察到的细皱纹。更显著的效应包括面部表情细纹部位的皱纹和眼睑、颈部、颌和臂部上的松垂褶皱。在许多给皮肤提供营养物的小的精细血管内发生异常。这种情况在鼻部和面颊上特别明显。老年斑为作为日光暴露区中色素细胞失调结果在表面出现的色素沉着。
人类皮肤的美感改善可以是皮肤的任何属性或特征的改善,包括但不限于:(a)治疗、减轻和/或预防细纹或皱纹;(b)皮肤孔径减小;(c)皮肤厚度、丰满度和/或紧致度改善;(d)皮肤光滑性、柔韧性和/或柔软性改善;(e)皮肤色调、光泽度和/或清透度改善;(f)前胶原蛋白和/或胶原蛋白产生改善;弹性蛋白的维持和重塑改善;皮肤肌理改善和/或再肌理化的促进;(g)皮肤屏障修复和/或功能的改善;(h)皮肤轮廓的外观的改善;(i)恢复皮肤光泽和/或亮度;(j)补充皮肤中的必需营养物和/或成分;(k)因衰老和/或更年期而减少的皮肤外观改善;(l)皮肤保湿性改善;(m)皮肤弹性和/或回弹力的增加;(n)治疗、减轻和/或预防皮肤松垂;(o)皮肤紧实度的改善;(p)色素斑和/或斑驳的皮肤的减轻;和(q)皮肤因光衍射或反射导致的光学特性改善。
本公开还提供了用于治疗和/或预防伤口或皮肤的结疤的方法,所述方法包括向有需要的皮肤区域局部应用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。
本公开还提供了用于预防和/或治疗皮肤的老化的方法,所述方法包括向有需要的皮肤区域局部应用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观(例如修复、逆转、减轻、改善或预防老化的皮肤病学迹象)的时间。皮肤老化包括但不限于皱缩、皱纹、垂肉、晒伤、皮肤的暗淡外观、皮肤紧致度的丧失、角化病、色素沉着过度、黑斑病、日光性着色斑、日光性角化病、皮肤日射病或皮肤色素减退。
本公开提供了用于在人类皮肤区域中再生胶原蛋白、在人类皮肤中增强胶原蛋白和/或HA的产生的方法,所述方法包括向有需要的皮肤区域(例如,松垂皮肤、减薄皮肤、遭受皱纹和细纹的皮肤等)局部应用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。在一些实施方案中,所述受试者在所述皮肤区域中具有皮肤发红。在一些实施方案中,所述受试者在所述皮肤区域中具有皱纹。在一些实施方案中,所述皮肤区域易于发展皱纹。在一些实施方案中,所述皮肤区域是在受试者的前额、脸颊、颈部或眼睛周围。
本公开提供了用于预防或减少人类皮肤(典型地,面部皮肤)上皱纹和/或细纹的存在或用于减轻人类皮肤上皱纹或细纹的严重程度、减少所述皱纹或细纹数目或预防或预先阻止所述皱纹或细纹的发作的方法,所述方法包括向有需要的皮肤区域(例如,松垂皮肤、减薄皮肤、遭受皱纹和细纹的皮肤等)局部应用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。组合物可以任选地进一步包含有效改善皮肤的外观的量的类视黄醇(例如,视黄醇或棕榈酸视黄酯)和/或α-羟基酸(例如,乙醇酸)和/或β-羟基酸(例如,水杨酸或衍生物)。
组合物对细纹和皱纹的形成或外观的作用可以例如通过目视检查来定性评价或例如通过对皱纹形态(例如每单位面积皮肤的皱纹数目、深度、长度、面积、体积和/或宽度)的显微镜或计算机辅助测量来定量评价。
本公开提供了用于在有需要的受试者中减少皮肤发红的方法,所述方法包括施用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。皮肤发红可能起因于但不限于痤疮、接触刺激、皮肤敏感性、酒渣鼻、湿疹、手术、激光处理、过敏、微晶换肤术、擦皮术或其组合。
本公开提供了用于在有需要的受试者中减少、预防痤疮、降低痤疮的严重程度、或预先阻止痤疮的发作的方法,所述方法包括施用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。
本公开提供了用于治疗薄皮肤的方法,所述方法包括施用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。“薄皮肤”旨在包括由于时间性老化、更年期或光损伤而变薄的皮肤和过早变薄的皮肤。在一些实施方案中,治疗是针对男性的薄皮肤,而其他实施方案治疗更年期前或更年期后的女性的薄皮肤,因为据信皮肤在男性和女性中随着年龄而不同地变薄,并且特别是在处于不同生命阶段的女性中。
本公开提供了用于在尚未显现皮肤老化迹象的个体中(最通常在25岁以下的个体中)预防或预先阻止老化皮肤的方法,所述方法包括施用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善或预防皮肤老化的外观的时间。所述方法也可以逆转或治疗曾经显现出的如年龄超过25岁的个体中常见的老化迹象,或者用于减缓此类个体中皮肤病学老化的进展。
本公开提供了用于改善和/或预防人类皮肤光老化和内源性老化的迹象的方法,所述方法包括施用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善或预防皮肤老化的外观的时间。
本公开提供了用于减少皮脂产生或改善受到脂肪团影响的皮肤的外观、和/或减少不想要的脂肪生成或增加脂肪分解的方法,所述方法包括施用包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。在面部组合物的情况下,药物组合物或制剂可以包含一种或多种另外的剂,诸如抗痤疮成分(例如,水杨酸、过氧化苯甲酰和其他过氧化物、硫磺、类视黄醇等),或者在脂肪团治疗的情况下,制剂可以包含任何适于治疗脂肪团的成分,包括但不限于紫苏子油和其他不饱和脂肪油及ω-3脂肪酸诸如α-亚麻酸;咖啡因;茶碱;黄嘌呤;类视黄醇(例如,视黄醇)等。根据本发明的脂肪团治疗将典型地局部应用于存在脂肪团的皮肤,包括臀部和大腿的皮肤,持续足以改善其外观的时间段,包括例如每日治疗,持续至少四周、至少八周、至少十二周或更长。在一个实施方案中,局部应用组合物以治疗痤疮。
本公开提供了用于治疗和/或预防皮肤和/或毛发的色素沉着过度、例如以增亮皮肤或毛发的方法,所述方法包括包含有效量的本发明肽的局部用组合物、药物组合物或制剂,持续足以改善皮肤的外观的时间。色素沉着过度包括个体皮肤或头发的比个体所需的颜色更深且是由黑素细胞引起的任何着色。这种不希望的色素沉着也可以称为变色。皮肤的色素沉着过度区域包括离散或斑驳的色素沉着过度的区域。离散的色素沉着过度的区域可以是明显的、均匀的深色区域,并且可以在皮肤上呈现为褐色斑或雀斑,包括通常称为色素斑点或“老年斑”的标记。皮肤的斑驳色素沉着过度的区域可以为深色斑块,其在大小和形状上比离散的色素沉着的区域更大且更不规则。色素沉着过度的区域也包括晒黑的皮肤区域,例如由于UV暴露引起的晒黑的皮肤。色素沉着过度的毛发包括比所需更深的任何色度的毛发。
治疗色素沉着过度或色素沉着过度的皮肤/毛发包括但不限于根除、减轻、改善或逆转一种或多种与色素沉着过度相关的不需要的特征,诸如在受影响的区域中产生可感觉到的皮肤或毛发的增亮。增亮皮肤的色素沉着过度区域可能是希望的,并且可以包括但不限于:减少老年斑;增亮晒黑的皮肤;均匀化或最佳化皮肤色调(例如,在斑驳的色素沉着过度的区域中;在治疗黑斑块和黄褐斑块、雀斑、烧伤后瘢痕和损伤后色素沉着过度中)。预防色素沉着过度或色素沉着过度的皮肤包括但不限于为还没有受色素沉着过度影响的皮肤提供下述益处,所述益处用于避免、延迟、预先阻止或最小化一种或多种与皮肤色素沉着过度相关的不需要的特征,诸如减少最终发展出的色素沉着过度区域的暗度或大小。
在一些方面,将包含本公开的肽的组合物、药物组合物或制剂以有效量局部应用于皮肤,所述有效量是指足以实现可测量的人类皮肤的美感改善的量。在一些实施方案中,每天至少一次、每天至少两次、且每天至少3次、每天至少4次或每天至少5次施用组合物、药物组合物或制剂。在一些实施方案中,将组合物、药物组合物或制剂施用至少一周、至少2周、至少3周、至少4周、至少5周、至少6周、至少7周、至少8周、至少9周、至少10周、至少11周、或至少12周的时间段。在一些实施方案中,将本公开的组合物、药物组合物或制剂以下述量应用于皮肤:从约0.001至约100mg/cm2、更典型地从约0.01至约20mg/cm2、或从约0.1至约10mg/cm2。
VI.制品或试剂盒
本发明涵盖制品或试剂盒,当由医疗从业者使用时,所述制品或试剂盒可以简化将适当量的本发明的组合物、药物制剂或局部用制剂向患者的施用。
在本发明的另一方面,提供了含有可用于治疗和/或预防上述的皮肤病症的材料的制品。制品包含容器以及在所述容器上或与所述容器相联的标签或包装说明书。合适的容器包括例如瓶子、小瓶、注射器、IV溶液袋等。容器可以由各种材料(诸如玻璃或塑料)形成。容器可以提供保护免受光降解。容器容纳组合物自身或组合物与有效治疗和/或预防所述病症的另一种组合物的组合。组合物中的至少一种活性剂是本发明的肽。组合物可以进一步包含本文所述的载体(例如水凝胶和/或壳聚糖)。标签或包装说明书指示组合物用于治疗所选病症。此外,制品可以包含(a)其中含有组合物的第一容器,其中所述组合物包含本发明的肽;和(b)其中含有组合物的第二容器,其中所述组合物包含另外的治疗剂。本发明的此实施方案中的制品可以进一步包含指示组合物可用于治疗和/或预防特定病症的包装说明书。可替代地或另外,制品可以进一步包含第二(或第三)容器,其包含局部施用可接受的赋形剂或药学上可接受的缓冲液,诸如抑菌注射用水(BWFI)、磷酸盐缓冲盐水、林格氏溶液和右旋糖溶液。从商业和用户的角度来看,它可以进一步包括其他所需材料,包括其他缓冲液、静脉内插管设备、滴注袋、药贴、局部用凝胶、泵、稀释剂、过滤器、自动注射器、吸入器、针头和注射器。
实施例
以下为本发明的方法和组合物的实施例。应当理解,根据以上提供的一般描述可以实施各种其他实施方案。
实施例1.使用QHREDGS(SEQ ID NO:1)肽改善人类皮肤的外观和敏感性
以异常的感官刺激为特征的敏感皮肤是一种复杂的皮肤病学病症,其影响着全球许多人。仅在美国,就有60%-70%的女性和50%-60%的男性报告有某种敏感的皮肤症状(Farage等人,Front Med.2019;6:98),诸如瘙痒、灼热、刺痛、收紧感和干燥。对于许多人来说,痤疮加剧了与干性和敏感的皮肤相关的问题。虽然青春期和青年期非常流行,但成人痤疮或在25岁以后经历的痤疮却变得越来越普遍。事实上,据报道,大约40%-54%的男性和女性在25岁以后会经历痤疮的迹象(Cordain L等人,Arch Dermatol.2002;138(12):1584-1590)。对皮肤老化和皱纹的担心加剧了以上护肤忧虑。随着皮肤老化,它会发生许多结构和功能变化,诸如胶原蛋白和油脂产生的减少,从而导致皱纹和干燥。追求光洁的皮肤带来的持续挫败感和痛苦不仅会导致心理影响和生产力下降,而且还会给患者和消费者带来明显的财务负担。全球护肤市场目前价值1483亿美元,并且预计每年以大约90亿美元的速度增长(护肤行业:2012-2025年全球护肤市场规模|数据来源于https://www.statista.com/ statistics/254612/global-skin-care-market-size/。2020年10月2日访问的)。使事情变得复杂的是,消费者不断受互联网上的宣传次佳护肤产品的广告,和使皮肤保持洁白且美丽的社会压力的轰击。这产生了这样的信息传递,即消费者需要花费数百美元来用依靠流行语和有影响力的人而不是科学和事实的产品进行多步骤护肤程序。
皮肤是最大的器官,并且负责提供保护、并保持湿度和水合。皮肤是由表皮和真皮2层构成的复杂系统。最外层或表皮含有角化细胞(其主要负责屏障功能)、黑素细胞、树突状细胞、朗格汉斯细胞和其他免疫细胞。含有成纤维细胞和免疫细胞的真皮含有提供细胞支持的细胞外基质(-Dorantes等人,Int J Inflam.2019;2019)。
与所有器官一样,皮肤易于老化,其特征是皮肤薄而干,并有着皱纹。虽然老化皮肤是不可避免的,但诸如空气污染、吸烟和日光暴露的外部因素会促使皮肤老化的迹象早日发生,从而最终导致皮肤弹性的丧失和粗大的皱纹。在生理上,存在角质形成细胞和成纤维细胞的增殖的显著减少,和胶原蛋白产生的减少。对于老化皮肤的常见非侵入性治疗和预防性措施包括应用含有抗氧化剂和类视黄醇的霜剂和凝胶,然而由于角化细胞产生的保护性屏障,在设计产生最大化分子传递和渗透作用的霜剂时,必须谨慎(Zhang S等人,CellTransplant,2018;27(5):729-738)。
相反地,寻常痤疮是主要影响青年期的一种皮肤病症,然而近年来,其流行率在20多岁和30多岁的年轻人中有所上升。与老化皮肤不同,痤疮困扰的皮肤通常与油脂产生增加相关,从而导致炎症延长(Bhate K等人,Br J Dermatol.2013;168(3):474-485)。虽然治疗方案视情况而不同,但已证明局部用类视黄醇有效减少炎症和面部病变(Leyden JJ.JAm Acad Dermatol.2003;49(增刊3):S200-S210)。
在本文中,我们描述了轻质保湿剂的研发及其在北美洲和亚洲受试者中的非正式调查中的使用。使用新型仿生肽序列QHREDGS(SEQ ID NO:1)(INCI名称:sh-七肽-10SP)配制了这款名为Kerra的保湿剂,所述保湿剂展示减少在活性氧物质存在下的角化细胞死亡(Xiao等人,doi:10.1073/pnas.1612277113)。当由北美洲受试者使用时,在年龄较大的群体(>40岁)中绝大多数是积极反应,而在中国,具有干性和油性皮肤的更年轻受试者报告出积极效果。此外,由一小群患有中度至重度痤疮的受试者使用了Kerra,所述受试者在使用的5天内报告了改善。
方法
霜剂制剂
轻质保湿剂Kerra由油包水乳液配制。简而言之,将含有水(water/aqua)、甘油、DL-黄原醇和黄原胶的水相,以及含有罗莎籽油、鲸蜡醇、硬脂酸甘油酯、牛油果、橄榄油酸鲸蜡硬脂酯、橄榄油酸脱水山梨醇酯的油相加热。一旦融化并搅拌,将水相添加至油相并乳化直至光滑。一旦将霜剂冷却至室温,就添加胶原蛋白和新型肽序列sh-七肽-10SP以及防腐剂苄醇和乙基己基甘油。混合冷却相直至被掺入,并将霜剂添加至试管中并密封。
北美洲调查收集
一周后与接受免费Kerra样品的北美洲受试者联系,并要求他们填写调查表。调查表收集了他们的年龄范围,并要求参与者选择其皮肤类型(允许他们选择多于一种)。然后,向参与者询问根据其使用Kerra的体验的以下是/否问题:
1.我感觉到Kerra使我的皮肤看起来受更少刺激。
2.我感觉到Kerra使我的皮肤感觉到更水润。
3.我感觉到Kerra使我的皮肤看起来更健康。
4.我感觉到Kerra使我的皮肤感觉更光滑。
5.我感觉到Kerra改善了我的皮肤的总体外观。
中国调查收集
邀请30名前往上海美容院的志愿者参加这项调查。提供同意后,将给予每名参与者2管霜剂以在家中使用。7天后,要求参与者填写有关他们使用Kerra的体验的在线调查。26名参与者完成了调查,其中14名具有干性或油性皮肤,并且有8名报告有痤疮。调查收集了他们的年龄范围和皮肤类型。对参与者询问了以下问题:
1.Kerra与您当前的护肤产品相比如何?
2.对以下问题回答是/否。在Kerra后,我的皮肤感觉到...
3.更收紧
4.更光滑
5.较不敏感
6.更水润
7.不予置评
8.根据您应用Kerra的体验,使用李克特量表(非常同意至非常不同意)评价以下陈述
9.Kerra感觉粘稠
10.Kerra感觉清爽
11.Kerra不柔滑
12.Kerra不太油腻
13.Kerra不太湿水
14.Kerra具有均匀的质感
15.Kerra具有舒适的粘度
16.Kerra是非常能吸收的
17.Kerra易于散开
根据您使用Kerra一周后的体验,使用李克特量表(非常同意至非常不同意)评价以下陈述。
1.我的皮肤不太油腻
2.我的皮肤感觉湿润
3.我的皮肤感觉清爽
4.我的皮肤感觉柔软
5.我的皮肤感觉光滑
6.我的皮肤不感觉粘腻
7.我的皮肤感觉紧致
8.Kerra良好渗透我的皮肤
9.我认为Kerra适于我的皮肤
如果志愿者报告了易长痤疮皮肤,则指示他们回答以下调查:
10.从非常轻度、轻度、重度至非常重度,评价痤疮的疼痛。
11.从非常轻度、轻度、重度至非常重度,评价痤疮的发红。
12.在第1、2、3、4、5天,您是否注意到:
a.疼痛减轻
b.发红减轻
c.皮肤的总体改善
d.痤疮减轻
e.没有变化
f.不确定
13.评价Kerra对你皮肤的总体作用:非常好、好、中立、不好、非常差。
结果和讨论
受访者群体
对北美洲和中国的受试者给予了轻质面部保湿剂Kerra,并且在使用约一周后,询问受试者一系列旨在增加我们对用户体验的了解的问题。在北美洲内,问题旨在快速地深入了解产品使其皮肤感觉如何,而在中国的调查促使用户反映产品体验和其皮肤感觉到如何两者。在北美洲内,总共对12名参与者进行了调查,其中大多数年龄在40岁以上(图1A)。要求调查参与者对他们的皮肤类型进行分类。允许参与者选择多种皮肤类型,其中老化是观察到的最常见的皮肤类型,然后是敏感皮肤和混合性皮肤(图1B)。在中国调查中,总共对18名参与者进行了调查,并且调查受访者的平均年龄在40岁以下(图1C)。中国受访者报告出干性和油性皮肤的均匀分布(图1D)。在北美洲,十二名受访者中有两名为男性,而所有中国受访者确定为女性。这两个调查受访者子组使我们深入了解3个不同的受试者群体;具有1)老化皮肤,2)年轻的干性皮肤和3)年轻的油性皮肤的受试者。
北美洲调查受访者感觉到Kerra改善了皮肤外观。
为了最大程度地提高受访者参与度,我们向最近接受免费Kerra样品的北美洲受试者发送了简短调查。除年龄和皮肤类型外,还向受试者询问了一系列5个“是/否”问题,旨在深入了解其使用体验。结果绝大多数是积极的并支持Kerra。
约92%(11/12)的受访者感觉到Kerra使其皮肤看起来受更少刺激、感觉更水润和更光滑(图2A、2B、2D),并且100%的受访者感觉到Kerra使其皮肤看起来更健康且感觉到Kerra改善了其皮肤的总体外观(图2C、2E)。有趣的是,当我们查看原始数据时,当询问Kerra是否使其皮肤看起来受更少刺激、更水润和更光滑时,同一受试者回答“否”。实际上,此受试者未满40岁,不属于大多数受访者,这表明Kerra可能最适合40岁以上的受试者。然而,在仅12名受访者的情况下,本调查仅用作了解北美洲用户体验的第一步。
中国受访者根据皮肤类型而对Kerra的感知程度不同。
在分发给中国受试者的调查中,问题旨在提取有关产品本身以及对所述产品使用一段时间后的用户体验的反馈。总体上,大多数受访者(>57.2%)报告出喜欢Kerra,其中仅28.6%更喜欢他们目前使用的护肤产品(图3A)。有趣的是,如果根据皮肤类型进行分析,则会出现多种趋势。当询问一系列“是/否”问题时,具有干性皮肤的受试者中100%回答说他们的皮肤在使用Kerra后感到更水润,而具有油性皮肤的受试者中仅25%回答说他们的皮肤在使用Kerra后感到更水润。相反地,具有油性皮肤的更多(50%)受试者感觉到Kerra改善了其敏感区域,并且他们的皮肤总体上感觉到更光滑(图3B)。
然后,向受访者提出一系列有关他们使用Kerra的体验以及使用Kerra一周后的皮肤的陈述,并要求他们使用李克特量表进行回答。具有干性皮肤的受访者更普遍地感觉到Kerra粘稠但总体上清爽,而具有油性皮肤的受访者不认为Kerra感觉清爽(图3C、3E)。相反,具有干性皮肤的受访者不认为Kerra太油腻,而是感觉到它在其皮肤上吸收良好。在使用Kerra 7天后,具有油性皮肤的受访者总体上感到满意,并且100%赞成他们的皮肤没有感觉到油腻或粘腻,而是感觉到湿润和清爽(图3D)。同时,干性皮肤受访者指出,使用7天后,其皮肤感觉到湿润和柔软(图3F)。这项调查证明,Kerra适于干性和油性皮肤两者,然而,用户体验会根据皮肤类型而异。这对于理解以下情况很重要:虽然Kerra可以被具有不同皮肤类型的受试者使用,但是他们的使用案例和Kerra将满足的需求有所不同。这些信息对于设计未来的营销材料很重要,这将使我们能够开展出针对不同皮肤类型进行个性化的使用活动或方案。
使用5天后,Kerra有助于改善痤疮的症状。
为了了解Kerra对易长痤疮皮肤的作用,向八名患有不同程度痤疮的受试者给予样品,并要求他们报告Kerra如何影响其痤疮。在基线时,许多参与者报告有由于其痤疮导致的轻度至非常重度的疼痛或发红(图4A)。引人注目地,仅使用1天后,25%的受访者报告了疼痛减轻和其皮肤的总体改善。到第5天,2名受访者(25%)报告了痤疮的减轻,并且另有25%报告了发红的减轻和皮肤的总体改善(图4B)。总体上,75%的痤疮用户感觉到好像Kerra对其痤疮总体上具有积极效果(“好”或“非常好”的反应),其余的25%经历了中性效果(图4C)。这项研究的结果显示出Kerra可能是减轻中度痤疮迹象的有效疗法的早期希望。
总之,报告了Kerra对大多数皮肤类型(包括老化、干燥、油腻和易长痤疮皮肤)都具有积极效果。在中国或北美洲,均未报告负面反馈或不良反应。
序列表
<110> 科思柔
<120> 用于治疗或改善皮肤的状况和外观的组合物和使用方法
<160> 22
<170> PatentIn版本3.5
<210> 1
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 1
Gln His Arg Glu Asp Gly Ser
1 5
<210> 2
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 乙酰化作用
<220>
<221> MOD_RES
<222> (16)..(16)
<223> 酰胺化作用
<400> 2
Arg Ala Arg Ala Asp Ala Asp Ala Arg Ala Arg Ala Asp Ala Asp Ala
1 5 10 15
<210> 3
<211> 4
<212> PRT
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Arg Glu Asp Gly
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Arg Leu Asp Gly
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Gln His Arg Glu Asp Gly
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Gln His Arg Leu Asp Gly
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Gln His Arg Glu Asp Val Ser
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Gln His Arg Glu Asp Gly Ser
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Gln His Arg Leu Asp Gly Ser
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<210> 16
<211> 6
<212> PRT
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Lys Arg Leu Asp Gly Ser
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Gln His Arg Glu Asp Gly Ser Leu
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Gln His Arg Leu Asp Gly Ser Leu
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Gln His Arg Leu Asp Gly Ser Leu Asp
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<400> 20
Gln His Arg Glu Asp Gly Ser Leu Asp
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<212> PRT
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<221> 尚未归类的特征
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Gln His Arg Glu Asp Gly Ser
1 5
Claims (27)
1.一种改善有需要的受试者上皮肤的状况或外观美感的方法,所述方法包括以有效改善所述皮肤的所述状况或外观美感的量向所述皮肤局部施用包含含有QHREDGS(SEQ IDNO:1)的氨基酸序列的肽的制剂。
2.如权利要求1所述的方法,其中所述皮肤的状况或外观美感的改善选自由以下项组成的组:减轻时间性老化、光老化、激素老化和/或光化性老化的皮肤病学迹象;预防和/或减轻细纹和/或皱纹的外观;减轻面部细纹和皱纹、面颊、前额上的面部皱纹、两眼之间的垂直皱纹、眼上方和口周围的水平皱纹、木偶纹且特别是深度皱纹或皱褶的引人注目性;预防、减轻和/或减少细纹和/或皱纹的外观和/或深度;改善眼眶下细纹和/或眼眶周围细纹的外观;减轻鱼尾纹外观;使皮肤,特别是老化皮肤恢复年轻和/或恢复活力;减轻皮肤脆性;预防和/或逆转糖胺聚糖类和/或胶原蛋白丧失;改善雌激素失衡效应;预防皮肤萎缩;预防、减轻和/或治疗色素沉着过度;将皮肤色素减退减轻到最低限度;改善皮肤色调、光亮度、清透度和/或紧致度;预防、减轻和/或改善皮肤松垂;改善皮肤紧实度、丰满度、柔韧性和/或柔软性;改善前胶原蛋白和/或胶原蛋白产生;改善皮肤肌理和/或促进再肌理化;改善皮肤屏障修复和/或功能;改善皮肤轮廓的外观;恢复皮肤光泽和/或亮度;将疲劳和/或紧张状态的皮肤病学迹象减轻到最低限度;抵抗环境压力;补充因衰老和/或更年期而减少的皮肤中的成分;改善皮肤细胞间通讯;增加细胞增殖和/或繁殖;增加因衰老和/或更年期而减少的皮肤细胞代谢;延缓细胞老化;改善皮肤保湿性;增加皮肤厚度;增加皮肤的弹性和/或回弹力;增强表皮脱落;改善微循环;减少和/或防止脂肪团形成;及其任何组合。
3.如权利要求2所述的方法,其中时间性老化的皮肤病学迹象选自由以下项组成的组:皱缩、皱纹、垂肉、晒伤、皮肤的暗淡外观、皮肤紧致度的丧失、角化病、色素沉着过度、黑斑病、日光性着色斑、日光性角化病、皮肤日射病、皮肤色素减退及其任何组合。
4.一种在有需要的受试者的皮肤区域中再生胶原蛋白的方法,所述方法包括以有效地在所述皮肤区域中再生胶原蛋白的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
5.如权利要求4所述的方法,其中所述受试者在所述皮肤区域中具有皱纹。
6.如权利要求4所述的方法,其中所述皮肤区域易于发展皱纹。
7.如权利要求5或6所述的方法,其中所述皮肤区域是在所述受试者的前额上、脸颊上、颈部上、眼睛周围或其任何组合。
8.如权利要求4所述的方法,其中所述受试者在所述皮肤区域中具有皮肤发红。
9.一种在有需要的受试者中预防或减少皱纹的方法,所述方法包括以有效预防或减少皱纹的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
10.一种在有需要的受试者中减少皮肤发红的方法,所述方法包括以有效减少皮肤发红的量向所述皮肤局部施用包含含有QHREDGS(SEQ ID NO:1)的氨基酸序列的肽的制剂。
11.如权利要求10所述的方法,其中所述皮肤发红起因于痤疮、接触刺激、皮肤敏感性、酒渣鼻、湿疹、手术、激光处理、过敏、微晶换肤术、擦皮术或其任何组合。
12.如前述权利要求中任一项所述的方法,其中所述制剂进一步包含局部施用可接受的媒介物。
13.如权利要求12所述的方法,其中所述局部施用可接受的媒介物选自羟乙基纤维素、羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、透明质酸钠、透明质酸、卡波姆钠、芦荟凝胶、黄原胶、鲸蜡醇、鲸蜡硬脂醇、丙二醇1,3甘油、玫瑰果油、乳木果油、荷荷巴油、蓖麻油、澳洲坚果油、摩洛哥坚果油、夏威夷核果油、凡士林、矿物油、月见草油、硬脂酸甘油酯、聚山梨酯60、橄榄油酸鲸蜡硬脂酯、橄榄油酸脱水山梨醇酯、硬脂酰乳酸钠、硬脂酸、PEG 100硬脂酸酯、苄醇、乙基己基甘油、苯甲酸、山梨酸、葡糖酸内酯、苯甲酸钠、葡糖酸钙及其任何组合。
14.如前述权利要求中任一项所述的方法,其中,所述制剂进一步包含载体。
15.如权利要求14所述的方法,其中所述载体选自由以下项组成的组:水凝胶、甘油、丙二醇、聚乙二醇、壳聚糖、藻酸盐、琼脂糖、聚醚、聚酯、甲基纤维素、透明质酸、胶原蛋白、层粘连蛋白、基质胶、纤连蛋白、玻连蛋白、聚-l-赖氨酸、蛋白聚糖、纤维蛋白胶、通过脱细胞化工程化和天然组织制得的凝胶、聚乙醇酸(PGA)、聚乳酸(PLA)以及PGA和PLA的组合如PLGA、聚ε-己内酯、聚乙烯醇(PVA)、聚乙二醇(PEG)、甲基丙烯酸甲酯、聚(甲基丙烯酸甲酯)(PMMA)、聚(甲基丙烯酸2-羟乙酯)(聚HEMA)、聚(癸二酸甘油酯)、自组装肽水凝胶AcN-RARADADARARADADA-CNH(SEQ ID NO.2)、聚氨酯、聚(异丙基丙烯酰胺)、聚(N-异丙基丙烯酰胺)[聚(NIPAM)]及其任何组合。
16.如权利要求14所述的方法,其中所述载体包括水凝胶。
17.如权利要求16所述的方法,其中所述载体进一步包括壳聚糖。
18.如权利要求14-17中任一项所述的方法,其中所述肽缀合至所述载体。
19.如权利要求14-18中任一项所述的方法,其中所述制剂包含0.5重量%-50重量%载体。
20.如前述权利要求中任一项所述的方法,其中所述制剂包含0.001重量%-1重量%肽。
21.如前述权利要求中任一项所述的方法,其中所述制剂进一步包含胶原蛋白。
22.如权利要求21所述的方法,其中所述制剂包含0.02重量%-2重量%胶原蛋白。
23.如前述权利要求中任一项所述的方法,其中所述制剂呈凝胶、酊剂、霜剂、软膏、洗剂或气溶胶喷雾剂的形式。
24.如前述权利要求中任一项所述的方法,其中所述制剂在贴剂或绷带上递送。
25.如前述权利要求中任一项所述的方法,其中所述受试者是哺乳动物。
26.如权利要求25所述的方法,其中所述哺乳动物选自人、马、狗、猫、猪和牛。
27.如权利要求1-24所述的方法,其中所述受试者是非哺乳动物。
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