CN102811704A - 稳定化的植物来源的生长因子在皮肤护理中的使用方法 - Google Patents
稳定化的植物来源的生长因子在皮肤护理中的使用方法 Download PDFInfo
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Abstract
本发明公开了用于皮肤护理的美容和皮肤病学组合物,其含有含生长因子的转基因植物提取物、或从转基因植物纯化的生长因子、或源自于转基因植物的作为提取物或采取纯化形式的生长因子的混合物,用于局部治疗、皮肤病学和美容品。重要的是,本发明提供了可用于美容和局部治疗的稳定化并且更安全的生长因子。优选的组合物包含植物产生的生长因子和透明质酸。具有稳定化的生长因子的皮肤护理/皮肤病学组合物不具有不想要的分解产物以及由此引起的组合物活性丧失的风险。此外,所述组合物不含可能来自于动物或基于动物或细菌细胞的表达系统的污染物和可传播因子。
Description
发明领域
总的来说,本发明涉及用于皮肤护理、皮肤病学应用的包含稳定化生长因子和细胞因子的美容和皮肤病学组合物,以及皮肤护理产品的制造方法。具体来说,本发明涉及从转基因植物获得的稳定化异源生长因子及其在美容和药物产品中的用途。
发明背景
皮肤是人体的最大器官,其执行各种功能例如保护、屏障、温度控制、排泄和呼吸。随着时间和衰老,这些功能快速衰退,皮肤发生各种生理变化。这些变化表现为作为皮肤主要组分的表皮、真皮和皮下组织的厚度减小。脂质组成的变化削弱了脂质层的水分屏障作用,导致皮肤干燥。此外,老年斑、雀斑、色素沉着或各种皮肤病变的发生也随着衰老而增加。
年龄依赖性的表皮更新率降低参与了低质量角质层的积累,引起老年干燥、过度色素沉着和细纹。这可能部分是由于异常的角质细胞分化。
环境成分例如污染和紫外线能够加速皮肤的老化。反应性氧物质和自由基以及一些生理状态例如疲劳或紧张对蛋白质、核酸和膜脂特别有害,引起皮肤老化。因此,对于皱纹、老年斑或雀斑、皮肤失去弹性、色素沉着和皮肤干燥与皲裂的发生,已进行了许多研究。
为了阻止或减缓皮肤老化和皮肤皱纹的问题,已开发了各种美容组合物,其目的在于改善由日光引起的皱纹、松弛和皮肤弹性降低。日本专利特开Hei 5-246838号公开了通过胶原蛋白的合成改善皮肤皱纹的方法。它讲授了分解胶原蛋白以促进胶原蛋白代谢的胶原蛋白酶活性可能随着衰老而减少,导致交联胶原蛋白的增加和皮肤皱纹的增加。
皮肤病症:
牛皮癣是引起皮肤发红和鳞斑以及斑点处皮肤脱落的皮肤病症。牛皮癣斑块是由表皮中细胞的生长行为改变引起这些细胞的发育和细胞分裂速率的变化而造成的皮肤过度产生的位点。已知牛皮癣斑块位点处的细胞产生引起炎性反应的细胞信号传导化合物。已经假设牛皮癣是可以由外部条件例如感染触发的一种免疫应答形式,其可能导致自体不相容性。
湿疹:
湿疹是皮炎或表皮炎症的一种形式。术语湿疹被广泛用于多种持久性皮肤病症。它们包括干燥和复发性皮疹,其可以具有下列一种或多种症状:发红,皮肤水肿(肿胀),瘙痒和干燥,结痂,片状剥落,起泡,龟裂、或甚至渗液或出血。皮炎经常用皮质类固醇治疗。由于与类皮质激素相伴的风险例如皮肤变薄,类固醇必须有节制地使用,只用于控制湿疹的发作期。
当湿疹严重并对对其他形式的治疗无响应时,有时开出免疫抑制药物例如环孢菌素。它们抑制免疫系统并能改善湿疹,但是也能引起副作用。
对于严重瘙痒来说,可以使用镇静性抗组织胺药物,但是可能引起嗜睡。
瘢痕组织是留在受伤组织内部和外部、例如在手术或创伤后已愈合的皮肤上的标记。瘢痕组织是在愈合的伤口或切口上和/或周围形成的致密纤维状结缔组织,能够不利地影响皮肤弹性,并且当在可以皮肤上看见时引起美观问题和不方便。大范围瘢痕组织对于从创伤性经历例如烧伤恢复的个体的外表和生活质量,具有不利影响。
生长因子是调控细胞增殖和分化的关键作用者,并参与受伤和损伤后表皮和基底层的重建。它们对于细胞更新来说是重要的,因此能够对抗老化的几个方面,使角质细胞分化、成纤维细胞生长正常化,并诱导细胞和细胞产物的周转和更新。
Ito等(2009)讲授了基质金属蛋白酶(MMP)和金属蛋白酶的组织抑制剂(TIMP)在气道平滑肌(ASM)细胞中的表达可能参与胶原蛋白更新和这些细胞的迁移,因此可能有助于气道重塑。PDGF在mRNA和蛋白质水平上强烈上调基质金属蛋白酶-1(MMP-1)的表达。当与TGF-β组合时,PDGF引起MMP-3的协同上调。TIMP-1被TGF-β和PDGF累加性上调。
Nakatani等(2009)讲授了透明质酸在牙周韧带细胞中影响MMP-1的表达和蛋白水平。透明质酸低聚物(HAoligo)在mRNA和蛋白质两种水平上显著增强MMP-1表达,但是对TIMP-1和TIMP-2mRNA的表达没有显示出影响。已提出HAoligo在HPDL细胞中诱导MMP-1表达,并且p38MAPK在MMP-1被HAoligo诱导的信号传导中发挥关键作用。
尽管Ito和Nakatani的实例局限于气道平滑肌和韧带细胞中的信号途径,但他们分别描述了生长因子和透明质酸可以如何影响细胞外基质和基底膜的组分重构和更新。
已经认识到,生长因子可以对各种皮肤病和皮肤受伤具有有益效应,并对抗由于细胞水平的保护机制受损或退化而造成的老化的影响。生长因子能够促进细胞更新和增殖,并且是伤口愈合过程的天然组分。
表皮生长因子(EGF)促进起源于外胚层和中胚层的各种上皮细胞的分化。它在体液、特别是尿液和乳汁中广泛分布(Carpenter,G.和Cohen,S.,“表皮生长因子”(Epidermal growth factor),Ann.Rev.Biochem.,48,192-216(1979))。它是由53个氨基酸残基构成的单个多肽,并具有6,200道尔顿的分子量(Campion,S.R.和Niyogi,S.K.,“表皮生长因子与其受体的相互作用”(Interaction of epidermal growthfactor with its receptor)。1962年,Cohen从成年雄性小鼠的颌下腺体分离到EGF。1972年,Savage和Taylor鉴定了小鼠EGF的一级结构以及EGF中对生理功能来说必需的三个分子内二硫键的位置。
由于EGF强烈促进上皮细胞、内皮细胞和成纤维细胞的增殖以及上皮细胞向缺乏它们的地点的迁移和增殖,因此相信EGF对皮肤损伤具有出色效果。生长因子在保持组织完整性和细胞间通讯中是关键作用者,从而在对抗表皮组织退化的战斗中发挥保护性作用。
在此以其全文引为参考的美国专利5,618,544号公开了一种包含EGF、TGF-a和FGF的美容组合物,其用于减缓皮肤衰老并改善皮肤外观。
美国专利6,589,540号讲授了EGF显著增强在美容品中使用视黄醇的效果,并且也有效减轻视黄醇的皮肤刺激。
生长因子例如PDGF在凝血阶段期间被释放到伤口部位,并起到中性粒细胞、巨噬细胞和成纤维细胞的化学吸引剂的作用。这些细胞在杀死伤口部位的细菌和清除坏死碎片中发挥重要作用。活化的巨噬细胞进而释放促进血管生成的生长因子,并与介导免疫应答的B-细胞和T-细胞通讯。巨噬细胞分泌刺激成纤维细胞产生新的细胞外基质的TGF-β以及刺激血管生成的VEGF。当角质细胞分裂并覆盖创面床时,上皮形成开始进行。因此,已确认生长因子是愈合过程的重要介导物,并且研究表明G-CSF可能对治疗被感染的糖尿病性溃疡有益。EGF刺激成纤维细胞和角质细胞的增殖。
FGF对上皮细胞具有增殖效应,并且已在动物模型中观察到其加速骨和伤口愈合。KGF-2显著加速伤口愈合,特别是伤口的闭合。
从动物组织或血液分离的生长因子具有不想要的污染物和可传播因子的风险,例如但不限于病毒、病毒粒子、朊病毒、其他共纯化的生长因子。在通过生物技术手段在动物或人类细胞中生产的生长因子中,存在同样的污染性可传播因子和内源生长因子的风险。使用生物技术手段在细菌中生产的生长因子引起遗留已知扰乱免疫系统的细菌内毒素的风险。细菌通常不能产生天然形式的生长因子或细胞因子,而是将它们的生物活性所必需的三级结构变形成变性状态,并将其包装在细胞内的包含体中。为了重新获得生物活性,来自于分离的包含体中的变性生长因子需要富有挑战性和彻底的重折叠。此外,细菌不能使蛋白糖基化,这在几种情况下已知使它们不太稳定并且更易于被蛋白酶降解。对于将在细菌、酵母或动物细胞中生产的生长因子用于治疗开放伤口和具有炎症症状的受损表皮、以及进而用于皮肤病学和美容应用来说,可传播因子、内毒素或污染物的风险是显然的顾虑。
对于高质量的、被制备成最小化或消除上述问题和缺点的生长因子和其他生物活性蛋白,存在着持续不断的需求
发明概述
在植物中生产的生长因子和细胞因子不含可传播的感染性因子例如动物或人类病毒、病毒粒子和朊病毒以及细菌内毒素。与许多动物疾病能够感染人类相反,没有植物疾病能够在人类中引起疾病的报道例。因此,对于生长因子的生产来说,与上面提到的细胞类型、动物细胞、动物组织、酵母和细菌相比,植物构成了更安全的生产生物体。植物缺少与需要生长因子作为信号传导要素起作用并参与的动物免疫系统相当的免疫系统。因此植物自身不产生与动物或人类生长因子类似的生长因子,为使用转基因技术生产重组生长因子提供了纯净的宿主源。植物能够将蛋白质糖基化,这提高了蛋白质的稳定性并能影响它们的活性,因此能够生产与细菌中生产的生长因子相比更优越的生长因子。植物产生采取其天然生物活性形式的生长因子和细胞因子,因此,质量比细菌中生产的变性和重折叠的生长因子相优越。使用本发明的生物技术手段在植物中生产生长因子避开了这些安全性、质量和纯度问题。因此,对于在皮肤学、局部治疗学、皮肤移植、毛发移植、皮肤护理和美容品中的使用来说,与使用现有生产方法生产的生长因子相比,植物来源的生长因子不论是在提取物中还是采取纯化的天然形式,都更加安全和干净。
植物产生在植物中起到保护作用并减轻由非生物和生物因素引起的胁迫例如脱水和氧化胁迫的许多蛋白质。几种这样的蛋白特异性积累在种子成熟后的植物种子中,参与细胞组织的脱水。脱水蛋白素是对胁迫例如干旱做出响应或作为成熟过程例如种子发育的一部分而积累的一类蛋白。
本发明的目的是提供稳定化的、异源植物产生的重组生长因子在低致敏性配方中的使用方法,所述方法能够使生长因子在美容品和皮肤护理产品中进行表面使用。由于蛋白质在本性上对分解和催化敏感,因此生长因子在长时间内的稳定性对于其用作表面治疗来说是关键的。
本发明的重要特点是提供异源植物产生的生长因子在具有最少数量成分的稳定化组合物中的制剂,以获得非致敏、无刺激性的组合物,其允许生长因子不仅可施加和使用于健康皮肤,而且可施加和使用于敏感和受损的皮肤,例如湿疹和牛皮癣中。
本发明的一个方面是提供具有植物来源的生长因子的组合物,其对伤口、烧伤、脓疮、溃疡、病损或手术例如医疗手术和整形手术的愈合期间和之后瘢痕组织的形成具有正性减轻效果。本发明的这个实施方案在减少皮肤上的瘢痕组织印迹,从而改善破裂皮肤的肤色和愈合、改善皮肤的外观方面,特别有用。
本发明的目的是提供一种用于皮肤护理的美容组合物,其含有含生长因子的转基因植物提取物、或从转基因植物纯化的生长因子、或源自于转基因植物的作为提取物或采取纯化形式的生长因子的混合物,用于表面治疗和美容品。在本文中,植物提取物是指产生目标异源生长因子的宿主植物的蛋白提取物(例如种子蛋白提取物)。可以使用一个或多个适合的纯化步骤将提取物部分或基本纯化,这表示所述提取物富集了目标蛋白。重要的是,本发明制造了可用于美容和表面治疗的更安全的生长因子。这些植物产生的生长因子当在其氨基酸骨架中携带糖基化位点时,可以在植物中被糖基化,这种特点已知提高蛋白质的稳定性并可能影响它们的生物活性。通过本发明,使得以天然形式生产这些用于美容和表面使用的组合物中的活性成分变得更加经济。更具体来说,本发明的目的是提供皮肤护理组合物,其包含生长因子并任选与其他天然存在的基于植物的有益多肽例如提取物中的脱水蛋白和球蛋白组合。这些种子蛋白在植物中在细胞和生物化学水平上具有保护功能,并且作为本发明的目的,在与生长因子的独特组合中,它们能够提供营养和愈合条件,并在细胞水平上减轻脱水和氧化胁迫。本发明的目的是提供稳定的皮肤护理组合物,其适用于治疗痤疮、表皮炎症、湿疹、牛皮癣,改善皮肤皱纹、老年斑、雀斑、疹块或其他色素沉着、皲裂表皮特别是手、肘、足跟和足的皲裂表皮,润湿皮肤,伤口愈合以及减少瘢痕组织。
在本发明的一个方面,通过在毛发移植手术期间和之后治疗切断的毛囊单位(FU),稳定化的生长因子可用于提高移植的成功率。
用于本发明的适合的生长因子或两种或以上生长因子的组合可以选自植物来源的重组生长因子,其包括但不限于表皮生长因子(EGF)、角质细胞生长因子(KGF)、血小板衍生生长因子(PDGF)、转化生长因子-β(TGF-β)、肿瘤坏死因子α(TNF-α)、血管上皮生长因子(VEGF)、神经生长因子(NGF)、胰岛素样生长因子(IGF)、成纤维细胞生长因子2(FGF-2)、酸性FGF、粒细胞巨噬细胞集落刺激因子GM-CSF、粒细胞集落刺激因子(G-CSF)、白介素(IL,IL-1、IL1-α、IL-6、IL-8、IL-10)、头蛋白、胸腺肽β4和骨形态发生蛋白(BMP)。这些植物产生的生长因子可按照本发明用于愈合受患、病变和手术伤口和减少/阻止瘢痕组织形成。所选的生长因子可用于手术例如毛发移植中的离体处理,例如通过将切下的毛囊单位浸泡在含有植物来源的重组生长因子的溶液中以提高切下的毛囊单位的生存力并加速和推进移植后的愈合过程。
所选的生长因子例如胸腺肽β4和头蛋白是用于本发明的这种用途的优选生长因子,已发现它们在移植后阶段时中断毛囊中细胞的不应期(refractive stage),并诱导毛发生长。本发明提供了组合物和手段,其使用安全的植物来源的人类生长因子在低致敏性配方中处理不应期中的头皮和毛囊和/或毛囊单位(FU),以恢复毛发生长并从移植手术的影响中愈合。在大量治疗性应用中,能够使用不源自于人类或动物来源并且不被细菌内毒素污染的重组人类生长因子,是显著的改进。
本发明的另一方面提供了具有一种或多种植物来源的生长因子例如上述的任何生长因子以及透明质酸的组合物。合在一起,生长因子和透明质酸对皮肤代谢的影响可以引起对皮肤组成的正协同效应,使细胞分化正常化,促进细胞分裂,并导致基底层组分的更新,引起皮肤更生、伤口愈合、减轻持久性皮肤病症,并减轻炎症。
另一方面,本发明提供了表面美容产品的制造方法,所述方法包含将含有生长因子的转基因植物提取物提供在稳定化介质中。植物来源的异源生长因子优选选自下文中列出的任何生长因子。优选,转基因植物提取物是大麦种子提取物。所生产的生长因子对于制造皮肤护理/皮肤病学组合物来说特别有用。
另一方面,本发明提供了从转基因植物分离的一种或多种异源生长因子。所述生长因子也可用于本技术领域的专业人员已知的其他应用中。
在本发明的另一方面,提供了含有生长因子的新的植物提取物,其用于美容目的并在愈合软膏或其他形式的表面药物组合物中用作活性成分。
附图简述
图1显示了带有含EGF的转基因植物提取物的两块染色凝胶。
图2显示了带有含VEGF的转基因植物提取物的两块染色凝胶。
图3显示了带有含IGF-1的转基因植物提取物的两块染色凝胶。
图4显示了带有含IL-1a的转基因植物提取物的两块染色凝胶。
图5显示了纯化的、复溶的冻干植物制EGF的稳定性激发试验。
图6显示了实施例7中所解释的在施用本发明的表面组合物之前(a)和之后(b)表现出冬季湿疹征象的受试者的手。
图7显示了实施例8中所解释的有“冬季足”(冬季湿疹)皮肤问题的足,(a)和(b)是施用本发明的表面组合物之前的足照片,图(c)和(d)是施用5天之后的照片。
图8:具有实测和计算参数的典型的皮肤变形曲线。
图9:在半边脸研究中,用稳定化的异源的植物来源EGF制剂和无EGF的对照处理的面部皮肤机械性质的比较性测量结果,参见实施例9。
图10:在接受含有植物来源的异源EGF(pd-EGF)的配方植物提取物或安慰剂的表面治疗的12位个体中,测量相对弹性的无创性皮肤分析的结果。
发明详述
当在本文中使用时,“植物来源的”生长因子是从转基因植物或转基因植物的后代获得的生长因子,并可以与术语“植物生产的”互换使用。因此,术语“植物来源的生长因子”在应用的背景中一般是指异源的生长因子,对于用作生产介质的宿主植物来说是非天然的。本发明的生长因子可以是任何人类或非人类生长因子,其基因优选使用重组技术导入到植物或前辈植物中。分离的生长因子可以在美容组合物或治疗性表面组合物中用作活性成分。
用于在植物中导入并表达外来基因的方法在本技术领域中是公知的。可以被遗传转化的植物是异源DNA序列、包括编码区的DNA序列可以在其中导入、表达、稳定维持并传递到随后的后代的植物。遗传操作和转化方法已被用于生产利用除草剂抗性包括例如双丙氨磷或basta抗性或抗生素抗性例如潮霉素抗性作为选择标记的大麦植物。
选择适合的栽培品种并选择用于导入外来基因的适合方法。术语“转化”或“遗传转化”是指将核酸分子转移到宿主生物体的基因组中,产生遗传稳定的遗传性。含有转化的核酸片段的宿主生物体被称为“转基因”生物体。本发明的“转基因植物宿主细胞”含有稳定整合在基因组中的至少一个外来的、优选两个外来的核酸分子。植物转化方法的实例包括土壤杆菌介导的转化(De Blaere等,1987)和粒子轰击或“基因枪”转化技术(Klein等,(1987);美国专利4,945,050号)。
WO 2006/016381描述了适合于转化的特别有用的大麦栽培品种,并详细描述了适合的转化方法。
WO 2005/021762公开了通过制造易于大规模纯化的嵌合蛋白来修饰蛋白质的方法。
可以按照本发明适当生产和使用的生长因子可以选自但不限于下述种类和族:转化生长因子-b(或β)(TGF-b或TGF-β,包括TGFβ1、TGFβ2、TGFβ3),转化生长因子-a(或α)(TGF-a或TGFα),TNFα,表皮生长因子(EGF),血小板衍生生长因子(PDGF AA、PDGF BB、PDGF Rb),角质细胞生长因子(KGF),成纤维细胞生长因子a和b(aFGF和bFGF)、FGF-4、FGF-6,肝细胞生长因子(HGF),血管上皮生长因子(VEGF),红细胞生成素(Epo),胰岛素样生长因子-I(IGF-I),胰岛素样生长因子-II(IGF-II),白介素-1(IL-1)包括IL-1α和IL-1β,白介素-2(IL-2),白介素-4(IL-4),白介素-5(IL-5),白介素-6(IL-6),白介素-7(IL-7),白介素-8(IL-8),白介素-10(IL-10),白介素-13(IL-13),白介素-15(IL-15),白介素-18(IL-18),白介素-20(IL-20),瘦素,肿瘤坏死因子-a(TNF-a),肿瘤坏死因子-b(TNF-b),干扰素-g(INF-g),粒细胞集落刺激因子(G-CSF),粒细胞巨噬细胞集落刺激因子(GM-CSF),巨噬细胞集落刺激因子(M-CSF),胎盘生长因子(PLGF),神经生长因子(NGF),头蛋白,骨形态发生蛋白(BMP-4)和胸腺肽β4。
在本发明的某些实施方案中,在转基因植物中生产的目标多肽在所述多肽的N-端或C-端或在两端含有亲和标签。这样的标签可以包括重复HQ序列、聚组氨酸尾、GST、CBM或简化异源肽的纯化的任何其他有用亲和标签。
透明质酸(hyaluronan)也称为玻尿酸(hyaluronic acid)和透明质酸盐(hyaluronate),这些术语在本文中同义并可互换。透明质酸是阴离子性非硫酸化的糖胺聚糖,广泛分布于结缔、上皮和神经组织中。
当在本文中使用时,术语皮肤护理/皮肤病学组合物涵盖用于治疗性皮肤病学应用的医学/药物组合物和美容用途的组合物两者,以及可用于治疗和美容用途两者的组合物。
剂量
对于本发明的表面治疗性应用来说,生长因子的剂量优选在每克组合物0.01至100μg的范围内,更优选在每克0.1至50μg的范围内。用于治疗皮肤老化或脱发的局部美容用组合物优选每克组合物包含0.2至50μg活性物质。
治疗的时长根据病理或所需效果而异。在硬皮病治疗的情形中,根据病情严重性,用药在1天至12个月的范围内。在对抗皮肤的天然或早期老化的治疗情形中,用药在1至400天范围内,优选至少30天。同样地,在防止脱发或促进毛发再生长的治疗情形中,用药在1至400天范围内。
本发明的皮肤病学组合物可以适合用于治疗皮肤病症,包括皮肤干燥、湿疹、皮炎、皮疹、牛皮癣、皮肤发红和水肿。本发明的组合物也可用于愈合和减轻瘢痕组织以及愈合和改善足跟皮肤皲裂。
优选转基因植物提取物从大麦谷粒制备,所述大麦谷粒含有任一种或多种上面列出的生长因子的蛋白、它们的模拟物或至少其能够结合于并激活生长因子受体的结构域。所公开的非限制性实例显示了源自于转基因大麦提取物的不同生长因子的示例性用途。
本发明使用的提取物是指来自于转基因宿主植物的包含目标生长因子的蛋白提取物。生长因子可以仅仅是提取物的少量组分,只要其他蛋白不干扰生长因子的活性或引起任何其他不想要的效应即可。这样的提取物是例如来自于在其种子中表达异源生长因子的植物的种子蛋白提取物。提取物也可以被纯化至或高或低的程度,即可以通过一个或多个纯化步骤对它们进行部分纯化,以富集异源生长因子。
用于美容和药物组合物的表面施用的众多介质是本技术领域中已知的。参见例如《Remington药物学》(Remington's PharmaceuticalSciences),Gennaro,A.R.主编,第20版,2000:Williams and Wilkins PA,USA。常用于表面施用美容组合物的所有组合物都可以使用,例如霜剂、露剂、凝胶、敷剂、香波、酊剂、糊剂、精华液(serums)、软膏、油膏、粉剂、液体或半液体制剂、贴片、脂质体制剂、溶液、悬液、脂质体悬液、W/O或O/W乳液、润发脂和糊剂等,只要作为活性成分的异源蛋白被稳定化即可。如果合适,可以通过例如使用推进剂如氮气、二氧化碳、氟利昂或不使用推进剂例如泵喷雾的气溶胶、滴剂、露剂、或半固体例如可以通过拭子施用的增稠组合物来施用所述组合物。在特定组合物中,将方便使用半固体组合物例如油膏、霜剂、露剂、糊剂、凝胶、软膏等。
本发明的组合物可以被提供用于肠胃外、全身或局部使用,其包括溶液、悬液、脂质体悬液、W/O(水/油)或O/W(油/水)乳液。在优选实施方案中,活性物质被配制成冷冻干燥形式,与适合的冷冻干燥添加剂混合,并易于用治疗可接受的稀释剂重新溶解。有用的冷冻干燥添加剂是:缓冲剂,多糖,蔗糖,甘露糖醇,肌醇,多肽,氨基酸以及与活性物质相容的任何其他添加剂。在本发明的优选实施方案中,将活性物质溶解在磷酸盐缓冲液(NaH2PO4/H2O--Na2HPO4/2H2O)中,其量使得冷冻干燥后的生长因子/磷酸盐比率在1:1至1:2之间。适合于肠胃外使用的稀释剂是:水,生理溶液,糖溶液,水醇溶液,油性稀释剂,多元醇例如甘油、乙二醇或聚丙二醇,或在无菌性、pH、离子强度和粘度方面与给药方法相容的任何其他稀释剂。
优选,表面施用的介质是天然抗菌并且不含任何非天然防腐剂或抗微生物剂的制剂。使用少数成分并排除可能起到过敏原和/或刺激物作用的复杂成分,是值得赞赏的。制剂还应该确保活性蛋白质成分的长期稳定性,优选提供长的储存期限,例如在室温储存时一年或更长的储存期限。
在优选实施方案中,向适合于表面施用的制剂添加活性化合物、即所选的植物产生的重组生长因子,所述制剂含有下列的一种或多种:甘油,盐例如但不限于氯化钠、氯化钾和氯化钙,其中氯化钙最为优选,纯水和乙醇;并且优选含有所有这些物质。这样的组合物令人吃惊地显示出有效地稳定化以所选生长因子为代表的重组蛋白。本发明的一个方面在于,不论重组蛋白是否被糖基化,该制剂都有效地稳定所述蛋白。所述制剂优选天然抗菌,因此特别适合作为用于皮肤病学和美容用途的表面制剂。
本发明的组合物还可以包含任选的添加剂,例如透明质酸(透明质酸盐)。
在乳液或悬液的情形中,组合物可以含有普遍用于药物制剂的适合的非离子、两性离子、阴离子或阳离子型表面活性剂。油/水(O/W)亲水性乳液优选用于肠胃外系统应用,而水/油(W/O)亲脂性乳液优选用于局部或表面应用。
此外,本发明的组合物可以包含任选的添加剂,例如等渗剂如糖或多元醇、缓冲剂、螯合剂、抗氧化剂、抗菌剂。
本发明的液体形式可以包括溶液或露剂。它们可以是水性、水醇性例如乙醇/水、或醇性的,并通过溶解冷冻干燥的物质来获得。
或者,可以通过添加已知的胶凝剂将活性物质溶液配制成凝胶形式,所述胶凝剂例如:淀粉,甘油,聚乙二醇或聚丙二醇,聚(甲基)丙烯酸酯,异丙醇和羟基硬脂酸酯。
用于表面用途的其他类型的组合物是采取润发脂、糊剂、霜剂形式的乳液或悬液。W/O乳液是优选的,能提供更快的吸收。亲脂性赋形剂的实例是:液体石蜡,无水羊毛脂,白凡士林,鲸蜡醇,硬脂醇,植物油,矿物油。可以有利地使用增加皮肤渗透性从而促进吸收的剂。这样的剂的实例是生理上可接受的添加剂如聚乙烯醇、聚乙二醇或二甲亚砜(DMSO)。
在表面组合物中使用的其他添加剂是等渗剂如糖或多元醇、缓冲剂、螯合剂、抗氧化剂、抗菌剂、增稠剂、分散剂。
因此,制剂还可以含有常用于本文所述制剂的常规组分,包括油类、脂肪、蜡、表面活性剂、保湿剂、增稠剂、抗氧化剂、粘度稳定剂、螯合剂、缓冲剂、防腐剂、香料、着色剂、低级烷醇等。
用于局部或全身应用的延迟释放组合物可能是有用的,并包含聚合物例如聚乳酸酯、聚(甲基)丙烯酸酯、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素和本技术领域已知的其他物质。基于例如聚乳酸酯或其他可生物降解聚合物的皮下植入物形式的延迟释放组合物,可能也是有用的。
尽管活性物质优选以冷冻干燥因而稳定的形式包装,但药物组合物有利地包含使生长因子稳定在活性形式的物质。这样的稳定剂抑制分子间二硫键的形成,从而防止活性物质聚合。然而,为了同时防止活性物质还原成无活性单体形式,稳定剂的量应该被仔细度量。这样的物质的实例是:半胱氨酸,半胱胺或还原型谷胱甘肽。
油类的非限制性实例包括脂肪和油,例如橄榄油和氢化油;蜡,例如蜂蜡和羊毛脂;烃类,例如液体石蜡、地蜡和鲨烯;脂肪酸,例如硬脂酸和油酸;醇类,例如鲸蜡醇、硬脂醇、羊毛脂醇和十六醇;以及酯类,例如肉豆蔻酸异丙酯、棕榈酸异丙酯和硬脂酸丁酯。作为表面活性剂的实例,可以提到的是阴离子型表面活性剂例如硬脂酸钠、鲸蜡基硫酸钠、聚氧化乙烯月桂基醚磷酸盐、N-酰基谷氨酸钠;阳离子型表面活性剂,例如硬脂基二甲基苯甲基氯化铵和硬脂基三甲基氯化铵;两性表面活性剂,例如烷基氨基乙基甘氨酸盐酸盐溶液和卵磷脂;以及非离子型表面活性剂,例如单硬脂酸甘油酯、单硬脂酸失水山梨糖醇酯、蔗糖脂肪酸酯、单硬脂酸丙二醇酯、聚氧化乙烯油基醚、单硬脂酸聚乙二醇酯、聚氧化乙烯失水山梨糖醇单棕榈酸酯、聚氧化乙烯椰油脂肪酸单乙醇酰胺、聚氧化丙烯二醇(例如在商标“Pluronic”下销售的物质)、聚氧化乙烯蓖麻油和聚氧化乙烯羊毛脂。保湿剂的实例包括甘油、1,3-丁二醇和丙二醇;低级醇的实例包括乙醇和异丙醇;增稠剂的实例包括黄原胶、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇和羧甲基纤维素钠;抗氧化剂的实例包括丁基羟基甲苯、丁基羟基苯甲醚、没食子酸丙酯、柠檬酸和乙氧喹;螯合剂的实例包括乙二胺四乙酸二钠和乙烷羟基二磷酸盐;缓冲剂的实例包括柠檬酸、柠檬酸钠、硼酸、硼砂和磷酸氢二钠;防腐剂的实例是对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、脱氢乙酸、水杨酸和苯甲酸。这些物质仅仅是示例性的,本技术领域的专业人员将会认识到可以用其他物质代替而不损失功能。
实施例
实施例1:含有重组EGF的转基因植物提取物的制备
通过将收获的含有生长因子EGF的转基因大麦种子在磨机中研磨以获得细粉(面粉),来制备转基因植物提取物。以5/1的提取缓冲液与磨好的面粉体积/重量比,向磨好的大麦面粉加入提取缓冲液(50mM磷酸钾,pH 7.0)。将得到的溶液在4℃搅拌60分钟。在冷冻离心机(Heraeus Primo R)中以8300rpm或以上离心15分钟,通过离心力将固体与液体提取物分离,并将上清液倾析至干净小瓶中。通过SDS-PAGE和使用EGF特异性抗体的Western印迹来分析提取物的生长因子含量。在本实验中,EGF含量约为提取物蛋白含量的0.01%。结果显示在图1中。
图1(A)显示了考马斯亮蓝染色的部分凝胶,对总可溶性蛋白进行染色。(B)显示了使用抗EGF抗体对同样的提取物进行的western印迹,显示出在转基因植物提取物中存在生长因子EGF。道:1:分子量标志物,2:转基因大麦种子提取物,3:来自于IMAC纯化步骤的穿流液,4:来自于IMAC捕获步骤的EGF洗脱液。
实施例2:含有生长因子VEGF和脱水蛋白的部分纯化的转基因
植物提取物
通过向提取物加入有效结合VEGF的IMAC层析树脂,对按照实施例1制备的含有VEGF的转基因大麦种子提取物进行进一步加工。将提取物与树脂的混合物在pH7.0的50mM磷酸钾、0.5M NaCl、50mM咪唑中,在+4℃搅拌60分钟。以5000xg离心15分钟,将IMAC树脂与液体分离。倾析掉液体相,将树脂重悬浮在清洗缓冲液(50mM磷酸钾,0.5M NaCl,50mM咪唑;pH7.0)中并离心,从树脂上倾析掉液体相。将清洗重复三次。将树脂重悬浮在含有咪唑的洗脱缓冲液(50mM磷酸钾,0.5M NaCl,500mM咪唑;pH7.0)中以将VEGF从树脂洗脱下来,并在离心后从树脂上倾析掉上清液,通过凝胶过滤层析进行缓冲液更换。将得到的蛋白峰在SDS-PAGE和Western印迹上进行分析。在这种情况下,存在的VEGF约为蛋白提取物的25%。结果显示在图2中。
图2,含有重组生长因子VEGF和脱水蛋白的部分纯化的转基因植物提取物。A)考马斯亮蓝染色的SDS-PAGE凝胶,对提取物中存在的总蛋白进行染色。B)Western印迹显示了在含有脱水蛋白的部分纯化的大麦种子提取物中存在VEGF。道编号:1分子量标准量,2提取物,3IMAC穿流液,4IMAC洗脱液。箭头指示部分纯化的提取物中存在脱水蛋白和VEGF,其已通过氨基酸测序得到鉴定。
实施例3:含有大麦球蛋白和IGF-1的部分纯化的转基因植物提取
物
按照实施例1在提取缓冲液II(50mM磷酸钾,pH7.0,200mMNaCl)中提取转基因大麦种子。按照实施例2中所解释的将提取物结合于IMAC树脂并从其上洗脱下来,随后将洗脱液脱盐并将缓冲液改变成pH 6.8的100mM KPi。然后通过在有效结合IGF-1的条件下向离子交换色谱树脂加入部分纯化的提取物,对所述提取物进行进一步加工,其中所使用的基质是SP-Sepharose(GE Healthcare)。通过SDS-PAGE和银染以及使用特异性抗IGF-1抗体的western印迹,对相应的级份进行分析。部分纯化的植物提取物的IGF-1含量为60%。
图3,含有大麦球蛋白和IGF-1的部分纯化的转基因植物提取物。A)银染的SDS-PAGE凝胶。道编号:1分子量标准品,2来自于IMAC柱的脱盐并缓冲液更换过的洗脱液,3来自于SP-Sepharose IEC的穿流液,4来自于SP-Sepharose IEC的含有IGF-1和大麦球蛋白的洗脱液,5阳性对照:在细菌中生产的重组IGF-1。
实施例4:从转基因大麦种子提取物纯化的纯化和分离的生长因
子IL-1α
可以对转基因植物提取物进行进一步纯化,以分离纯化形式的生长因子:将IMAC洗脱液在用凝胶过滤进行缓冲液更换后,施加到离子交换柱Sepharose FF上,并通过逐渐增加洗脱缓冲液的NaCl含量的逐步洗脱来分离提取物中的蛋白质。通过这种方式,能够成功地将生长因子与脱水蛋白分离。如图4中所示,通过这种方式,可以将生长因子纯化至>95%(第7道)的高纯度,产生从转基因植物提取物分离和纯化的分离和纯化的IL-1α。
图4,从转基因植物提取物纯化和分离IL-1α。A)考马斯亮蓝染色的SDS-PAGE凝胶,对提取物中存在的总蛋白进行染色。B)含有IL-1α的提取物的Western印迹。道编号:1和9是分子量标志物,2提取物,3IMAC穿流液,4IMAC洗脱液,5浓缩的IMAC洗脱液,6来自于IEC的35%NaCl洗脱液,775%NaCl洗脱液,8100%NaCl洗脱液。D:脱水蛋白,IL-1a:白介素1α。
实施例5:植物来源的生长因子在组合物中的使用
下面的实施例示例说明了本发明的美容组合物的制剂,但是不打算以任何方式限制本发明。
制剂1:皮肤软化剂(柔肤水,精华液)
可以制备在6-9的pH范围内缓冲的稳定组合物。
制剂2:营养乳剂(乳液)
制剂3:营养霜
制剂4:按摩霜
制剂5:面膜
制剂1-5也可以使用在详细描述部分中列出的任何备选生长因子配制。
制剂6:用于表面施用的W/O乳液
将含有20μg活性物质的量的冷冻干燥物质加入到含有10%DMSO的5ml 10%乙醇水醇性溶液中。使用HLB系数<10的适用于W/O乳液的表面活性剂,将溶液在用于皮肤施用的无菌植物油中乳化。乳液所含的活性物质等于约2μg/g组合物。
制剂7:O/W乳液
将含有约20μg活性物质的量的冷冻干燥物质溶解在含有30%DMSO的5ml水醇性溶液中,并使用适合的表面活性剂在基于植物油的亲脂性溶剂中乳化。得到的O/W乳液含有浓度约为3μg/g组合物的活性物质。
制剂8:凝胶形式的表面组合物
将含有100μg活性物质的量的冷冻干燥物质加入到含有20%DMSO的20ml 10%乙醇水醇性溶液中。然后向溶液加入聚乙二醇(400-4000)和聚丙二醇的混合物。活性物质以等于2μg/g组合物的量存在。所述凝胶适合于美容品应用。
制剂9:含有卡波姆(1%)的表面凝胶制剂
使用上述给定量的组分按照常规方法来制备所述制剂。具体来说,将对羟基苯甲酸甲酯溶解在适量的注射用蒸馏水中,向溶液加入卡波姆934P并通过搅拌分散在其中。使用氢氧化钠控制溶液的pH,将溶液与丙二醇掺混,并通过加热进行灭菌。然后向其加入EGF在注射用蒸馏水中的过滤除菌溶液,以获得100g制剂。
制剂10:含泊洛沙姆(15%)的表面制剂
使用上述给定量的组分按照常规方法来制备制剂。具体来说,使用给定量的磷酸氢钠、氯化钠和磷酸制备磷酸缓冲液。将作为防腐剂的对羟基苯甲酸甲酯溶解在磷酸缓冲液中。向溶液加入泊洛沙姆407(BASF,德国)并通过搅拌分散在其中。然后将溶液与丙二醇掺混,通过搅拌分散在其中。然后使用氢氧化钠控制溶液的pH,将溶液与丙二醇掺混,并通过加热进行灭菌。然后向其加入EGF在注射用蒸馏水中的过滤除菌溶液,以获得100g制剂。
制剂11:含有卡波姆(0.1%)的霜剂制剂
使用上述给定量的组分按照常规方法来制备制剂。具体来说,将甘油和对羟基苯甲酸甲酯溶解在适量注射用蒸馏水中,向溶液加入卡波姆940(BF Goodrich,U.S.A.)并通过搅拌分散在其中。然后向溶液加入对羟基苯甲酸丙酯和其他成分,并通过熔化进行乳化。然后,在用三乙醇胺控制pH后将溶液灭菌,并与在植物中表达并分离的EGF在注射用蒸馏水中的过滤除菌溶液混合,以获得100g制剂。
实施例6:植物产生的EGF的稳定性试验
本实施例显示了复溶的冻干、未糖基化的、植物制造的纯化EGF,在实施例5制剂1中所示的制剂中、在各种不同温度下温育的稳定性激发试验:在+4℃冷藏,在+37℃和室温(RT)温育,最长为三周。结果显示在图5中。第一道为11和17kDa的分子量标志物。结果显示出生长因子在37℃、RT和+4℃下为期几周的出色稳定性。根据制造商的描述,细菌(大肠杆菌)制造的、复溶的、纯化形式的、来自于细菌的重组EGF在2℃-4℃下只有一周的稳定性。(参见http://www.cellsciences.com/PDF/CRE100.pdf)。
实施例7:减轻手上冬季湿疹的应用
将在实施例5制剂1的蛋白稳定化配方中含有部分纯化的转基因大麦种子提取物和植物来源的异源表皮生长因子(EGF)的本发明的组合物,表面施用于一名9岁男孩的干裂、发痒、发红的带有皮疹(即冬季湿疹)的皮肤。将三滴表面制剂均匀分布在明显患有冬季湿疹的手背上。图6a)显示了将本发明的组合物作为制剂表面施用之前的手,图6b)显示了在用本发明的组合物治疗后24小时的同一只手,显示出皮肤恢复和冬季湿疹症状减轻的明显征象。
实施例8:冬季湿疹-“冬季足”
图7a)和b)显示了患有引起严重皮肤问题的“冬季足”的一名10岁男孩的脚。干燥、发痒、发红的皮肤引起刺痛和皮肤深裂纹的出血和严重受损的表皮。
图7a)和b)在治疗开始前获取,图7c)和d)在每日表面施用本发明的组合物、每只足4-5滴5天后获取,所述组合物在包含实施例5制剂1的蛋白稳定化配方中含有部分纯化的转基因大麦种子提取物,所述提取物中具有植物来源的异源表皮生长因子(EGF)。表皮已经愈合并已极大程度地恢复弹性和柔软性并重新水花。
实施例9:皮肤弹性
本发明的组合物在包含实施例5制剂1的蛋白稳定化配方中含有部分纯化转基因大麦种子提取物,所述提取物具有植物来源的异源表皮生长因子(EGF),为了客观地测量所述组合物对面部皮肤的弹性和紧致性的效应,利用受控抽吸技术对皮肤的机械性质进行评估。
典型的皮肤变形曲线如图8中所示。分析了下面的参数:Ue,即时扩张——其测量皮肤在变形后回复到其初始位置的能力,并与弹性纤维的功能相关;Uv,延迟扩张;[R0]Uf,最终扩张[皮肤扩张性];Ur,即时收缩;R,在测量周期结束时的残余变形[回弹扩张];[R2]Ua/Uf,皮肤的总弹性,包括粘滞变形;[R5]Ur/Ue,皮肤的净弹性neto-elasticity,不包括粘滞变形;[R7]Ur/Uf,生物学弹性,即即时收缩与总扩张的比率;[R6]Uv/Ue,粘弹性与弹性扩张的比率;以及R8,粘性部分(viscopart),即变形曲线的抽吸部分下的面积。在随后的计算中使用两次测量的平均值。
使用无创抽吸装置(MPA580),研究了面部皮肤的机械性质。该装置测量被拉入到小孔隙中并受到负压的皮肤的生物机械性质。将两种不同的皮肤护理制剂,即含有本发明的具有稳定化的植物产生的异源EGF的组合物的精华液和不含EGF的相应精华液,各自施加在包括面颊、眼周和前额的脸的相对侧上。在四(4)个月处理后,使用MPA580测量弹性和紧致性。简单来说,向皮肤施加从0至450mbar的逐渐增加的抽吸力,其中使用恒定压力的施加时间为2秒,然后是2秒的松弛期,总运行时间为4秒。测量并评估每侧脸的皮肤弹性和粘弹性,然后比较两个不同处理区域之间的值。
结果显示在图9中。用EGF处理的皮肤(上方曲线)的特征在于明显更高的弹性参数(即Ue、Ur、Ua/Uf、Ur/Uf、Ur/Ue)和更低的粘弹性参数(即Uv和Uv/Ue)。显然,当比较两个不同的处理区域时,皮肤弹性的增加和粘弹性的降低与使用含有本发明的具有稳定化的植物来源的异源EGF的组合物的精华液进行的处理相关。用当前创新的组合物处理的皮肤以皮肤弹性和紧致性的增加为特征。
实施例10:在施用配制好的含有植物来源的异源EGF(pd-EGF)
的植物提取物一个月后面部皮肤弹性的评估
受试者是12位30至70岁之间的女性。本研究不包括老化皮肤的明显迹象作为任何入选标准。八(8)位受试者使用在包含实施例5制剂1的蛋白稳定化配方中具有植物来源的异源表皮生长因子(EGF)的转基因大麦种子提取物,而四(4)位受试者使用不含转基因大麦种子提取物的精华液、即安慰剂精华液,所述精华液每日两次施用在前额、面颊和眼周,共一个月。在研究期间允许受试者继续她们正常的每日皮肤护理程序。
在施用期开始(基线=第0日)和结束时,在被处理的区域的皮肤表面上执行无创皮肤分析研究,并将基线(第0日)的结果与施用一个月后的结果进行比较。通过Soft Plus皮肤分析系统(Callegari1930)获得定量测量值。在本研究中测试的参数是通过对抽吸的阻力所度量的皮肤弹性。对于完成研究的所有个体来说,所有数据作为研究之前的平均值(基线=第0日)和研究结束时的平均值进行分析。最终结果呈现(图10)为处理与未处理区域与基线值相比的诱导倍率(即相对值,1=第0日)的比较。
实施例10:抗微生物活性
本实施例显示了实施例5制剂1的本发明组合物的微生物激发试验,以及抗微生物防腐功效的测定。
将组合物用细菌激发以确立组合物的抗菌性质。将0.5ml铜绿假单胞菌(Pseudomonas aeruginosa)(菌株ATCC 9027)的液体培养物接种到50ml稳定化组合物上。将样品在标准化条件下温育,并根据在欧洲药典(European Pharmacopoeia)5.1.3.中对“抗微生物保护效能”(Efficacy ofAntimicrobial preservation)所详细描述的方法来测定细菌数量;接种物从细菌的储用培养物、含有9g/L氯化钠的无菌悬液流体来制备。将培养物用流体稀释以获得每ml 107个细菌,取1ml作为接种物添加到含有稳定化组合物的容器中并充分混合。将接种的产物避光维持在22℃下。以特定时间间隔从接种的产物抽取1ml样品,并通过平板计数法测定细菌的数量。
结果显示出本发明的组合物的明显的抗微生物活性,并且不使用常规防腐剂和抗菌剂即可满足欧洲药典对表面用制剂的推荐抗细菌活性效能。因此,这些制剂适用于表面美容用和/或治疗性组合物,并避开了潜在刺激性防腐剂、抗微生物剂和对敏感皮肤有损的其他添加剂的可能的副作用。
参考文献:
Ito I,Fixman ED,Asai K,Yoshida M,Gounni AS,Martin JG,HamidQ.
“血小板衍生生长因子和转化生长因子-β调节基质金属蛋白酶的表达和人类气道平滑肌细胞的迁移功能”(Platelet-derived growth factorand transforming growth factor-beta modulate the expression of matrixmetalloproteinases and migratory function of human airway smooth musclecells.),Clin Exp Allergy.2009Sep;39(9):1370-80.Epub 2009 Jun 11.
Nakatani Y,Tanimoto K,Tanaka N,Tanne Y,Kamiya T,KunimatsuR,Tanaka E,Tanne K.
“透明质酸寡糖对在牙周韧带细胞中MMP-1的表达的影响”
(Effects of hyaluronan oligosaccharide on the expression of MMP-1 inperiodontal ligament cells),Arch Oral Biol.2009Aug;54(8):757-63.Epub2009 Jun 11.
技术规格表,EGF重组人类表皮生长因子(Technical specificationsheet,EGF Recombinant Human Epidermal Growth Factor),Cell Sciences,MA,USA(http://www.cellsciences.com/PDF/CRE100.pdf)
5.1.3抗微生物防腐效能(Efficacy of Antimicrobial Preservation):528-529,欧洲药典(European Pharmacopoeia)6.0
Claims (35)
1.一种皮肤护理/皮肤病学组合物,其包含透明质酸和至少一种源自于转基因植物的生长因子和至少一种药学和/或美容学可接受的赋形剂。
2.权利要求1的皮肤护理/皮肤病学组合物,其包含稳定化生长因子蛋白的赋形剂配方。
3.权利要求1或2的皮肤护理/皮肤病学组合物,其中透明质酸以约0.01至约2重量%范围内的浓度提供。
4.权利要求1-3任一项的皮肤护理/皮肤病学组合物,其中生长因子作为包含在美容组合物中的转基因植物提取物的组分提供。
5.权利要求4的皮肤护理/皮肤病学组合物,其中生长因子在转基因植物提取物中的存在量在总蛋白含量的约0.0001%至约70%范围内。
6.权利要求4或5的皮肤护理/皮肤病学组合物,其中所述植物提取物已被纯化以富集所述生长因子。
7.权利要求4或5的皮肤护理/皮肤病学组合物,其适用于治疗选自皮肤干燥、湿疹、皮炎、皮肤皲裂、皮疹、皮肤发红、瘢痕组织、牛皮癣和水肿的一种或多种的皮肤病症。
8.权利要求2至7任一项的皮肤护理/皮肤病学组合物,其中所述蛋白稳定化配方包含甘油、水和氯化钙。
9.权利要求8的皮肤护理/皮肤病学组合物,其中所述蛋白稳定化配方包含下列成分(重量%):10至90%范围内的甘油,0.1mM至200mM范围内的氯化钙,在pH6-9范围内缓冲,以及适量纯水。
10.权利要求8或9的皮肤护理/皮肤病学组合物,其不含其他抗微生物剂或防腐剂。
11.权利要求1-10任一项的皮肤护理/皮肤病学组合物,其包含一种以上源自于转基因植物的生长因子。
12.权利要求11的皮肤护理/皮肤学组合物,其中所述一种以上生长因子作为来自于转基因植物的提取物的混合物的组分存在。
13.权利要求11的皮肤护理/皮肤病学组合物,其中所述一种以上生长因子在所述转基因植物提取物的混合物中的存在量在蛋白含量的约0.0001%至约70%范围内。
14.权利要求1-13任一项的皮肤护理/皮肤病学组合物,其中所述至少一种生长因子或一种以上生长因子是从转基因植物分离并纯化至约70%至约99.9%范围内的纯度水平。
15.权利要求1-14任一项的皮肤护理/皮肤病学组合物,其中向已经含有植物来源生长因子的转基因植物提取物添加一种或多种植物来源的纯化的生长因子。
16.权利要求1-15任一项的皮肤护理/皮肤病学组合物,其中所述至少一种生长因子或一种以上生长因子选自表皮生长因子(EGF),血管上皮生长因子(VEGF),血小板衍生生长因子(PDGF)包括PDGF-AA、PDGF-BB和PDGF-Rb,成纤维细胞生长因子(FGF)包括FGF-a、FGF-b、FGF-4和FGF-6,转化生长因子-β(TGF-b)包括TGFβ-1、TGFβ-2、TGFβ-3,转化生长因子-α(TGF-a),红细胞生成素(Epo),胰岛素样生长因子-I(IGF-I),胰岛素样生长因子-II(IGF-II),白介素-1(IL-1)包括IL-1α和IL-1β,白介素-2(IL-2),白介素-4(IL-4),白介素-5(IL-5),白介素-6(IL-6),白介素-7(IL-7),白介素-8(IL-8),白介素-10(IL-10),白介素-13(IL-13),白介素-15(IL-15),白介素-18(IL-18),白介素-20(IL-20),肿瘤坏死因子-α(TNF-a),肿瘤坏死因子-β(TNF-b),干扰素-γ(INF-g),粒细胞集落刺激因子(G-CSF),粒细胞巨噬细胞集落刺激因子(GM-CSF),巨噬细胞集落刺激因子(M-CSF),胎盘生长因子(PLGF),神经生长因子(NGF),角质细胞生长因子(KGF),骨形态发生蛋白(BMP-4),肝细胞生长因子(HGF),瘦素,头蛋白和胸腺肽β4。
17.权利要求1-16任一项的皮肤护理/皮肤病学组合物,其中所述生长因子或细胞因子源自于相应的人类基因序列。
18.权利要求1-16任一项的皮肤护理/皮肤病学组合物,其中所述生长因子或细胞因子源自于与相应的生长因子或细胞因子的人类基因序列相对应的合成基因。
19.权利要求4至6任一项的皮肤护理/皮肤病学组合物,其中所述转基因植物提取物含有脱水蛋白和/或球蛋白或其他种子蛋白。
20.权利要求1-19任一项的皮肤护理/皮肤病学组合物,其中所述组合物采取选自霜剂、露剂、凝胶、敷料、香波、酊剂、糊剂、软膏、油膏、粉剂、液体或半液体制剂、精华液、贴片、脂质体制剂、溶液、悬液、脂质体悬液、W/O或O/W乳液、软膏、润发脂和糊剂以及皮肤软化霜、面膜、按摩霜和营养霜或营养乳液的形式。
21.一种皮肤护理/皮肤病学组合物,其包含至少一种源自于转基因植物的生长因子和包含甘油和适量纯水的蛋白稳定化配方。
22.权利要求21的皮肤护理/皮肤病学组合物,其还包含选自氯化钠、氯化钾和氯化钙的盐。
23.权利要求21或22的皮肤护理/皮肤病学组合物,其还包含透明质酸。
24.权利要求22或23的皮肤护理/皮肤病学组合物,其包含源自于转基因植物的生长因子以及蛋白稳定化配方,所述蛋白稳定化配方至少包含下列成分(重量%):10至90%范围内的甘油,0.1mM至200mM范围内的氯化钙,缓冲剂和适量纯水。
25.权利要求21-24任一项的皮肤护理/皮肤病学组合物,其不包含其他抗微生物剂或防腐剂。
26.权利要求17-25任一项的皮肤护理/皮肤病学组合物,其中所述生长因子是选自下列的一种或多种:表皮生长因子(EGF),血管上皮生长因子(VEGF),血小板衍生生长因子(PDGF)包括PDGF-AA、PDGF-BB和PDGF-Rb,成纤维细胞生长因子(FGFs)包括FGF-a、FGF-b、FGF-4和FGF-6,转化生长因子-β(TGF-b)包括TGFβ-1、TGFβ-2、TGFβ-3,转化生长因子-α(TGF-a),红细胞生成素(Epo),胰岛素样生长因子-I(IGF-I),胰岛素样生长因子-II(IGF-II),白介素-1(IL-1)包括IL-1α和IL-1β,白介素-2(IL-2),白介素-4(IL-4),白介素5(IL-5),白介素-6(IL-6),白介素-7(IL-7),白介素-8(IL-8),白介素-10(IL-10),白介素-13(IL-13),白介素-15(IL-15),白介素-18(IL-18),白介素-20(IL-20),肿瘤坏死因子-α(TNF-a),肿瘤坏死因子-β(TNF-b),干扰素-γ(INF-g),粒细胞集落刺激因子(G-CSF),粒细胞巨噬细胞集落刺激因子(GM-CSF),巨噬细胞集落刺激因子(M-CSF),胎盘生长因子(PLGF),神经生长因子(NGF),角质细胞生长因子(KGF),骨形态发生蛋白(BMP-4),肝细胞生长因子(HGF),瘦素,头蛋白和胸腺肽β4。
27.一种植物产生的非植物遗传来源的异源生长因子,其用作药物。
28.一种植物产生的非植物遗传来源的异源生长因子,其用作药物来治疗选自皮肤干燥、湿疹、皮炎、皮肤皲裂、皮疹、瘢痕组织、牛皮癣、皮肤发红和水肿的一种或多种的皮肤病症。
29.权利要求27或28的植物产生的异源生长因子,其选自表皮生长因子(EGF),血管上皮生长因子(VEGF),血小板衍生生长因子(PDGF)包括PDGF-AA、PDGF-BB和PDGF-Rb,成纤维细胞生长因子(FGF)包括FGF-a、FGF-b、FGF-4和FGF-6,转化生长因子-β(TGF-b)包括TGFβ-1、TGFβ-2、TGFβ-3,转化生长因子-α(TGF-a),红细胞生成素(Epo),胰岛素样生长因子-I(IGF-I),胰岛素样生长因子-II(IGF-II),白介素-1(IL-1)包括IL-1α和IL-1β,白介素-2(IL-2),白介素-4(IL-4),白介素5(IL-5),白介素-6(IL-6),白介素-7(IL-7),白介素-8(IL-8),白介素-10(IL-10),白介素-13(IL-13),白介素-15(IL-15),白介素-18(IL-18),白介素-20(IL-20),肿瘤坏死因子-α(TNF-a),肿瘤坏死因子-β(TNF-b),干扰素-γ(INF-g),粒细胞集落刺激因子(G-CSF),粒细胞巨噬细胞集落刺激因子(GM-CSF),巨噬细胞集落刺激因子(M-CSF),胎盘生长因子(PLGF),神经生长因子(NGF),角质细胞生长因子(KGF),骨形态发生蛋白(BMP-4),肝细胞生长因子(HGF),瘦素,头蛋白和胸腺肽β4。
30.权利要求27或28的植物产生的异源生长因子,其是表皮生长因子。
31.一种制造局部用产品的方法,所述方法包含将透明质酸、至少一种赋形剂和包含生长因子的转基因植物提取物混合在一起,所述生长因子选自:表皮生长因子(EGF),血管上皮生长因子(VEGF),血小板衍生生长因子(PDGF)包括PDGF-AA、PDGF-BB和PDGF-Rb,成纤维细胞生长因子(FGF)包括FGF-a、FGF-b、FGF-4和FGF-6,转化生长因子-β(TGF-b)包括TGFβ-1、TGFβ-2、TGFβ-3,转化生长因子-α(TGF-a),红细胞生成素(Epo),胰岛素样生长因子-I(IGF-I),胰岛素样生长因子-II(IGF-II),白介素-1(IL-1)包括IL-1α和IL-1β,白介素-2(IL-2),白介素-4(IL-4),白介素5(IL-5),白介素-6(IL-6),白介素-7(IL-7),白介素-8(IL-8),白介素-10(IL-10),白介素-13(IL-13),白介素-15(IL-15),白介素-18(IL-18),白介素-20(IL-20),肿瘤坏死因子-α(TNF-a),肿瘤坏死因子-β(TNF-b),干扰素-γ(INF-g),粒细胞集落刺激因子(G-CSF),粒细胞巨噬细胞集落刺激因子(GM-CSF),巨噬细胞集落刺激因子(M-CSF),胎盘生长因子(PLGF),神经生长因子(NGF),角质细胞生长因子(KGF),骨形态发生蛋白(BMP-4),肝细胞生长因子(HGF),瘦素,头蛋白和胸腺肽β4。
32.权利要求31的方法,其中所述至少一种赋形剂包含甘油、氯化钙和水。
33.权利要求31或32的方法,其中所述转基因植物提取物是大麦种子提取物。
34.权利要求31-33任一项的方法,其还包含从所述转基因植物提取物分离所述生长因子。
35.权利要求34的方法,其中所述分离步骤包含使用离子交换色谱。
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JP (1) | JP2013516460A (zh) |
KR (1) | KR20120115535A (zh) |
CN (1) | CN102811704A (zh) |
AU (1) | AU2011204391A1 (zh) |
BR (1) | BR112012016575A2 (zh) |
CA (1) | CA2785631A1 (zh) |
RU (1) | RU2012133444A (zh) |
SG (1) | SG181969A1 (zh) |
WO (1) | WO2011083500A2 (zh) |
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JP2016172707A (ja) * | 2015-03-18 | 2016-09-29 | 株式会社UniBio | 植物体内で発現させた上皮細胞増殖因子の精製品の製造方法 |
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CN103908424A (zh) * | 2014-03-03 | 2014-07-09 | 奥思达干细胞有限公司 | 一种用于美容保养的精华液及其制备方法 |
CN103908416A (zh) * | 2014-04-22 | 2014-07-09 | 黄忠亨 | 一种护肤活性因子组合物 |
CN105055285A (zh) * | 2015-08-26 | 2015-11-18 | 浙江奥瑞健生物技术有限公司 | 一种皮肤营养液及其制备方法 |
CN105055285B (zh) * | 2015-08-26 | 2018-01-19 | 浙江奥瑞健生物技术有限公司 | 一种皮肤营养液及其制备方法 |
CN109414600A (zh) * | 2016-06-16 | 2019-03-01 | 皮埃尔·法布尔皮肤化妆品公司 | 含羞草未分化细胞的提取物及其在皮肤美容中的用途 |
CN109803671A (zh) * | 2016-07-21 | 2019-05-24 | 哈比尔·F·赫拉基瓦拉 | 用于促进毛发生长和减少脱发的局部药物组合物 |
CN106389290A (zh) * | 2016-11-14 | 2017-02-15 | 天津贝罗尼生物科技有限公司 | 一种含pdgf的祛疤膏及其制备方法 |
CN109260457A (zh) * | 2017-07-18 | 2019-01-25 | 苏州高泓利康生物科技有限公司 | 一种透明质酸-白介素10复合物、其制备方法及其应用 |
CN109260457B (zh) * | 2017-07-18 | 2023-06-13 | 苏州高泓利康生物科技有限公司 | 一种透明质酸-白介素10复合物、其制备方法及其应用 |
CN111315387A (zh) * | 2017-11-13 | 2020-06-19 | 梁美京 | 用于预防或治疗毛发脱落或者促进毛发生长的药物组合物或化妆品组合物 |
CN110237236A (zh) * | 2018-07-25 | 2019-09-17 | 贝妮芙生物研究室株式会社 | 用于治疗小阴唇皮肤的皮肤软膏 |
CN116889545A (zh) * | 2023-06-27 | 2023-10-17 | 上海腾瑞制药股份有限公司 | 一种重组人酸性成纤维细胞生长因子凝胶剂及其制备工艺 |
CN116889545B (zh) * | 2023-06-27 | 2023-12-29 | 上海腾瑞制药股份有限公司 | 一种重组人酸性成纤维细胞生长因子凝胶剂及其制备工艺 |
Also Published As
Publication number | Publication date |
---|---|
US20130266536A1 (en) | 2013-10-10 |
JP2013516460A (ja) | 2013-05-13 |
KR20120115535A (ko) | 2012-10-18 |
EP2521532A2 (en) | 2012-11-14 |
AU2011204391A1 (en) | 2012-08-16 |
BR112012016575A2 (pt) | 2016-04-12 |
WO2011083500A2 (en) | 2011-07-14 |
WO2011083500A3 (en) | 2011-12-08 |
CA2785631A1 (en) | 2011-07-14 |
SG181969A1 (en) | 2012-08-30 |
RU2012133444A (ru) | 2014-02-20 |
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