CN102027008A - 生长因子-模拟肽及其用途 - Google Patents
生长因子-模拟肽及其用途 Download PDFInfo
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- CN102027008A CN102027008A CN2009801169048A CN200980116904A CN102027008A CN 102027008 A CN102027008 A CN 102027008A CN 2009801169048 A CN2009801169048 A CN 2009801169048A CN 200980116904 A CN200980116904 A CN 200980116904A CN 102027008 A CN102027008 A CN 102027008A
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Abstract
本发明涉及具有生长因子活性的生长因子-模拟肽,及包含所述模拟肽的皮肤状况改善用或创伤治疗用组合物及皮肤状况改善或创伤治疗方法。本发明的生长因子-模拟肽与天然的人生长因子具有相同功能或作用,及比天然的生长因子更优的稳定性及皮肤渗透能力。因此,本发明的含肽组合物可对治疗,预防及改善要求生长因子活性的疾病或状况表现出优良的功效。此外,本发明的肽的优良的活性及稳定性可有利地应用于药物组合物,准药品及化妆品。
Description
【技术领域】
本发明涉及具有生长因子活性的生长因子-模拟肽,及包含所述模拟肽的皮肤状况改善用或创伤治疗用组合物及皮肤状况改善或创伤治疗方法。
【背景技术】
已知人垂体分泌的生长激素与细胞生长及分化直接相关,及由此影响各种细胞反应,例如包括促进软骨或骨骼的生长及发育,复原内部器官,例如肌肉或肝脏,创伤再生,及抗感染免疫应答。而且,已报道生长激素量由于老化而逐渐减少,及60来岁的组的生长激素水平仅为20来岁的组的1/4。因此,已常利用补充不足的生长激素的抗老化激素治疗。
在细胞中生长激素直接结合于生长激素受体,或诱导胰岛素样生长因子I(IGF-I)分泌,导致活化细胞信号分子,例如JAKs(Janus激酶)/STATs(转录信号转导子及活化物),MAPKs(丝裂原活化的蛋白激酶),或PI3K(磷脂酰基-3激酶)。结果,预计生长激素促进毛囊或皮肤中的成纤维细胞生长,及通过调节bcl-2样基因来抑制凋亡。生长因子的这些活性已被诸多研究人员阐明,且各公司基于其有用性已尝试将生长因子商业化。
成纤维细胞生长因子(FGF)被分为2种类型,即酸性FGF(aFGF)及碱性FGF(bFGF),已报道所述两种类型均分离及纯化自哺乳动物脑(Thomas and Gimenez-Gallego,TIBS 11:81-84(1986))。
生长因子中,酸性成纤维细胞生长因子(aFGF)是由154个氨基酸构成的蛋白,其为组织复原及创伤愈合的生物医学研究中的主要分子之一,例如调节动物细胞(尤其是人细胞)生长的活性。酸性成纤维细胞的丝裂原首先被Trowell等人(J.Exp.Biol.16:60-70(1939))及Hoffman(Growth 4:361-376(1940))发现。此外,发现垂体提取物具有促成纤维细胞的有丝分裂活性的能力(Amelin,Proc.Natl.Acad.Sci.USA 70:2702-2706(1973))。
多个细胞应对纯化的aFGF的刺激一齐合成DNA及分裂,其包括:原代成纤维细胞、血管及角膜上皮细胞、软骨细胞、成髓细胞、成肌细胞、平滑肌肉细胞、神经胶质细胞及成神经细胞(Each et al.,Proc.Natl.Acad.Sci.USA 82:6507-6511(1985);Kuo et al.,Fed.Proc.44:695(1985);Gensburger et al.,C.R.Acad.Sc.Paris 303:465-468(1986))。此外,aFGF不仅是血管上皮细胞的强促有丝分裂分子,还诱导血管体内生长(Thomas.et al.,Proc.Natl.Acad.Sci.USA 82:6409-6413(1985))。纯化的aFGF的促有丝分裂活性还可用于促进创伤愈合(Thomas,美国专利No.4,444,760)。
同时,角质形成细胞生长因子(KGF)是由163个氨基酸构成的蛋白,且加速上皮细胞分裂,贡献于几个创伤的快速再生。KGF作为成纤维细胞生长因子家族成员影响各种细胞类型。KGF在治疗几种原因产生的细胞损伤中起关键作用,所述原因包括细胞之间粘连,细胞分裂及老化。此外,KGF在毛发生长早期起重要的细胞之间的桥的作用。除了改善皮肤弹性,促进毛发生长及加速创伤愈合之外,KGF还可用于各种用途。
同样,转化生长因子(TGF)是对于皮肤细胞的生长及分化具有重要活性的细胞因子,其使皮肤的深位点维持非常年轻及健康。例如,通过转化及复原,损伤的老化细胞可被改变为具有更高分裂活性的非常健康的细胞。TGF治疗损伤的细胞,从而可预防组织中瘢痕形成。TGF结合于EGF受体,导致基底膜蛋白的合成增加及刺激上皮细胞生长。TGF除了增强皮肤弹性,促进毛发生长,加速创伤愈合及诱导抗老化环境之外,还可发挥多种功效。
为了大量生产上述生长因子,许多研究人员对使用大肠杆菌表达系统生产重组蛋白进行了锐意研究。但是,这些制剂面临需要耗时及耗成本的再折叠过程及除去大肠杆菌来源的污染物的复杂的纯化过程。为了摆脱这样的缺点,已通过固相合成方法制备了生长因子样肽。例如,Jameson等人提交的美国专利No.5,473,054公开了JB2(对应于IGF-1的氨基酸29~38)及JB1(对应于氨基酸61~70)片段具有细胞增殖潜力,及JB3(JB1的对映体)对IGF-1具有抑制活性。Teruo等人提交的WO 03/048192教导了由IGF-1的氨基酸33~37构成的肽片段及物质-P衍生的四肽在创伤愈合中起到互补功效。此外,Kodama等人报道了由IGF-1的氨基酸50~70构成的肽片段对小鼠的糖尿病具有治疗效果(Autoimmunity,37:481-487(2004))。
本说明通篇参照了多个论文及专利文献及标注了其索引。引用的论文及专利文献的公开内容以其整体并入本文,从而更明确说明本发明所述领域的现有技术及本发明的内容。
【发明内容】
为开发与天然的角质形成细胞生长因子、酸性成纤维细胞生长因子或转化生长因子具有相同作用,且相比天然的角质形成细胞生长因子、酸性成纤维细胞生长因子或转化生长因子具有更显著特征(例如活性,皮肤渗透性及稳定性)的肽,本发明人进行了锐意研究。结果,本发明人基于天然的生长因子氨基酸序列合成了几种具有上述优良的特征的生长因子-模拟(mimicking)肽,从而完成本发明。
因此,本发明旨在提供具有生长因子活性的肽。
本发明还旨在提供皮肤状况改善用组合物。
本发明又旨在提供创伤治疗用组合物。
本发明又旨在提供皮肤状况改善方法。
本发明又还旨在提供创伤治疗方法。
本发明的其他目的及优点将通过以下详述结合随附的权利要求及附图被本领域技术人员明晰。
本发明的一方面提供具有生长因子(GF)活性的肽,其源于GF,且含选自SEQ ID NO:1~4的氨基酸序列。
为开发与天然的角质形成细胞生长因子、酸性成纤维细胞生长因子或转化生长因子具有相同作用,且相比天然的角质形成细胞生长因子、酸性成纤维细胞生长因子或转化生长因子具有更显著特征(例如活性,皮肤渗透性及稳定性)的肽,本发明人进行了锐意研究。结果,本发明人基于天然的生长因子氨基酸序列合成了几种具有上述优良的特征的生长因子-模拟(mimicking)肽。
本发明的肽含人生长因子衍生的选自SEQ ID NO:1~4的氨基酸序列。优选地,肽基本上由选自SEQ ID NO:1~4的氨基酸序列构成。最优选地,肽由选自SEQ ID NO:1~4的氨基酸序列构成。
本文中的术语“肽”是指氨基酸残基通过肽键连接形成的线性分子。
本发明的肽可通过本领域技术人员已知的常规化学合成过程,尤其是,固相合成技术制备(Merrifield,J.Amer.Chem.Soc.85:2149-54(1963);Stewart,et al.,Solid Phase Peptide Synthesis,2nd.ed.,Pierce Chem.Co.:Rockford,111(1984))。
本发明的肽设计例示于图1。
可通过预测生长因子的能够结合受体蛋白的部位及优化预测的部位的氨基酸序列来制备本发明的肽。例如,将氨基酸100~140(对于KGF(角质形成细胞生长因子)),氨基酸110~125(对于aFGF),及氨基酸35~49(对于TGF-α)预测为能够结合受体蛋白的部位。然后,参考上述氨基酸序列制备候选肽,然后筛选具有最优良的活性的肽,从而得到本发明的肽。
SEQ ID NO:1源于天然的人KGF(角质形成细胞生长因子)的氨基酸120~127。SEQ ID NO:2源于天然的人aFGF的氨基酸111~122。SEQ ID NO:3及SEQ ID NO:4分别源于天然的人TGF-α的氨基酸10~20及38~49。
尽管本发明的肽本身比天然的生长因子具有更高稳定性,但它们的修饰能使它们具有甚更高稳定性。根据优选实施方式,本发明的肽C端经修饰而带有羟基(-OH)或氨基(-NH2)。
根据优选实施方式,本发明的肽N端经保护基保护,所述保护基选自:乙酰基,芴基甲氧基羰基,甲酰基,棕榈酰基,肉豆蔻酰基,硬脂酰基或聚乙二醇(PEG)。
上述肽修饰大大增加本发明的肽的稳定性。本文中的术语“稳定性”是指体内稳定性及保存稳定性(例如于室温的保存稳定性)。上述保护基保护肽免受体内蛋白酶攻击。
本发明另一方面提供皮肤状况改善用组合物,其含本发明的生长因子-模拟肽作为有效成分。
本发明再一方面提供创伤治疗用组合物,其含本发明的生长因子-模拟肽作为有效成分。
本发明再一方面提供皮肤状况改善方法,包括给受试者施用含本发明的肽的组合物。
本发明又再一方面提供创伤治疗方法,包括给受试者施用含本发明的肽的组合物。
因为本发明的组合物含上述本发明的生长因子-模拟肽作为有效成分,略去它们之间的共同内容,以避免本说明书的过度复杂。
如下述实施例所述,本发明的生长因子-模拟肽与天然的生长因子(例如KGF,aFGF及TGF-α)具有相同的促进成纤维细胞及角质形成细胞增殖,及生产胶原及纤连蛋白的作用。因此,本发明的组合物对改善皮肤状况具有优良的功效。
根据优选实施方式,本发明的组合物可用于改善皮肤状况,例如改善皱纹或皮肤弹性、防止皮肤老化、防止毛发脱落、促进毛发生长、改善皮肤保湿、消除黑斑或治疗痤疮。
有趣的是,如下述实施例所述,本发明的生长因子-模拟肽具有优良的创伤愈合作用。
根据优选实施方式,本发明的组合物可用于闭合的创伤及开放的创伤。例如,闭合的创伤包括挫伤或擦伤,及开放的创伤包括擦破伤,撕裂伤,撕脱伤,穿透的创伤及枪伤。
本发明的组合物可制备成药学或化妆组合物。
根据优选实施方式,组合物是药物组合物,其含:(a)药学有效量的本发明的生长因子-模拟肽;及(b)药学可接受载质。
本文中的术语“药学有效量”是指足以显示及实现本发明的肽的功效及活性的量。
含于本发明的药物组合物中的药学可接受载质是药学制剂时通常使用的,但不限于,包括:乳糖,右旋糖,蔗糖,山梨醇,甘露醇,淀粉,阿拉伯橡胶,磷酸钾,藻酸盐,明胶,硅酸钾,微晶纤维素,聚乙烯吡咯烷酮,纤维素,水,糖浆,甲基纤维素,羟苯甲酯,羟苯丙酯,滑石,硬脂酸镁,及矿物油。本发明的药物组合物还可包括润滑剂,致湿剂,甜味剂,调味剂,乳化剂,悬浮剂,及防腐剂。适宜药学可接受载质及制剂的明细可见于Remington′s Pharmaceutical Sciences(19th ed.,1995),其通过引用并入本文。
本发明的药物组合物可口服或经肠外施用,及优选地,经肠外施用,例如通过静脉内,皮下,肌内,腹膜内,局部或透皮施用。
本发明的药物组合物的适宜剂量可依赖于药学制剂方法,施用方法,患者年龄,体重,性别,患病状态,饮食,施用时间,施用途径,排泄速度及对所用药物组合物的敏感度而变化。优选地,本发明的药物组合物可以每日0.001~100mg/kg的剂量施用。
根据本领域技术人员已知的常规技术,本发明的药物组合物可与上述药学可接受载质和/或媒质制成制剂,最终提供几种单位剂型及多剂型。制剂的非限制性例包括,但不限于,溶液,悬浮液或油或水介质中的乳液,提取物,酏剂,粉末,颗粒,片剂及胶囊,及还可含分散剂或稳定剂。
根据优选实施方式,组合物是化妆组合物,其含:(a)化妆学有效量的本发明的生长因子-模拟肽;及(b)化妆学可接受载质。
本文中的术语“化妆学有效量”是指足以实现改善上述皮肤状况的功效的量。
本发明的化妆组合物可以广泛多种形式制成制剂,例如,包括溶液,悬浮液,乳液,糊剂,软膏剂,凝胶,乳霜,洗剂,粉末,皂,含表面活性剂的清洁剂,油,粉底,乳液底,蜡底及喷雾剂。具体而言,本发明的化妆组合物可制成柔润化妆水,营养化妆水,营养霜,按摩霜,精华液,眼霜,清洁霜,清洁泡沫,清洁水,面膜,喷雾剂或粉末形式。
当化妆组合物是糊剂,乳霜或凝胶形式时,其可含动物及植物脂肪,蜡,石蜡,淀粉,黄著胶,纤维素衍生物,聚乙二醇,硅酮,皂粘土,硅石,滑石,氧化锌或这些物质的混合物。
在粉末或喷雾剂制剂中,其可含乳糖,滑石,硅石,氢氧化铝,硅酸钙,聚酰胺粉末及这些物质的混合物。喷雾剂可再含惯用喷射剂,例如,氯氟烃,丙烷/丁烷或二甲酯。
溶液及乳液制剂可含溶剂,增溶剂及乳化剂,例如:水,乙醇,异丙醇,碳酸乙酯,醋酸乙酯,苄醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,油,脂肪酸甘油酯,聚乙二醇及山梨坦的脂肪酸酯。
悬浮液制剂可含液体稀释剂,例如水,乙醇或丙二醇,悬浮剂,例如,乙氧基化的异硬脂醇,聚氧基乙烯山梨醇酯及聚氧基乙烯山梨坦酯,微晶纤维素,偏氢氧化铝,皂粘土,琼脂及黄著胶或这些物质的混合物。
含表面活性剂的清洁组合物制剂可含:脂肪醇硫酸,脂肪醇醚硫酸,磺基琥珀酸单酯,异硫代磷酸酯,咪唑鎓衍生物,牛磺酸甲酯,肌氨酸酯,脂肪酸酰胺醚硫酸,烷基氨基甜菜碱,脂肪醇,脂肪酸甘油酯,脂肪酸二乙醇酰胺,植物油,羊毛酯衍生物,乙氧基化的脂肪酸甘油酯或这些成分的混合物。
而且,本发明的化妆组合物可含辅助剂及bFGF修饰剂作为有效成分,以及载质。辅助剂的非限制性例包括:抗氧化剂,稳定剂,增溶剂,维生素,着色剂,气味改善剂或这些物质的混合物。
本发明的特征及优点总结如下:
(a)本发明的生长因子-模拟肽与天然的人生长因子具有相同功能或活性;
(b)本发明的肽比天然的生长因子具有甚更高稳定性及皮肤渗透能力;
(c)因此,含肽组合物对要求生长因子活性的疾病或状况表现出优良的治疗,预防或改善功效;及
(d)本发明的肽的优良的活性及稳定性可有利地应用于药物组合物,准药品及化妆品。
【附图说明】
图1显示天然的生长因子氨基酸序列及制备本发明的肽的选定区域。
图2a显示实施例中制备的SEQ ID NO:1的肽的高效液相色谱分析。
图2b显示实施例中制备的SEQ ID NO:2的肽的高效液相色谱分析。
图2c显示实施例中制备的SEQ ID NO:3的肽的高效液相色谱分析。
图2d显示实施例中制备的SEQ ID NO:4的肽的高效液相色谱分析。
图3a是显示用实施例中制备的SEQ ID NO:1~4的肽处理对角质形成细胞的生长刺激效果的坐标图。
图3b是显示用实施例中制备的SEQ ID NO:1~4的肽处理对成纤维细胞的生长刺激效果的坐标图。
图4是显示用实施例中制备的SEQ ID NO:1~4的肽处理对角质形成细胞及成纤维细胞的生长刺激效果的显微图像。
图5a是显示与本发明的肽(肽1~4)温育的角质形成细胞中升高的胶原水平的坐标图。
图5b是显示与本发明的肽(肽1~4)温育的角质形成细胞中升高的纤连蛋白水平的坐标图。
图6是比较本发明的肽及天然的aFGF的热稳定性的坐标图。
图7显示含本发明的肽的水凝胶照片。
图8是用含本发明的肽的水凝胶对Balb/C小鼠的创伤区处理10天后观察Balb/C小鼠创伤组织中的创伤愈合效果的组织照片。
【实施方式】
以下将通过实施例更详细说明本发明。本领域技术人员明晰,这些实施例仅旨在更详细阐释本发明,权利要求给出的本发明的保护范围不受这些实施例的限制。
【实施例】
【合成例1】Ac-Tyr-Lys-Ser-Lys-Lys-Gly-Gly-Trp-Thr-His(SEQID NO:1)的合成
将700mg氯三苯甲基氯树脂(CTL树脂,Nova Biochem Cat No.01-64-0021)导入反应容器,加入10ml二氯甲烷(MC),及搅拌3分钟。除去溶液后,将10ml二甲基甲酰胺(DMF)加入生成物,然后进行搅拌3分钟,而后除去溶剂。将10ml二氯甲烷溶液加入反应容器,然后将200mM Fmoc-His(Trt)-OH及400mM二异丙基乙胺(DIEA)加入反应容器,而后将混合物搅拌溶解,然后一边搅拌一边进行反应1小时。反应后,洗涤生成物,及在溶于DCM的甲醇及DIEA(2∶1)中反应10分钟,之后用过量的DCM/DMF(1∶1)洗涤。除去溶剂后,将10ml DMF加入反应容器及搅拌3分钟,之后除去溶剂。将10ml去保护溶液(20%哌啶/DMF)加入反应容器,及于室温搅拌10分钟,及除去溶液。加入相同体积去保护溶液后,进行反应10分钟及除去溶液,之后依次用DMF(2次),MC(1次)及DMF洗涤(每次3分钟)以得到His-(Trt)-CTL树脂。将10ml DMF溶液加入新反应容器,然后加入200mM Fmoc-Thr(tBu)-OH(Bachem,Swiss)、200mM HoBt及200mM Bop,之后搅拌助溶。将400mM DIEA分两次加入反应容器,及进行搅拌至少5分钟,溶解全部固体内容物。将溶解的氨基酸溶液导入含去保护的树脂的反应容器中,及于室温一边搅拌一边进行反应1小时。除去反应溶液后,用DMF溶液搅拌生成物3次,每次5分钟,以除去未反应的残留物。取少量反应的树脂通过茚三酮测试评估反应程度。使用去保护溶液,以如同上述的方式进行去保护两次,以得到Thr(tBu)-His-(Trt)-CTL树脂。用DMF及MC洗涤后,进行茚三酮测试后,进行上述氨基酸附着。基于示于图1的氨基酸序列,将Fmoc-Trp、Fmoc-Gly、Fmoc-Gly、Fmoc-Lys(Boc)、Fmoc-Lys(Boc)、Fmoc-Ser(tBu)、Fmoc-Lys(Boc)及Fmoc-Tyr(tBu)依次附着到树脂。通过与去保护溶液温育两次(每次10分钟)来除去Fmoc-保护基。至于乙酰化,将乙酸酐,DIEA及HoBt与肽基树脂温育两次(每次1小时),及将制备的肽基树脂依次用DMF,MC及甲醇洗涤3次,在氮气流下干燥,通过在P2O5下真空干燥来完全干燥,然后在中速搅拌下于室温与30ml离去溶液〔含81.5%TFA(三氟乙酸),5%蒸馏水,5%苯甲硫醚,5%苯酚,2.5%EDT及1%TIS〕反应2小时。过滤树脂,及用小体积TFA溶液洗涤,而后将滤出物与母液合并。减压蒸馏至减少到总体积之一半后,使用50ml冷醚诱导沉淀,及通过离心收集形成的沉淀物,之后用冷醚洗涤两次。除去母液后,在氮气气氛下干燥生成物,以提供1.18g未纯化的SEQ IDNO:1的Ac-YKSKKGGWTH(产率,72.6%)。使用质谱仪测定最终产物的分子量为1233.8(理论MW 1233.4)。
【合成例2】其他肽的合成
如合成例1所述过程合成SEQ ID NO:2~4的肽。SEQ ID NO:2(Tyr-Ile-Ser-Lys-Lys-His-Ala-Gly-Lys-Asn-Trp-Phe:YISKKHAGKNWF)对应于aFGF的氨基酸111~122,SEQ ID NO:3(Asp-Ser-His-Thr-Gln-Tyr-Cys-Phe-His-Gly-Thr:DSHTQYCFHGT)对应于TGF-α的氨基酸10~20,及SEQ ID NO:4(Gly-Tyr-Val-Gly-Val-Arg-Cys-Glu-Ala-Ala-Asp-Leu-Asp-Ala:GYVGVRCEAADLDA)对应于TGF-α的氨基酸38~49。测定的肽的分子量总结于表1:
【表1】
【实验例1】所述合成肽对HaCaT角质形成细胞及NIH3T3成纤维细胞的生长的影响
为评估合成例1~2中制备的4种肽是否具有与生长因子-1相似的活性,使用HaCaT角质形成细胞及NIH3T3成纤维细胞,根据Rizzino等人的方法进行SRB(硫代罗丹明B;Sigma-Aldrich)比色测定(Rizzino,et al.Cancer Res.,48:4266(1988))。
在含补充了10%FBS(牛血清白蛋白)的EMEM(Eagle′s minimal essential media;Gibco,U.S.A.)的250ml培养皿中培养HaCaT角质形成细胞(韩国细胞系银行)及NIH3T3成纤维细胞(韩国细胞系银行)。用0.25%胰蛋白酶溶液处理培养的细胞以使细胞从培养皿底部脱离,及离心收集细胞沉淀。将细胞重悬浮于不含FBS的EMEM中后,将其等份(4×103细胞)加入96孔平板的各孔,及于37℃在7%CO2下培养24小时。培养24小时后,将培养基用不含血清的新鲜培养基替换,及将细胞与人酸性成纤维细胞生长因子(NIBSC,UK)和溶于水及10%DMSO的4种合成肽(10ng/ml或1,000ng/ml)在与上述相同条件下温育72小时。除去上清后,将细胞使用PBS(磷酸缓冲液)洗涤一次。除去洗涤溶液后用SRB溶液处理。用PBS充分洗涤细胞,及在显微镜想观察细胞活力。此外,测量590nm处的吸光度以分析细胞增殖。
图3a及图3b分别显示角质形成细胞及成纤维细胞生长的分析数据。图4显示用肽处理72小时后在显微镜下观察的角质形成细胞及成纤维细胞的生长模式。
如图3a所示,本发明的4种肽显著促进角质形成细胞生长。尤其是,本发明的肽1,3及4对角质形成细胞生长有甚更优效果。此外,如图3b所示,观察到本发明的4种肽促进成纤维细胞生长。尤其是,本发明的肽1及2对成纤维细胞生长具有优良的效果。如图4所示,本发明的肽被发现显著促进角质形成细胞及成纤维细胞生长。
【实验例2】所述合成肽对胶原及纤连蛋白生成的影响
将培养48小时的HaCaT角质形成细胞与本发明的4种肽温育72小时。使用原胶原ELISA试剂盒(Takara,Japan)及纤连蛋白ELISA试剂盒(CHEMICON,USA)进行原胶原及纤连蛋白水平(显示皮肤皱纹改善的指示)的检查和定量。如图5a所示,本发明的4种肽被发现升高角质形成细胞中原胶原水平。首先,本发明的肽2表现出显著促进原胶原生产。此外,如图5b所示,本发明的肽被发现升高角质形成细胞中纤连蛋白水平。尤其是,本发明的肽1及4表现出显著促进原胶原生产。
从实验1和2的结果得知,这些结果显示本发明的肽表现出显著改善皮肤状况的效果。
【实验例3】制备的肽的热稳定性
将合成例1~2中制备的4种肽及购自NIBSC(UK)的标准品生长因子(KGF、aFGF及TGF-α)溶于磷酸缓冲液至浓度0.11mg/ml。将制备的溶液(1ml)导入玻璃瓶中,及保持在37℃。然后,在第0,5,10,20,25,30,40,60及100天时取出静置于37℃的溶液离心除去变性的肽或蛋白,之后取上清使用HPLC定量(图6)。合成肽的残量比天然的生长因子更高。将残余肽作为样品根据与实施例1中所述相同方法处理细胞,及利用MTT测定(Scudiero,D.A.,et al.Cancer Res.48:4827-4833(1988))来测定肽及天然的生长因子的残余活性。得知本发明的全部肽具有比天然的生长因子更优的活性。
【实施例1】纳米化肽的制备
将50mg合成例中得到的4种肽通过剧烈搅拌溶于500ml蒸馏水。将肽溶液与5g卵磷脂,0.3ml油酸钠,50ml乙醇及少量油混合,及用蒸馏水调节其体积至1L。将得到的溶液用微流化仪在高压下乳化,由此提供具有100nm尺寸的纳米体。将制备的纳米体以最终浓度约50ppm单独或与其他物质组合用于化妆品制备。
【剂型例1】柔润化妆水
根据常规制备方法制备含实施例1中制备的4种肽纳米体中的至少一种纳米体、且具有下列组成的柔润化妆水。
【表2】
成分 | 含量(wt%) |
肽纳米体 | 0.001 |
1,3-丁二醇 | 6.0 |
甘油 | 4.0 |
PEG 1500 | 1.0 |
透明质酸钠 | 1.0 |
聚山梨酯20 | 0.5 |
乙醇 | 8.0 |
防腐剂,色素 | 适量 |
二苯甲酮-9 | 0.05 |
香料 | 少量 |
蒸馏水 | 残量 |
总 | 100 |
【剂型例2】营养霜
根据常规制备方法制备含实施例1中制备的4种肽纳米体中的至少一种纳米体、且具有下列组成的营养霜。
【表3】
成分 | 含量(wt%) |
肽纳米体 | 0.001 |
白芒花油 | 3.0 |
棕榈醇 | 1.5 |
硬脂酸 | 1.5 |
硬脂酸甘油酯 | 1.5 |
液体石蜡 | 10.0 |
蜡 | 2.0 |
聚山梨酯60 | 0.6 |
倍半油酸山梨坦 | 2.5 |
角鲨烷 | 3.0 |
1,3-丁二醇 | 3.0 |
甘油 | 5.0 |
三乙醇胺 | 0.5 |
醋酸生育酚 | 0.5 |
防腐剂,色素 | 适量 |
香料 | 适量 |
蒸馏水 | 残量 |
总 | 100 |
【剂型例3】营养化妆水
根据常规制备方法制备含实施例1中制备的4种肽纳米体中的至少一种纳米体、且具有下列组成的营养化妆水。
【表4】
成分 | 含量(wt%) |
肽纳米体 | 0.002 |
1,3-丁二醇 | 4.0 |
甘油 | 4.0 |
棕榈醇 | 0.8 |
硬脂酸甘油酯 | 1.0 |
三乙醇胺 | 0.13 |
醋酸生育酚 | 0.3 |
液体石蜡 | 5.0 |
角鲨烷 | 3.0 |
夏威夷核油 | 2.0 |
聚山梨酯60 | 1.5 |
倍半油酸山梨坦 | 0.5 |
羧基乙烯聚合物 | 1.0 |
防腐剂,色素 | 适量 |
香料 | 适量 |
蒸馏水 | 残量 |
总 | 100 |
【剂型例4】精华液
根据常规制备方法制备含实施例1中制备的4种肽纳米体中的至少一种纳米体、且具有下列组成的精华液。
【表5】
成分 | 含量(wt%) |
肽纳米体 | 0.005 |
甘油 | 10.0 |
1,3-丁二醇 | 5.0 |
PEG 1500 | 2.0 |
尿囊素 | 0.1 |
DL-泛醇 | 0.3 |
EDTA-2Na | 0.02 |
羟乙基纤维素 | 0.1 |
透明质酸钠 | 8.0 |
羧基乙烯聚合物 | 0.2 |
三乙醇胺 | 0.18 |
辛基十二醇聚醚-16 | 0.4 |
乙醇 | 6.0 |
香料,防腐剂,色素 | 适量 |
蒸馏水 | 残量 |
总 | 100 |
【剂型例5】创伤治疗用水凝胶
制备含实施例1中制备的4种肽纳米体、且具有下列组成的水凝胶罩(图7)。使用医生刀片及辊子加工后制成1×1cm2的水凝胶薄片用于实验。薄片的照片示于图7。
【表6】
成分 | 含量(wt%) |
肽纳米体 | 0.005 |
甘油 | 10.0 |
1,3-丁二醇 | 5.0 |
黄原胶 | 2.0 |
丙烯酸酯聚合物 | 23 |
琼脂糖 | 2 |
霍霍巴油 | 5 |
香料,防腐剂,色素 | 适量 |
蒸馏水 | 残量 |
总 | 100 |
【实验例4】制备的肽纳米体在Balb/C小鼠中的创伤愈合效果
将Balb/C雄性小鼠的背部毛完全除去后,使用一次性手术刀创建大小约3mm及5mm之间的创伤。一天后,将合成肽水凝胶罩和作为阳性对照的aFGF分别局部施用于小鼠创伤区。3天后,将等量的水凝胶罩及aFGF再附着到相同创伤区。7天后,肉眼观察创伤愈合效果,其结果示于图8。如图8所示,相比未处理(阴性对照),在用合成肽处理的创伤部位肉眼观察到创伤愈合效果,尤其是,相比经aFGF处理的创伤部位,经合成肽处理的创伤部位随着经过的时间加长,肉眼观察到治疗效果更好。这些结果提示,本发明的肽相比天然的生长因子具有更优体外稳定性,可长时间在创伤部位起作用。此外预示着,含本发明的肽的化妆品及水凝胶,可维持生长因子活性的同时,且由增长的体内半衰期导致具有显著的皮肤改善效果及治疗创伤效果。
以上详细说明了本发明的特定部分,对于本领域技术人员而言,这些具体记载仅为优选实施例,本发明的范围不由其所限。因此,认为,本发明的实际范围应由随附的权利要求书及其等效表述确定。
Claims (8)
1.具有生长因子活性的肽,其,
●源于生长因子,且
●含选自SEQ ID NO:1~4的氨基酸序列。
2.权利要求1的肽,其中所述肽C端经修饰而带有羟基(-OH)或氨基(-NH2)。
3.权利要求1的肽,其中所述肽N端经保护基保护,所述保护基选自:乙酰基,芴基甲氧基羰基,甲酰基,棕榈酰基,肉豆蔻酰基,硬脂酰基及聚乙二醇(PEG)。
4.皮肤状况改善用组合物,其含权利要求1~3中任一项的肽作为有效成分。
5.创伤治疗用组合物,其含权利要求1~3中任一项的肽作为有效成分。
6.权利要求4的组合物,其中所述皮肤状况改善是:改善皱纹或皮肤弹性、防止皮肤老化、防止毛发脱落、促进毛发生长、改善皮肤保湿、消除黑斑或治疗痤疮。
7.皮肤状况改善方法,包括给受试者施用含权利要求1~3中任一项的肽作为有效成分的组合物。
8.创伤治疗方法,包括给受试者施用含权利要求1~3中任一项的肽作为有效成分的组合物。
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Cited By (8)
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CN103923210A (zh) * | 2013-01-14 | 2014-07-16 | 山东新时代药业有限公司 | 一种胸腺法新的固相合成工艺 |
CN108699112A (zh) * | 2016-03-09 | 2018-10-23 | 凯尔格恩有限公司 | 呈现生发和/或育发促进活性的肽及其的用途 |
CN108699112B (zh) * | 2016-03-09 | 2021-10-19 | 凯尔格恩有限公司 | 呈现生发和/或育发促进活性的肽及其的用途 |
CN109715217A (zh) * | 2016-08-19 | 2019-05-03 | 凯尔格恩有限公司 | 米诺地尔和肽的结合物 |
CN109715217B (zh) * | 2016-08-19 | 2022-07-29 | 凯尔格恩有限公司 | 米诺地尔和肽的结合物 |
US11617796B2 (en) | 2016-08-19 | 2023-04-04 | Caregen Co., Ltd. | Conjugate of minoxidil and peptide |
CN114007579A (zh) * | 2019-05-07 | 2022-02-01 | 凯尔格恩有限公司 | Trolox-肽缀合物及其用途 |
CN114007579B (zh) * | 2019-05-07 | 2023-09-12 | 凯尔格恩有限公司 | Trolox-肽缀合物及其用途 |
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US8501689B2 (en) | 2013-08-06 |
EP2275440A2 (en) | 2011-01-19 |
EP2275440A4 (en) | 2012-02-22 |
BRPI0911650B8 (pt) | 2021-05-25 |
WO2009125925A2 (ko) | 2009-10-15 |
BR122020010541B1 (pt) | 2021-06-22 |
BR122020010515B1 (pt) | 2021-04-27 |
ES2616658T3 (es) | 2017-06-13 |
WO2009125925A3 (ko) | 2009-12-17 |
JP5361988B2 (ja) | 2013-12-04 |
KR20090108323A (ko) | 2009-10-15 |
JP2011519358A (ja) | 2011-07-07 |
BRPI0911650B1 (pt) | 2021-04-27 |
EP2275440B1 (en) | 2016-12-21 |
KR101021197B1 (ko) | 2011-03-11 |
BRPI0911650A2 (pt) | 2016-07-12 |
US20110160131A1 (en) | 2011-06-30 |
CN102027008B (zh) | 2013-07-31 |
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