CN114478695B - 一类促进组织修复的新多肽及其应用 - Google Patents
一类促进组织修复的新多肽及其应用 Download PDFInfo
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- CN114478695B CN114478695B CN202111418086.6A CN202111418086A CN114478695B CN 114478695 B CN114478695 B CN 114478695B CN 202111418086 A CN202111418086 A CN 202111418086A CN 114478695 B CN114478695 B CN 114478695B
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Abstract
本发明公开了一种促进组织修复的新多肽及其应用,所述新多肽在较低浓度下可促进人永生化表皮细胞的增殖和人表皮成纤维细胞的迁移,能够促进创伤和溃疡的修复,改善皮肤美感,且毒副作用低,具有良好的应用前景,可用于制备治疗创面、烫伤、溃疡的药物和医疗器械或改善皮肤美感的日化用品。
Description
技术领域:
本发明涉及药物、医疗器械及日化领域,具体涉及一类促进组织修复的新多肽及其应用。
背景技术:
随着社会的发展及老龄化进程加速,组织创伤不仅包括烧伤、创伤等外伤,还包括难愈性创面和溃疡如胃溃疡、口腔溃疡、糖尿病溃疡、自身免疫性皮肤溃疡、静脉淤滞性溃疡以及长期卧床所致褥疮等。难愈性创面和溃疡的发病机制复杂、病程较长、治疗难度大、治疗费用高,给患者带来沉重的身心压力和经济负担。目前,生长因子类药物广泛应用于难愈性创面和溃疡的治疗,显示出良好的治疗效果,其中表皮生长因子、碱性成纤维细胞生长因子以及血管内皮生长因子等均对创面和溃疡愈合有重要作用,但是这些内源性因子制备成本高、稳定性差,限制了它们的临床应用。因此,很有必要寻找和开发活性显著、生产成本低、稳定性好的治疗组织创伤、难愈性创面和溃疡的活性物质。
发明内容:
本发明的目的在于,克服上述现有技术的不足,提供一类可以促进组织修复的新多肽及其应用。
为实现上述目的,本发明采用以下技术方案:
一种促进组织修复的新多肽,命名为TRF1~TRF12,其结构如式I所示:
式I中:R1=H或Ala或Gly或Ala-Ala-或Val-Ala-;
R2=Asn或Asp;
R3=Ser或Tyr或-Gly-Ser-Tyr或-Gly-Ser-Tyr-Ala-Pro-Leu-Gly-Tyr或-Gly-Ser-Tyr-Ala-Pro-Leu-Gly-Tyr-His-Val-Arg或-Gly-Ser-Tyr-Ala-Pro-Leu-Gly-Tyr-His-Val-Arg-Glu-Tyr-Pro-Ala-Gly-Val-Ser-Ala-Ala。
进一步的,在本发明的优选方案中,所述的新多肽类化合物,包括但不限于如下所示的TRF1~TRF12:
所述的新多肽(TRF1~TRF12)的制备,可采用现有技术中的公知方法进行,既可以用多肽合成仪进行化学合成,也可以通过将多肽序列推导出核苷酸序列,然后克隆到表达载体中进行生物合成;
本发明的另一目的在于,公开了所述的新多肽(TRF1~TRF12)在制备促进组织修复或改善皮肤美感的产品中的应用。
优选的,所述的新多肽(TRF1~TRF12)在制备治疗创伤、烫伤、溃疡或改善皮肤美感的产品中的应用。
较佳的,所述的产品优选为药品、医疗器械或日化用品。
较佳的,所述的药品、医疗器械或日化用品中含有有效剂量的一种或多种新多肽(TRF1~TRF12),或其药学上可接受的盐或其立体异构体,余量为辅料或其它可配伍的药物。
所述的辅料是指常规的赋形剂,如溶剂、崩解剂、矫味剂、防腐剂、着色剂和粘合剂等。
所述的其它可配伍的药物,是指其它天然药物、化学药品或生物药物。
所述的药品、医疗器械或日化用品可以采用片剂、胶囊剂、注射剂、脂质体纳米粒、控释剂、凝胶膏剂、软膏剂、外用搽剂、贴剂、霜剂、洗涤剂、乳液、凝胶、爽肤水等。
本发明相对于现有技术具有如下的优点及效果:
(1)本发明所述的多肽(TRF1~TRF12)是一类具有新结构的多肽,这些新多肽均含有二硫键,结构稳定,不易降解。
(2)本发明提供的新多肽(TRF1~TRF12)能显著促进人永生化表皮细胞(HaCAT)的增殖,同时能显著促进人皮肤成纤维细胞(HSF)的迁移,具有促进组织修复作用。
(3)本发明提供的新多肽(TRF1~TRF12)可用于促进组织修复、治疗消化道溃疡、口腔溃疡,并具有去除皱纹、疤痕和色斑作用。
(4)本发明提供的新多肽(TRF1~TRF12)毒性较低,在口服500mg/kg剂量下未观察到明显的毒副作用。
(5)本发明提供的新多肽(TRF1~TRF12)可以化学合成或生物合成,易于大量制备。
附图说明
图1为新多肽TRF1的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~580);C为MS2图(m/z 580~1110)。
图2为新多肽TRF2的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~420);C为MS2图(m/z 390~810);D为MS2图(m/z 810~1170)。
图3为新多肽TRF3的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~600);C为MS2图(m/z 600~1300)。
图4为新多肽TRF4的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~510);C为MS2图(m/z 510~1250)。
图5为新多肽TRF5的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~650);C为MS2图(m/z 620~1200)。
图6为新多肽TRF6的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~400);C为MS2图(m/z 400~900);D为MS2图(m/z 850~1800)。
图7为新多肽TRF7的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~400);C为MS2图(m/z 400~970);D为MS2图(m/z 970~1700)。
图8为新多肽TRF8的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~620);C为MS2图(m/z 620~1150)。
图9为新多肽TRF9的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z50~420);C为MS2图(m/z 390~810);D为MS2图(m/z 800~1200)。
图10为新多肽TRF10的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z 50~500);C为MS2图(m/z 450~1250)。
图11为新多肽TRF11的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z 50~420);C为MS2图(m/z 390~820);D为MS2图(m/z 800~1270)。
图12为新多肽TRF12的质谱图,其中A为其ESI-MS图;B为其MS2图(m/z 50~380);C为MS2图(m/z 380~920);D为MS2图(m/z 920~1560)。
图13为新多肽TRF1~TRF12对HaCAT细胞增殖影响的结果分析图。
图14为新多肽TRF1~TRF12对HSF细胞迁移影响的结果分析图。
具体实施方式
下面结合实施例及附图对本发明作进一步的描述,但本发明的实施方式不限于此。
实施例1新多肽TRF1~TRF12的合成
(1)新多肽TRF1的固相合成
将1g 0.3~0.5mmol带Fmoc及侧链保护的酪氨酸-Wang树脂置于固相合成仪中,加入20mL N,N-二甲基甲酰胺使其充分溶胀。将溶剂抽干后,加入20%哌啶(按体积比溶于N,N-二甲基甲酰胺),搅拌约10min后抽干,重复2次,使Fmoc基团脱除完全,加入20mL N,N-二甲基甲酰胺洗涤,抽干溶剂,重复3次;加入0.5mmol带Fmoc及侧链保护的半胱氨酸,再加入等量的HBTU/N,N-二甲基甲酰胺和N,N-二异丙基乙胺/N,N-二甲基甲酰胺溶液,于N2保护下反应40~60min;用N,N-二甲基甲酰胺洗脱未反应的药品和试剂,茚三酮检测;后续采用相同的方法连接剩余氨基酸,经过脱保护、活化、缩合、洗涤等步骤合成得到接在树脂上的多肽。向树脂上的多肽加入裂解液(三氟乙酸/三异丙基硅烷/纯水/1,2-乙二硫醇,体积比94:2.5:2.5:1)切割2~3h后,加入冰乙醚,离心后得到下层沉淀。取出沉淀,除去残留的三氟乙酸,加入一定量的碘溶液,于室温下搅拌反应约1h,即得到目标多肽粗品。
上述多肽粗品用体积比为20%的乙腈水溶液溶解,过滤,采用高效液相色谱仪纯化,检测波长为214nm、254nm、280nm,流动相为乙腈-水(体积比10:90~50:50),流速为1mL/min,收集目标峰,浓缩、冻干,得到多肽纯品。
(2)新多肽TRF2~TRF12的固相合成
多肽TRF2~TRF12的合成过程与上述TRF1类似,将1g 0.3~0.5mmol带Fmoc及侧链保护的氨基酸(羧基端第一个)-王树脂置于固相合成仪中,经过脱保护、活化、缩合、洗涤等步骤依次连接序列中的氨基酸,合成得到连接在树脂上的多肽,再经切割、纯化得到多肽纯品。
实施例2新多肽TRF1~TRF12的质谱鉴定
称取多肽TRF1~TRF12分别溶解于去离子水中,配置成浓度为0.1mg/mL的样品溶液。将样品溶液分别注入AB Sciex5600+质谱仪进行分析。其中质量范围(m/z):50~2000Da;采集模式:正离子模式;扫描模式:选择离子扫描;毛细管电压:3.0kV;离子源温度:110℃;碰撞能量范围:50~80V。对母离子进行二级扫描,根据二级质谱碎片,对其进行b和y离子分析,从而验证新多肽的氨基酸残基序列,见图1~12。
实施例3新多肽TRF1~TRF12对HaCAT细胞增殖的促进作用
(1)细胞接种:选用对数生长期的细胞,消化后计数。取所需细胞数,加入适量培养基稀释至到1×104/mL。用排枪吹打均匀细胞,然后将细胞液加到96孔板中(每孔100μL),置于CO2培养箱中孵育。
(2)加药:待细胞贴壁后移除旧培养基,对照组加入空白培养基,阳性对照组加入EGF,药物组分别加入不同浓度的TRF1~TRF12,孔板四周加入PBS,实验设置6个复孔,置于培养箱中孵育48h。
(3)加MTT:吸除旧培养基,加入配置好的MTT(避光),每孔30μL,然后置于培养箱中继续孵育4h,形成甲瓒晶体。
(4)测定OD值:移除MTT,每孔中加入100μL DMSO溶液,使甲瓒溶解充分,用多功能酶标仪(检测波长:595nm)检测吸光度。计算细胞存活率,重复实验至少3次以上。
试验结果如图13所示,新多肽TRF1~TRF12在较低浓度(0.08~2.00μg/mL)下对HaCAT细胞具有显著的促增殖作用(细胞增殖率114±5%~135±3%)。
实施例4新多肽TRF1~TRF12对HSF细胞迁移的促进作用
(1)细胞接种及加药:将Transwell小室置于超净台中紫外灭菌30min,然后置于24孔板中。细胞消化后计数,用培养基稀释细胞至密度为2×105个/mL。将待测药物TRF1~TRF12及阳性对照药加到细胞液中,稀释成不同浓度的含药细胞液。给药组于上室加入100μL含药细胞液,空白组加入100μL细胞液,然后于各个小室加入600μL空白培养基,置于培养箱中培养。
(2)固定、染色及拍照:孵育结束后,弃去培养基,用PBS清洗,用4%多聚甲醛固定下室细胞(大约30min)。固定后用PBS清洗两次,在每孔下室加入600μL染色液染色20min。回收结晶紫,PBS清洗,用棉签小心抵住上室内膜,擦去没有迁移成功的细胞,风干后用荧光倒置显微镜拍照,每个小室随机拍取5个区域,最后用GraphPad Prism 6.0统计分析细胞平均迁移个数。
试验结果显示,新多肽TRF1~TRF12(2μg/mL)能明显促进HSF细胞的迁移,作用48h后,药物组平均迁移细胞数在578±9~396±14个,明显高于对照组132±10个,具有统计学意义(P<0.05),结果如图14所示。
实施例5新多肽TRF7对小鼠皮肤创伤的修复作用
选取15只8~10周雄性昆明小鼠(购自广东省动物中心)分笼饲养。随机分为对照组,阳性药组(康复新液),TRF7低剂量组(0.5mg/mL)和TRF7高剂量组(2.0mg/mL)。将小鼠麻醉,背部脱毛、消毒后,利用直径为6mm的打孔器于小鼠背部裸露皮肤处行打孔,切除一圆形皮肤,包括表皮和真皮层,将伤口部位贴上透明透氧敷料,起到屏蔽和保护作用。对照组给予生理盐水,给药时轻轻揭起透明透氧敷料,滴加0.1mL药液滴于伤口,再贴上新的敷料。连续给药10d,每天给药两次,每天测量伤口面积大小变化,给药10天后处死小鼠。按公式创伤愈合率%=(S1-Sn)/S1(S1为第一天创伤面积,Sn为第n天创伤面积)计算创面愈合率。结果见表1。
表1小鼠创伤愈合率统计结果
注:与模型组相比,*P<0.05有显著性差异
试验结果表明,新多肽TRF7能明显促进小鼠皮肤创伤的愈合,与对照组比较具有显著性差异,且优于康复新液。
实施例6新多肽TRF7对小鼠皮肤烫伤的修复作用
选取15只8~10周雄性昆明小鼠(购自广东省动物中心)分笼饲养,自由取食,实验前一天停止进食。用质量分数13%Na2S溶液涂抹脱毛,将20g的砝码置于水浴锅内一同加热至沸,维持10min,然后用钳子夹住砝码上端,迅速放在小鼠皮肤上5s,稍加压力,形成烫伤面积为2cm×2cm的浅Ⅱ度烫伤模型。次日,伤口滴加不同溶度的TRF7(0.5mg/mL或2.0mg/mL)、生理盐水和康复新液各0.1mL,每日换药一次。于3、5、10天观察创面愈合情况。按实施例5的方法计算创面愈合率。结果见表2。
表2小鼠烫伤愈合率统计结果
注:与模型组相比,*P<0.05有显著性差异
试验结果表明,新多肽TRF7能明显促进小鼠皮肤烫伤的愈合,与对照组比较具有显著性差异,且优于康复新液。
实施例7新多肽TRF7对大鼠应激性胃溃疡的保护作用
试验方法:取体重180~210g雄性SD大鼠20只(购自广东省动物中心),随机分为空白组、模型组、硫糖铝组(1g/kg,阳性药组)、TRF7低剂量组(12.5mg/kg)和TRF7高剂量组(50.0mg/kg)。给药组灌胃给药,连续7天。造模前24h禁食不禁水,除对照组外,采用束缚水浸法造模,将各组大鼠固定于鼠板,头向上垂直浸泡在恒温(20℃)水槽中8h,水面与大鼠剑突齐平。应激造模结束后,将大鼠颈椎脱臼处死,剖腹,结扎幽门。向胃内灌注体积分数10%甲醛溶液2mL,结扎贲门,取出胃体置于甲醛溶液中固定15min。沿胃大弯剪开,生理盐水冲洗后展开,观察胃黏膜损伤并计算胃溃疡指数。按Guth标准计算溃疡指数(UI):点状出血计为1分,线状出血长度<1mm为2分,1~2mm为3分,2~4mm为4分,>4mm为5分,宽度>1mm时分值×2。结果见表3。
表3大鼠溃疡指数统计结果
注:与模型组相比,*P<0.01有显著性差异
试验结果表明,新多肽TRF7对大鼠应激性胃溃疡具有明显保护作用,与模型组比较具有显著性差异,其保护效果优于阳性药硫糖铝。
实施例8新多肽TRF7对大鼠口腔溃疡的保护作用
试验方法:取体重180~210g健康SD大鼠15只(购自广东省动物中心),随机分为模型组、阳性药组(康复新液)、TRF7低剂量组(0.5mg/mL)和高剂量组(2.0mg/mL),采用化学灼烧法造模。取一直径为5mm的塑料管,将浸透95%苯酚溶液的小棉球置于塑料管一端,将棉花端固定于麻醉大鼠左侧颊黏膜上,保留60秒,用生理盐水清洗灼烧面。24h后观察,左侧实验区形成圆形溃疡,表面有黄白色脓肿,与周边分界明显,周围黏膜红肿充血,溃疡面直径>3mm者即造模成功。实验组、模型组和阳性药组的溃疡面分别滴加新多肽溶液、生理盐水和康复新液各0.1mL,每日给药两次。于1、3、5天后观察溃疡面愈合情况。溃疡积分标准如下:无充血、水肿溃疡面直径<1mm记1分;轻度充血、水肿,溃疡面直径1~2mm记2分;中度充血、水肿,溃疡面直径2~3mm记3分;重度充血、水肿溃疡面直径>3mm记4分。结果见表4。
表4大鼠口腔溃疡愈合积分
注:与模型组相比,*P<0.05
试验结果表明,新多肽TRF7能够明显促进大鼠口腔溃疡的愈合,与模型组比较具有显著性差异,且优于康复新液。
实施例9新多肽TRF1~TRF12的急性毒性实验
试验方法:取体重18~22g的昆明种小鼠(购自广东省动物中心),随机分组,每组10只,灌胃不同剂量的TRF1~TRF12,根据小鼠存活情况,计算半数致死剂量LD50。半数致死量按如下公式计算:半数致死剂量(mg/kg)=(小鼠一半死亡时的剂量/对应小鼠的体重)。
试验结果:新多肽TRF1~TRF12在500mg/kg的给药剂量下,均未观察到小鼠死亡和明显不良反应,说明其毒性都较低,LD50大于500mg/kg(表5)。
表5 TRF1~TRF12对小鼠的急性毒性作用
实施例10新多肽TRF7的皮肤安全性评价
受试人群:年龄18~55岁之间,女性10人,男性10人,总计20人。受试者皮肤健康,无皮肤病过敏史,符合受试者志愿入选标准。
试验方法:选用合格的斑贴器,以封闭式斑贴试验方法,将多肽TRF7约0.020~0.025mL(2mg/mL)滴于斑贴器内,外用专用胶带贴覆于受试者背部,24小时后去除试验品,分别于去除后0.5、6、12、24、48小时观察皮肤反应,按照《化妆品卫生规范》中皮肤反应分级标准记录其结果。
试验结果:本试验20名受试者通过斑贴试验,在0.5、6、12、24、48小时观察皮肤反应,均未观察到皮肤不良反应,说明本发明的新多肽TRF7均对皮肤使用安全。
实施例11片剂的制备
取多肽TRF7 0.1g,乳糖40g,淀粉浆60g,硬脂酸镁0.2g,混合,过筛,干燥后压片。每片含TRF7 0.001g。
实施例12注射剂的制备
多肽TRF7 0.1g,丙二醇50g,研磨,再加100mL注射用水稀释,混匀,然后加入氯化钠9g,溶解后再加入注射用水至1000mL,调pH值5.5~6.5,滤过,灌封,灭菌,即得1000支注射用针剂。
实施例13固体脂质纳米颗粒的制备
取多肽TRF7 0.1g,依次加入大豆卵磷脂500mg,溶于25mL乙醇中,另取硬脂酸200mg和大豆卵磷脂500mg溶于25mL环己烷中,混合搅拌均匀;于37℃恒温水浴中减压旋转蒸发除去有机溶剂,使药物及辅料在烧瓶壁形成均匀脂质薄膜,于真空干燥器中放置过夜,除尽有机溶剂;另取聚乙二醇单硬脂酸酯3750mg,搅拌溶解在175mL水中,加入上述薄膜中,超声10min,定容至250mL,得淡黄色透明溶液;将此溶液冷冻干燥可得冻干粉。用球磨机研磨24小时,制得粒径均匀的纳米粒,混匀并分装。每袋含TRF7 0.001g。
实施例14控释胶囊的制备
多肽TRF7 0.1g,依次加入乳糖40g和淀粉浆10g,直接装到旋转制粒机/包衣器制备颗粒,将稀释到质量分数为15%固体的塑化乙基纤维素包衣剂悬浮液喷雾到多肽颗粒的旋转床上。在喷雾期间,用泊洛沙姆188制成的分散体载体膜包衣颗粒,形成平均颗粒度大约为450μm的持续释放的颗粒。混匀装入胶囊,每个胶囊含TRF7 0.001g。
实施例15外用凝胶膏剂的制备
称取甘油2g,依次加入聚丙烯酸0.75g和氢氧化铝0.1g,充分混合,加入多肽TRF70.2g,在真空条件下充分搅拌混合得①;另外称取纯化水5g,将乳酸0.06g、羧甲基纤维素钠0.1g溶解在水得②;将②加入到①中,在真空条件下充分搅拌,经交联反应得到含药膏体,将含药膏体涂布(控制含药膏体层厚度在1.0mm左右),裁剪成常规贴膏剂的规格,每贴含药物的量为0.02g,晾干,包装。
实施例16软膏剂的制备
硬脂醇40g与白凡士林45g在水浴中熔化,加热至75℃,备用。十二烷基硫酸钠1.46g,羟苯甲酯0.025g,羟苯丙酯0.015g,丙二醇13g,多肽TRF7 0.2g依次溶于水中,加热至75℃,将75℃硬脂醇与白凡士林加入,搅拌至冷,制成含TRF7 0.2%的软膏剂。
实施例17外用搽剂的制备
取多肽TRF7 0.1g,将其溶解于45mL蒸馏水中,过滤,滤液加入甘油5mL,氮酮1mL,蒸馏水补足体积至50mL,制成含TRF7 0.2%的外用搽剂。
实施例18创可贴的制备
称取硬脂酸聚羟氧40酯2g、聚山梨酯80 2g、泊洛沙姆188 1g、磷酸二氢钠0.3g、羟苯乙酯0.1g、纯化水50mL,在130℃条件下灭菌30min~60min,降温至30~40℃,搅拌均匀得①;另称取轻质液状石蜡10g、十六醇0.5g、十八醇0.5g、白凡士林3g、单硬脂酸甘油酯1g,灭菌后在30~40℃保温,得②;取多肽TRF7 0.1g溶解于50mL蒸馏水中,过滤,加入①中,搅拌,得③。将②缓慢加入③中,加入15%乙醇3g,快速搅拌,调pH 6.0,保持温度在45℃,高速剪切,乳化5min,搅拌冷却至30~35℃,制得类白色均匀乳膏液;将膏液投到加料板上,用涂布机涂布于内垫上,低温烘干(45℃),按需要尺寸裁剪,得涂药的内垫;将涂药的内垫粘在基布中部,将离型纸附于基布两端的粘接部。
实施例19面霜的制备
取多肽TRF7 0.1g备用,将26号白油1g,十八醇1g,硬脂酸1g,单甘脂0.5g,350硅油0.05g,GTCC 0.5g,尼泊金甲酯0.03g混合,加热到90℃,制成第一半成品;在第一半成品中加入去离子水4g、多肽TRF7 0.1g、平平加-20 0.3g、甘油0.5g,并加热到80℃,形成第二半成品;将第二半成品在80℃下进行2次均质(转速3000转/分钟,时间10分钟)后继续搅拌30分钟,冷却到45℃形成膏霜状后加入0.005g卡松,混匀,分别制得含1%多肽的面霜。
实施例20面膜的制备
多肽TRF7 0.1g溶解于10mL去离子水中,过滤,滤液与甘油润湿的卡波姆0.3g混合,加入三乙醇胺,调节pH值为6~7,均匀涂布于面膜纸,制成每张含有多肽0.01g的面膜。
实施例21爽肤水的制备
取0.1g TRF7,配置为0.2mg/mL的水溶液;将甘油5g加入透明质酸1g中分散,加水溶解,搅拌均匀,得透明质酸溶液;将海藻糖1g和尿囊素1g用水溶解后与上述透明质酸溶液混合,搅拌均匀,得混合溶液;将多肽溶液、D-泛醇1g、燕麦β-葡聚糖10g、1,2-戊二醇10g和防腐剂0.05g依次加入上述混合溶液,加水搅拌均匀,即得。
实施例22乳液的制备
(1)将0.1g TRF7配置为0.2mg/mL的水溶液;
(2)将0.05g透明质酸钠加水溶解分散,搅拌均匀,得透明质酸溶液;
(3)将甘油5g、丁二醇3g、海藻糖2g、尿囊素0.2g、增稠剂0.1g,用水溶解,加热至75℃;
(4)将霍霍巴籽油2g、氢化聚癸烯3g、聚二甲基硅氧烷2g、辛酸/癸酸三甘油酯3g、乳化剂3g加热至75℃,搅拌均匀;
(5)将步骤(3)制得的产物快速倒入步骤(4)制得的产物中,恒温均质3~5min,冷却;
(6)冷却至60℃以下,加入(1)、(2),均质;冷却至40℃以下,加入防腐剂和香精,即得乳液。
实施例23洁面啫喱的制备
将0.1g TRF7配置为0.2mg/mL的水溶液;将上述多肽溶液、甘油2.5g、癸基葡糖苷3g、椰油酰苹果氨基酸钠3g、月桂醇聚醚硫酸酯钠1.5g、增溶剂0.1g、香精0.05g依次加入水中搅拌,再加入增稠剂0.5g,搅拌至完全溶胀即可得洁面啫喱。
实施例24新多肽乳液的美容效果评价
1.1试验品:本发明实施例22制备的多肽乳液
1.2受试人群:年龄18~55岁之间,女性18人,男性12人,总计30人。受试者皮肤有皱纹,色斑,色泽暗哑,以及皮肤上留有微创、手术后疤痕等不美观因素。
1.3测试方法:受试者皮肤清洁后,将实施例22制备的乳液涂覆到皮肤上,观察和感受使用效果。
1.4测试评估结果如下表6:
表6新多肽TRF7乳液的试用(8周)反馈总结表
受试者表示,使用新多肽TRF7乳液产品,可提高肌肤含水量,增强肌肤保湿力和皮肤弹性,提高肌肤水嫩润泽感。该产品具有美白,去皱纹、疤痕和色斑的效果。受试者未出现过敏现象。
实施例25新多肽面膜的美容效果评价
1.1试验品:本发明实施例20制备的面膜。
1.2受试人群:年龄18~58岁之间,女性21人,男性9人,总计30人。受试者脸部皮肤有皱纹,色斑,色泽暗哑,以及皮肤上留有微创、手术后疤痕等不美观因素。
1.3测试方法:受试者脸部清洁后,将实施例20制备的新多肽面膜涂覆于面部,每日一次,观察和感受使用效果。
1.4测试评估结果如下表7:
表7新多肽TRF7面膜的试用(8周)反馈总结表
受试者表示,使用新多肽TRF7面膜产品,可提高肌肤含水量,增强肌肤保湿力和皮肤弹性,提高肌肤水嫩润泽感。产品具有美白,去皱纹、疤痕和色斑的效果。受试者未出现过敏现象。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
SEQUENCE LISTING
<110> 暨南大学
<120> 一类促进组织修复的新多肽及其应用
<130> 1
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF1
Ala Cys* Pro Asn Tyr Pro Tyr Cys* Tyr
1 2 3 4 5 6 7 8 9
<210> 2
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF2
Ala Ala Cys* Pro Asn Tyr Pro Tyr Cys* Tyr
1 2 3 4 5 6 7 8 9 10
<210> 3
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF3
Ala Ala Ala Cys* Pro Asn Tyr Pro Tyr Cys* Tyr
1 2 3 4 5 6 7 8 9 10 11
<210> 4
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF4
Val Ala Ala Cys* Pro Asp Tyr Pro Tyr Cys* Ser
1 2 3 4 5 6 7 8 9 10 11
<210> 5
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF5
Ala Ala Ala Cys* Pro Asp Tyr Pro Tyr Cys* Ser
1 2 3 4 5 6 7 8 9 10 11
<210> 6
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF6
Ala Cys* Pro Asn Tyr Pro Tyr Cys* Gly Ser Tyr Ala Pro Leu Gly Tyr His Val Arg
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
<210> 7
<211> 28
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF7
Ala Cys* Pro Asn Tyr Pro Tyr Cys* Gly Ser Tyr Ala Pro Leu Gly Tyr His Val Arg
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Glu Tyr Pro Ala Gly Val Ser Ala Ala
20 21 22 23 24 25 26 27 28
<210> 8
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF8
Ala Ala Cys* Pro Asp Tyr Pro Tyr Cys* Ser
1 2 3 4 5 6 7 8 9 10
<210> 9
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF9
Gly Ala Cys* Pro Asp Tyr Pro Tyr Cys* Tyr
1 2 3 4 5 6 7 8 9 10
<210> 10
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF10
Ala Ala Ala Cys* Pro Asp Tyr Pro Tyr Cys* Tyr
1 2 3 4 5 6 7 8 9 10 11
<210> 11
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF11
Ala Cys* Pro Asn Tyr Pro Tyr Cys* Gly Ser Tyr
1 2 3 4 5 6 7 8 9 10 11
<210> 12
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 促进组织修复的多肽
<400> TRF12
Ala Cys* Pro Asn Tyr Pro Tyr Cys* Gly Ser Tyr Ala Pro Leu Gly Tyr
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Claims (9)
1.一种促进组织修复的新多肽,其特征在于,所述新多肽的结构如下所示:
,
其中:R1 =H、Ala、Gly、Ala-Ala-或Val-Ala-;
R2 = Asn 或Asp;
R3 = Ser、Tyr 、-Gly-Ser-Tyr、-Gly-Ser-Tyr-Ala-Pro-Leu-Gly-Tyr、-Gly-Ser-Tyr-Ala-Pro-Leu-Gly-Tyr-His-Val-Arg或-Gly-Ser-Tyr-Ala-Pro-Leu-Gly-Tyr-His-Val-Arg-Glu-Tyr-Pro-Ala-Gly-Val-Ser-Ala-Ala;
所述新多肽的结构如TRF1~TRF12中任一项所示:
。
2.权利要求1所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用。
3.根据权利要求2所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用,其中,所述的产品为药品或日化用品。
4.根据权利要求3所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用,其中,所述的药品或日化用品中含有新多肽的一种或多种,或其药学上可接受的盐,余量为辅料或其它可配伍的药物。
5.根据权利要求3所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用,其中,所述的药品或日化用品为片剂、外用搽剂、胶囊剂、注射剂或脂质体纳米粒。
6.根据权利要求3所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用,其中,所述的药品或日化用品为控释剂、凝胶膏剂、软膏剂、贴剂、霜剂、洗涤剂、乳液、或爽肤水。
7.根据权利要求3所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用,其中,所述的药品或日化用品为凝胶。
8.根据权利要求4所述的新多肽在制备促进组织修复或改善皮肤美感的产品中的应用,其中,所述的辅料为溶剂、崩解剂、矫味剂、防腐剂、着色剂或粘合剂。
9.一种药物组合物,其特征在于,含有权利要求1所述的新多肽和药学上可接受的载体。
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