CN109125709B - Trail突变体在制备治疗痤疮药物中的应用及一种制剂 - Google Patents
Trail突变体在制备治疗痤疮药物中的应用及一种制剂 Download PDFInfo
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Abstract
本发明提供了TRAIL突变体在制备治疗痤疮药物中的应用及一种制剂,其中TRAIL突变蛋白包括TRAIL‑Mu3、TRAIL‑MuR5、TRAIL‑MuR6、TRAIL‑MuR5S4TR和TRAIL‑MuR6S4TR 5种。实验研究证实,上述5种TRAIL突变体在体外能抑制原代培养皮脂腺细胞增殖,并诱导其凋亡,且它们的生物活性大大强于对照药异维A酸。上述突变体蛋白可以加工制备成乳霜剂、软膏剂、凝胶剂、喷剂、面膜等多种形式。动物实验证明,上述5种TRAIL突变体制剂能够明显抑制和减轻痤疮动物模型的皮损;对痤疮人体,具有较强的治疗作用。
Description
技术领域
本发明涉及药物技术领域,尤其涉及多种不同结构的TRAIL突变体在制备治疗痤疮药物中的应用及一种制剂。
背景技术
1.痤疮的发病与危害
痤疮是一种毛囊皮脂腺的慢性炎症性皮肤病,是皮肤科的常见病、多发病,尤其在青春期男、女的发病率最高。国内调查,在12~15岁年龄组中约有85%的个体在不同时期发病。国外报告,青春发育期的痤疮发生率女性达到90.6%,男性达100%。痤疮对青少年的心理和社交的影响超过了哮喘和癫痫。鉴于痤疮的流行广泛,而本病又主要在面部,出现粉刺、丘疹、囊肿,甚至个别患者形成瘢痕疙瘩,损毁人的面容,给人带来痛苦和烦恼,影响患者的生活质量。
痤疮在不同患者人群中的表现有差异,可根据皮损性质将痤疮分为3度和4级,其中轻度(I级):仅有粉刺;中度(II级):炎性丘疹;中度(III级):脓疱;重度(IV级):结节、囊肿。痤疮的治疗应该根据其分级选择相应治疗药物和手段。外用维A酸类药物是目前轻度痤疮的单独一线药物,中重度痤疮的联合用药以及痤疮维持治疗的首选药物。目前常用的外用维A酸类药物包括第一代维A酸类药物如0.025%~0.1%的全反式维A酸乳霜或凝胶和异维A酸凝胶,第三代维A酸类药物如阿达帕林凝胶和他扎罗汀等。由于痤疮的慢性过程和易复发的临床特点,无论哪一级痤疮,均没有一劳永逸的特效疗法。
痤疮的主要病理变化为:(1)皮脂腺分泌过多;(2)毛囊漏斗部角化过度与脱屑减少,形成黑头粉刺;(3)痤疮丙酸杆菌移生进入毛囊;(4)机体的炎症免疫反应。
2.TRAIL与痤疮发病和病理
肿瘤坏死因子相关凋亡诱导配体(Tumor necrosis factor-related apoptosis-inducing ligand,TRAIL)为肿瘤坏死因子(Tumor necrosis factor,TNF)超家族的成员,其基因序列分别于1995年由Wiley等人和1996年由Pitti等人独立克隆获得,后者将其命名为凋亡素2配体(Apo2Ligand,Apo2L)。后来的研究证实,Apo2L与TRAIL实质上是同一种蛋白质,因此习惯上可将其称为Apo2L/TRAIL。TRAIL的功能首先是作为生物体先天性或获得性免疫的调节剂,其次在细胞外源性凋亡途径中作为免疫监视发挥抗肿瘤作用。TRAIL的最大优点是可以选择性地诱导多种肿瘤细胞凋亡而对正常细胞几乎没有毒性。研究资料表明,无论在体外还是体内,Apo2L/TRAIL对于各种来源的人肿瘤细胞系,包括结(直)肠癌、肺癌、乳腺癌、前列腺癌、胰腺癌、肾癌、中枢神经系统肿瘤、甲状腺癌、淋巴瘤、白血病以及多发性骨髓瘤等都具有诱导凋亡的作用。
异维A酸是被FDA批准的,唯一能够改变痤疮病情的药物。A.M Nelson等通过研究发现,虽然异维A酸(13-cis RA)治疗痤疮的全部作用机制尚不清楚,但13-cis RA诱导参与凋亡的脂细胞中的关键基因。单独应用重组人TRAIL(rhTRAIL)蛋白处理可增加SEB-1脂细胞的TUNEL阳性染色,而TRAIL siRNA显著降低了TUNEL阳性SEB-1脂细胞对13-cis RA治疗应答的百分比。与基线相比,异维A酸治疗1周后痤疮患者皮肤中TRAIL表达增加,且TRAIL表达局限于皮脂腺。与脂细胞不同,TRAIL蛋白在正常人表皮角质形成中对13-cisRA的反应没有增加,rhTRAIL也没有诱导角质形成细胞凋亡。实验研究表明,TRAIL是13-cisRA脂细胞特异性凋亡作用的关键。
B.C.Melnik根据已有的研究提出以下假说。这个假说认为痤疮是一种PI3K-AKt-MTORC1驱动的皮脂腺毛囊过度增殖性疾病,伴有TRAIL介导的死亡信号受损。已有实验表明,抗痤疮剂异维A酸可增强TRAIL诱导的死亡信号,从而调整寻常性痤疮皮脂腺毛囊存活和死亡信号的紊乱平衡。假说认为,TRAIL是痤疮发病机制中的潜在关键因素。TRAIL不仅可以终止痤疮脂细胞的促存活信号,还通过诱导总蛋白和I型转谷酰胺酶参与晚期表皮分化。TRAIL诱导的Caspase激活诱导调节表皮增殖和分化的关键转录因子P63的降解。
3.TRAIL不能用于痤疮治疗
尽管rhTRAIL能够诱导体外传代皮脂腺细胞SEB-1的凋亡,但rhTRAIL用于痤疮的治疗仍存在无法逾越的障碍。其原因如下:(1)现有的永生化皮脂腺细胞(包括SEB-1和SZ95细胞)均为SV40大T抗原基因转染细胞,不能完全代表自然生长状态下的皮脂腺细胞,永生化皮脂腺细胞培养被视为痤疮发病机制关键特征不恰当的模型。(2)rhTRAIL在体外诱导SEB-1细胞凋亡的作用比较弱。经TUNEL染色分析,在SEB-1细胞中,12ng/ml和100ng/ml的rhTRAIL使SEB-1细胞的凋亡率分别增加到23%和35%,均未达到半数抑制的效果。(3)缺乏动物模型的支持。痤疮的动物模型已经比较成熟,常用的痤疮动物模型包括兔耳药物外擦模型、大鼠耳皮内丙酸杆菌注射模型、豚鼠腹部人角质蛋白皮内注射模型等。(4)rhTRAIL的理化特性和药代动力学特性缺陷使其并不适合于皮肤外用给药。由于毛囊、皮脂腺的主要结构均位于真皮层,rhTRAIL不能直接透过表皮作用于皮脂腺和毛囊的深部,故其在实际应用中不能发挥作用。活性的rhTRAIL为非共价结合的三聚体形式,为带正电荷的碱性蛋白质,而皮肤表面为PH5~6的酸性环境,蛋白在该条件的稳定性差。rhTRAIL生物半衰期短,其作用严格依赖于其与细胞表面的受体DR4和DR5的结合。以上的不足和缺陷决定了rhTRAIL单独用于痤疮的治疗仍然存在巨大障碍。
发明内容
针对TRAIL用于痤疮治疗具有的现实缺陷和不足,本申请在原已申请专利保护的5种TRAIL突变体的结构、制备方法和肿瘤药物用途领域外进行了拓展,将上述突变体蛋白用于治疗痤疮的药物中。因为,首先,上述5种TRAIL突变体具有高于野生型rhTRAIL的体内外生物活性,与细胞表面的DR4/DR5受体具有更强的亲和力,能够在细胞膜表面聚集和重分布,有利于其发挥作用。其次,上述蛋白突变体均具有细胞膜穿透功能,有助于克服细胞和组织屏障,可作用于真皮层的皮脂腺和毛囊结构,发挥抑制皮脂腺细胞功能的作用。第三,上述蛋白理化性质更为稳定,生物代谢半衰期更长,更有利于发挥作用。
鉴于此,本申请提供了TRAIL突变体在制备治疗痤疮药物中的应用。
进一步地,所述TRAIL突变体为:TRAIL穿膜肽样突变体蛋白TRAIL-Mu3(WO2015103894A1)、及TRAIL-MuR5(WO2016138618A1)、TRAIL-MuR6(WO2016138625A1)和TRAIL穿膜肽融合蛋白TRAIL-MuR5S4TR(WO2017066962A1)和TRAIL-MuR6S4TR(WO2017066963A1)等5种TRAIL突变体。
进一步的,上述TRAIL突变体在体外能抑制原代培养皮脂腺细胞的增殖并诱导凋亡,其抑制活性大大强于野生型rhTRAIL和阳性对照药异维A酸。
本申请还提供了一种制剂,所述制剂包括TRAIL突变体和药学上可接受的辅料。
进一步的,上述制剂的剂型乳霜剂、软膏剂、凝胶剂、喷剂、面膜等多种形式,本申请同时优化并完善了相关制剂的制备工艺。
进一步地,所述TRAIL突变体在所述制剂中的质量百分含量为0.1%~1.0%。
进一步地,所述TRAIL突变体在所述制剂中的质量百分含量为0.25%~0.5%。
进一步地,所述制剂适用于一天两次对患者施用。
本申请提供了TRAIL突变体在制备治疗痤疮药物中的应用。实验结果表明:TRAIL突变体在体外能抑制原代培养皮脂腺细胞的增殖并诱导凋亡,其抑制活性大大强于野生型rhTRAIL和阳性对照药异维A酸;本申请提供的制剂,在多种不同痤疮动物模型上具有明显的抑制和减轻痤疮的作用,而且在不少于30例痤疮人体试验中优于复方异维A酸乳膏具有良好的治疗作用。
附图说明
图1 TRAIL-Mu3和TRAIL-MuR5S4TR乳膏的生产工艺;
图2 TRAIL-Mu3和TRAIL-MuR5S4TR凝胶的生产工艺。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明优选实施方案进行描述,但应当理解,这些描述只是为了进一步说明本发明的特征和优点,而不是对本发明权利要求的限制。
实施例1 TRAIL-Mu3和TRAIL-MuR5S4TR乳膏的制备
1.处方
TRAIL-Mu3 | 5g |
尿囊素 | 10g |
维生素E | 20g |
凡士林 | 125g |
单甘油脂肪酸酯 | 25g |
甘油 | 62.5ml |
丙二醇 | 62.5ml |
十二烷基硫酸钠 | 10g |
硬脂醇 | 90g |
羟苯乙酯 | 1g |
纯化水 | 适量 |
制成 | 1000g |
2.制备工艺
2.1油相的制备(4种成分)
取硬脂醇、凡士林及单甘油脂肪酸加热熔融,加入维生素E,置于油相罐中,边搅拌边加热至80℃,使之完全熔融并搅拌均匀,得油相备用。
2.2水相的制备(5种成分)
在水相罐中加入甘油、丙二醇、十二烷基硫酸钠及水加热,加入尿囊素溶解,加入羟苯乙酯边搅拌边加热至80℃,直至溶解,得水相备用。
2.3乳化
将TRAIL-Mu3或TRAIL-MuR5S4TR加入适量纯化水中,并保存备用。将水相加入油相中快速搅拌(转速900r/min)15min,待温度降至20℃时加入TRAIL-Mu3或TRAIL-MuR5S4溶液,快速(转速900r/min)搅拌15min,混匀,分装即成。
3.工艺流程图
工艺流程图如说明书附图1所示。
按上述处方和生产工艺,分别制得TRAIL-Mu3乳膏和TRAIL-MuR5S4TR乳膏各95支(10g/支),有效成分含量为0.5%。
实施例2 TRAIL-Mu3和TRAIL-MuR5S4TR凝胶的制备
1.处方
2.制备工艺
将卡波姆与聚山梨醇酯80和300ml纯化水混合,将氢氧化钠用100ml纯化水溶解后加入上液搅匀,再将尼泊金溶于乙醇后缓慢加入搅匀,再加入丙二醇,搅匀。在上述混合物中加入预先溶解于100ml水的5g的TRAIL-Mu3或TRAIL-MuR5S4TR,加水至总量共1000g,搅匀,即得。
3.工艺流程图
工艺流程如说明书附图2所示。
按上述处方和生产工艺,分别制得TRAIL-Mu3凝胶和TRAIL-MuR5S4TR凝胶各98支(10g/支),有效成分含量为0.5%。
实施例3 TRAIL-Mu3和MuR5S4TR等5种蛋白对原代培养人皮脂腺细胞的生长抑制作用
1.人皮脂腺细胞的分离和原代培养
从皮肤科手术患者的正常人头皮组织中分理出皮脂腺细胞。正常人头部皮肤新鲜标本依次用PBS、70%酒精清洗一次,置于培养液中(加2%胎牛血清、抗生素混合物)。去除皮下脂肪,将皮肤切成0.5cm×0.5cm大小。加中性蛋白酶,置于4℃冰箱内过夜。目视显微镜下剥离表皮层,用镊子分离15个以上皮脂腺,置于具有胶原涂层的细胞培养皿(6cm直径,皿内培养液约为1.25ml),置于5%CO2培养箱中37℃培养,2~3天更换一次培养液,待细胞长满后进行传代或进行TRAIL-Mu3和TRAIL-MuR5S4TR增殖抑制活性检测。
2.CCK8检测TRAIL-Mu3和MuR5S4TR等5中蛋白对皮脂腺细胞的抑制作用(1)接板:取常规培养处于对数生长期的人皮脂腺细胞,0.25%的胰蛋白酶将培养瓶中的细胞消化,用Sebomed基础培养液稀释细胞,配置成单个细胞悬液,充分混匀后调整细胞浓度至5×105/ml,以每孔100ul的量接种于96孔板,置37℃、5%CO2饱和湿度培养箱中培养。
(2)加药:接板6h后,用倒置显微镜观察细胞完全贴壁后,分别在细胞培养板中加入100ulSebomed培养基配制的不同浓度的异维A酸或TRAIL-Mu3或MuR5S4TR等蛋白溶液。上述药物的上样起始浓度均为1ug/ml,进行10个梯度稀释上样。每个浓度设双复孔,继续培养48h。
(3)测活:培养48h后,超净台中操作培养板。吸弃旧的培养液,分别向每孔加入18ul Sebomed培养基和20ul CCK溶液,置37℃、5%CO2饱和湿度下继续培养1h。取出培养板,在离心机中1000rpm离心5分钟,置酶联检测仪上,设定检测波长为490/630nm,检测各孔吸光度(OD)值,按下列公式计算每种药物对皮脂腺细胞的生长抑制率。
皮脂腺细胞生长抑制率=[(Ac-As)/(Ac-Ab)]×100%
Ac:样品的OA/RLU(细胞+CCK8+待测化合物)
As:阴性对照的OA/RLU(细胞+CCK-8)
Ab:阳性对照的OA/RLU(细胞+CCK-8)
运用软件Graphpad Prism 5并采用计算公司log(inhibitor)vs normalizedresponse-Variable slope进行IC50曲线拟合并计算出各自的IC50值。
3.结果
本实验测试了异维A酸、TRAIL-Mu3、MuR5S4TR6等6个样品对原代培养人皮脂腺细胞的生长抑制作用,实验结果如下表所示:
表1.不同样品对皮脂腺细胞的生长抑制作用(ug/ml)
异维A酸和TRAIL-Mu3、MuR5S4TR等5个TRAIL类蛋白具有抑制皮脂腺细胞生长的作用,且5种TRAIL类蛋白的抑制活性比异维A酸强。初步机理研究显示,上述样品对皮脂腺细胞的生长抑制是通过诱导皮脂腺细胞凋亡而实现的。
实施例4 TRAIL-Mu3和TRAIL-MuR5S4TR乳膏对兔耳实验性角化模型的治疗作用
1.健康雄性新西兰兔(白色)64只,平均体重(2.5±0.2)kg,由四川实验动物中心提供,煤焦油原液(成都凯宜德公司)。
空白对照组8只不做任何处理,常规喂饲。余下56只兔,在兔耳内侧耳管开口处2.0×2.0cm范围内,左耳给予煤焦油原液0.5ml/次,1次/d,同时右耳作为自身对照给予纯净水0.5ml/次,1次/d,连续给药2周,予常规饲料。造模2周后,在涂药处作肉眼观察及组织学检查,以证实模型是否成功。每日除给药外,应肉眼观察局部给药处皮肤的变化、耳厚薄、硬度、粗糙程度、毛囊口有无黑色角栓等。
2.证实模型成功后,空白对照组(组1)不给药,余下56只兔随机分为7组,分别为组2(异维酸A乳膏)、组3(TRAIL-Mu3乳膏低剂量组,有效成分含量0.25%)、组4(TRAIL-Mu3乳膏中剂量组,0.5%)、组5(TRAIL-Mu3乳膏高剂量组,1%)、组6(MuR5S4TR乳膏低剂量组,0.25%)、组7(MuR5S4TR乳膏中剂量组,0.5%)、组8(MuR5S4TR乳膏大剂量组),分别在模型耳侧涂上上述药物0.25g/次,2次/d,连续2周。
3.按下表观察各组病理学组织变化,并每日观察各组动物临床症状,治疗组与阳性药物组均出现不同程度症状改善。症状改善包括表皮的变薄、毛囊内角化物的减少,毛囊漏斗部的恢复。
表2.兔耳痤疮模型病理组织学分级变化
4.异维A酸乳膏、TRAIL-Mu3乳膏各剂量组、MuR5S4TR乳膏各剂量组均能明显改善兔耳实验性痤疮模型的症状和病理变化,TRAIL-Mu3乳膏及MuR5S4TR乳膏中,高剂组明显优于异维A酸乳膏组。
实施例5 TRAIL-Mu3和TRAIL-MuR5S4TR乳膏对痤疮的治疗作用
1.诊断标准
纳入病例诊断标准参照《临床皮肤病学》,即皮损表现为白头粉刺、黑头粉刺、炎性丘疹、化脓丘疹,部分可见结节、囊肿、瘢痕形成,无自觉症状或局部有压痛,可伴有面部油脂分泌过多,毛孔扩大;好发于颜面部,尤其是前额、颊部、鼻部、下颌,其次是胸部和背部。多见于青年男女,各种皮损可同时存在。
2.病例纳入
共收集病例90例,随机分成两个治疗组(治疗组1和治疗组2)和对照组,其中治疗组1 30例,年龄18~39岁,病程4~58个月;治疗组2 30例,年龄19~37岁,病程4~56个月;对照组30例,年龄19-38岁,病程3~50个月。三组年龄、性别、病情及病情综合分级等情况无显著性差异(P>0.05)。
3.给药方法
治疗组1和2分别给予0.5%的TRAIL-MuR5S4和TRTRAIL-Mu3乳膏,每日2次,充分洁面后涂抹患处,厚涂,防止短时干燥,拭去;对照组给予0.1%的复方异维A酸乳膏,每日2次,用法同治疗组,疗程均为4周。
4.疗效判定
按照痤疮综合分级系统,以表格形式详细记录治疗前和治疗后1天、2天、3天、4天、5天、1周、2周、3周、4周各区皮损分值。
5.疗效标准
(1)痊愈:皮损消退,或仅留色素沉着,疗效指数>90%
(2)显效:皮损大部分消退,疗效指数在<90%与>60%之间
(3)有效:皮损部分消退,疗效指数在<60%与>20%之间
(4)无效:皮损消退不明显,疗效指数<20%
疗效指数:分别计算治疗前后的总分值,再用下列公式计算而得。
疗效指数=(治疗前总积分-治疗后总积分)/治疗前总积分×100%
痊愈率=痊愈例数/病例总数×100%
有效率=(痊愈例数+显效例数+有效例数)/病例总数×100%
6.评分方法
参照1997年,Doshi等人提出的痤疮综合分级系统(Global Acne GradingSystem,GAGS)。该法根据皮脂腺单位的密度、分布及大致面积,把好发部位分为6个区:Ⅰ区(前额):2;Ⅱ区(右颊):2;Ⅲ区(左颊):2;Ⅳ区(鼻部)1;Ⅴ区(下颌):1;Ⅵ区(胸或后背):3,数值为不同区域分值。同时将皮损严重程度分为5级,每级按皮损程度评分。无皮损:0;粉刺:1;丘疹:2;脓疱:3;结节、囊肿:4。总分值:先将每一区最严重皮损类型的分值与分区因素分值相乘即得每区分值,6个分区分值之和即为患者总的分值。
7.观察结果
观察结果见表3。
表3.两组痤疮治疗效果
结论:TRAIL-Mu3和TRAIL-MuR5S4TR乳膏对痤疮具有良好的治疗作用,其作用优于复方异维A酸乳膏。
实施例6 TRAIL-Mu3和TRAIL-MuR5S4TR凝胶对痤疮的治疗作用
1.诊断标准
纳入病例,诊断标准参照《临床皮肤病学》,即皮损表现为白头粉刺、黑头粉刺、炎性丘疹、化脓丘疹,部分可见结节、囊肿、瘢痕形成,无自觉症状或局部有压痛,可伴有面部油脂分泌过多,毛孔扩大;好发于颜面部,尤其是前额、颊部、鼻部、下颌,其次是胸部和背部。多见于青年男女,各种皮损可同时存在。
2.病例纳入
共收集病例93例,随机分成两个治疗组(治疗组1和治疗组2)和对照组,其中治疗组1 32例,年龄16-35岁,病程6-47个月;治疗组2 31例,年龄17-37岁,病程6-45个月;对照组30例,年龄19-36岁,病程3-40个月。三组年龄、性别、病情及病情综合分级等情况无显著性差异(P>0.05)。
3.给药方法
治疗组1和治疗组2分别给予0.25%的TRAIL-MuR5S4和TRTRAIL-Mu3凝胶,每日2次,充分洁面后涂抹患处,厚涂,防止短时干燥,拭去;对照组给予0.1%的复方异维A酸凝胶,每日2次,用法同治疗组,疗程均为4周。
4.疗效判定
按照痤疮综合分级系统,以表格形式详细记录治疗前和治疗后1天、2天、3天、4天、5天、1周、2周、3周、4周各区皮损分值。
5.疗效标准
(1)痊愈:皮损消退,或仅留色素沉着,疗效指数>90%
(2)显效:皮损大部分消退,疗效指数在<90%与>60%之间
(3)有效:皮损部分消退,疗效指数在<60%与>20%之间
(4)无效:皮损消退不明显,疗效指数<20%
疗效指数:分别计算治疗前后的总分值,再用下列公式计算而得。
疗效指数=(治疗前总积分-治疗后总积分)/治疗前总积分×100%
痊愈率=痊愈例数/病例总数×100%
有效率=(痊愈例数+显效例数+有效例数)/病例总数×100%
6.评分方法
参照1997年,Doshi等人提出的痤疮综合分级系统(Global Acne GradingSystem,GAGS)。该法根据皮脂腺单位的密度、分布及大致面积,把好发部位分为6个区:Ⅰ区(前额):2;Ⅱ区(右颊):2;Ⅲ区(左颊):2;Ⅳ区(鼻部)1;Ⅴ区(下颌):1;Ⅵ区(胸或后背):3,数值为不同区域分值。同时将皮损严重程度分为5级,每级按皮损程度评分。无皮损:0;粉刺:1;丘疹:2;脓疱:3;结节、囊肿:4。
总分值:先将每一区最严重皮损类型的分值与分区因素分值相乘即得每区分值,6个分区分值之和即为患者总的分值。
7.观察结果
观察结果见表4。
表4.两组痤疮治疗效果
结论:0.25%的TRAIL-Mu3和TRAIL-MuR5S4TR凝胶对痤疮具有良好的治疗作用,其作用优于复方异维A酸凝胶。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明披露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (8)
1.TRAIL穿膜肽突变体在制备用于治疗痤疮药物中的应用,所述TRAIL穿膜肽突变体为:TRAIL穿膜肽样突变体蛋白TRAIL-Mu3、TRAIL-MuR5、TRAIL-MuR6或TRAIL穿膜肽融合蛋白TRAIL-MuR5S4TR、TRAIL-MuR6S4TR。
2.权利要求1所述应用,其特征在于,TRAIL穿膜肽突变体在体外能抑制原代培养皮脂腺细胞的增殖并诱导凋亡。
3.TRAIL穿膜肽突变体在制备用于治疗痤疮面膜中的应用,所述面膜包括TRAIL穿膜肽突变体和药学上可接受的辅料,所述TRAIL穿膜肽突变体为:TRAIL穿膜肽样突变体蛋白TRAIL-Mu3、TRAIL-MuR5、TRAIL-MuR6或TRAIL穿膜肽融合蛋白TRAIL-MuR5S4TR、TRAIL-MuR6S4TR。
4.权利要求3所述应用,其特征在于,所述TRAIL穿膜肽突变体在所述面膜中的质量百分含量为0.1%~1.0%。
5.权利要求4所述应用,其特征在于,所述TRAIL穿膜肽突变体在所述面膜中的质量百分含量为0.25%~0.5%。
6.TRAIL穿膜肽突变体在制备用于治疗痤疮药物中的应用,所述药物的剂型为乳霜剂、软膏剂、凝胶剂、喷剂,所述TRAIL穿膜肽突变体为:TRAIL穿膜肽样突变体蛋白TRAIL-Mu3、TRAIL-MuR5、TRAIL-MuR6或TRAIL穿膜肽融合蛋白TRAIL-MuR5S4TR、TRAIL-MuR6S4TR。
7.权利要求6所述应用,其特征在于,所述TRAIL穿膜肽突变体在所述剂型中的质量百分含量为0.1%~1.0%。
8.权利要求7所述应用,其特征在于,所述TRAIL穿膜肽突变体在所述剂型中的质量百分含量为0.25%~0.5%。
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