CN117838686A - 三棱内酯b在制备预防或治疗痤疮药物中的应用 - Google Patents
三棱内酯b在制备预防或治疗痤疮药物中的应用 Download PDFInfo
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- CN117838686A CN117838686A CN202410007265.8A CN202410007265A CN117838686A CN 117838686 A CN117838686 A CN 117838686A CN 202410007265 A CN202410007265 A CN 202410007265A CN 117838686 A CN117838686 A CN 117838686A
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Abstract
本发明公开了三棱内酯B在制备预防或治疗痤疮药物中的应用。本发明中的三棱内酯B,能显著抑制炎性介质IL‑1β、TLR2和caspase1蛋白表达水平,减轻痤疮丙酸杆菌诱导的炎症反应,可作为预防或治疗痤疮的可选择性药物,填补了三棱内酯B在治疗痤疮或其他皮肤炎症上的空白。
Description
技术领域
本发明涉及医药技术领域,具体为涉及三棱内酯B在制备预防或治疗痤疮药物中的应用。
背景技术
黑三棱,又称三棱、光三棱、红蒲根,属黑三棱科。黑三棱系黑三棱科植物Sparganium stoloniferum Buch-Ham的块茎,其去皮干燥块茎为中药三棱,味辛、苦、性平,具有祛瘀通经、破血消症等功效。三棱内酯B,又称黑三棱内酯B,是从黑三棱块茎上的提取物,经核磁共振波谱和X射线晶体学鉴定其结构为8,5-二羟基-4-苯基-5,2′-氧化异香豆素,分子式为C15H8O5。
申请号为200910033686.3,发明名称为“抗动脉粥样硬化的黑三棱内酯B化合物及其制备方法”首次公开了黑三棱内酯B的提取方法,将黑三棱的干燥块茎粉碎、乙醇浸泡、乙醇水溶液加热回流、浓缩、柱层析纯化得到黑三棱内酯B的纯品。但,由于从植物块茎中提取,获得黑三棱内酯B的纯品相对较少,无法满足大范围推广的需求。申请号为201310405476.9,发明名称为“黑三棱内酯B及其关键中间体的合成”进一步公开了黑三棱内酯B的化学合成方法。
三棱内酯B是一种具有氧杂蒽酮和异香豆素类的多酚化合物,其中氧杂蒽酮具有抗氧化、免疫调节、降低胆固醇等功能,而异香豆素具有抗凝血、抗肿瘤、抗炎作用,近年来发现其可用于多种疾病的治疗。申请号为201110110987.9、发明名称为“黑三棱内酯B作为TLR2和TLR4拮抗剂在制药中的应用”从作用机理的角度阐述了黑三棱内酯B作为选择性TLR2和TLR4拮抗剂,用于治疗动脉粥样硬化、缺血再灌注、肿瘤、慢性炎性肠道疾病、糖尿病、阿尔茨海默氏症、慢性阻塞性肺疾病、脓毒症、系统性红斑狼疮、风湿性关节炎等与TLR信号传递相关的炎症疾病或者自身免疫过强疾病。申请号为201410172538.0,发明名称为“三棱内酯B用于制备治疗脑出血药物的用途”具体公开了三棱内酯B可以明显提高脑出血小鼠生存率,显著降低脑出血小鼠神经功能缺损评分,显著降低脑出血小鼠脑水肿含量,显著抑制血肿周围组织的炎症反应,显著提高血红蛋白诱导小胶质细胞损伤的神经元存活率,可以用于治疗脑出血。申请号为201611048855.7,发明名称为“三棱内酯B在制备抗肿瘤转移药物中的应用”,具体公开了三棱内酯B能抑制LPS诱导的小鼠黑色素瘤细胞B16的迁移和侵袭,能显著降低LPS诱导的小鼠黑色素瘤肺和肝转移能力,减少黑色素瘤转移灶的形成和数量,降低血清、肺和肝组织炎性因子的表达,是一种潜在的抗肿瘤转移药。申请号201510978843.3,发明名称为“一种含有3-甲基-1-苯基-2-吡唑啉-5-酮的组合物在脑血管病中的应用”,具体公开了3-甲基-1-苯基-2-吡唑啉-5-酮或其药学上可接受的盐和黑三棱内酯B或其药学上可接受的盐复配后的组合物可用于治疗脑血管病。
痤疮,是皮肤科最常见的毛囊皮脂腺慢性炎症性疾病,皮损好发于面颊、额部和下颌,亦可累及躯干,如前胸部、背部及肩胛部,以粉刺、丘疹、脓疱、结节、囊肿及瘢痕为特征,常伴皮脂溢出,好发于青春期男女,发病率无性别差异,也常称之为“青春痘”。
痤疮发病率高,可导致炎症后色素沉着甚至遗留永久性瘢痕,对患者心理及社交产生了严重不良影响。痤疮的发生主要与雄激素水平及皮脂分泌过多、毛囊皮脂腺导管堵塞、细菌感染和炎症反应等因素密切相关。
进入青春期后,因身体发育,导致人体内雄激素水平迅速升高,促进皮脂腺发育并产生大量皮脂,皮脂与脱落的表皮组织混合后所形成的混合物堵塞毛孔,引发痤疮;此外,毛囊皮脂腺导管的角化异常造成导管堵塞,皮脂排出障碍,也会形成角质栓即微粉刺,进而引发痤疮;同时,因皮脂溢出导致毛囊中多种微生物尤其是痤疮丙酸杆菌大量繁殖,痤疮丙酸杆菌产生的脂酶分解皮脂生成游离脂肪酸,游离脂肪酸刺激毛囊及毛囊周围发生炎症反应,痤疮丙酸杆菌还通过调节其它相关受体的表达而加剧不同程度的炎症。
目前,根据痤疮的发病机制,药物治疗痤疮应抑制皮脂腺分泌、消炎、抑菌等,痤疮治疗的常用方法及副作用如下:
(1)局部外用药物维A酸类:这类药物主要调节表皮形成细胞分化、改善毛囊皮脂腺导管角化等;但该药物会出现皮肤刺激性;
(2)过氧化苯甲酰:过氧化物外用后可缓慢释放出苯甲酸,具有杀菌作用;
(3)抗生素类(克林霉素、红霉素、氯霉素等):杀菌效果好,但外用抗生素易导致耐药性;
(4)壬二酸等:可减少皮肤表面、毛囊的菌群,对痤疮丙酸杆菌有抑制作用,但会导致局部红斑和刺痛;
(5)异维A酸:目前最有效的抗痤疮药物,可减少油脂分泌、抑制异常角化和粉刺形成,但这类药物有明确的致畸作用,女性患者在治疗前1个月、治疗期间和治疗后三个月内应严格避孕;
(6)糖皮质激素:适用于严重结节性痤疮等,长期大量使用会导致激素性痤疮或毛囊炎,会导致病情更加复杂;
(7)物理治疗如光动力疗法等:通过光动力效应破坏痤疮丙酸杆菌及减轻炎症反应,会出现疼痛、结痂、色沉等。
目前,众多研发者考虑以中药组分来抑制或治疗痤疮。申请号为201910676883.0,发明名称为“一种治疗痰瘀互结型痤疮的中药制剂及其制备方法”公开了郁金、柴胡、三棱等构成的中药制剂用于治疗痰瘀互结型痤疮;申请号为201510736208.4,发明名称为“一种治疗囊肿性痤疮的药物”具体公开了大生地、蒲公英、夏枯草、炒三棱等构成的药物用于治疗囊肿性痤疮;申请号为201811607494.4、发明名称为“一种治疗脾虚湿蕴型痤疮的中药组合物及其制备方法”具体公开了桂枝、丹皮、茯苓、三棱、夏枯草等组成的中药组合物用于治疗脾虚湿蕴型痤疮。申请号为202310624807.1、发明名称为“一种三棱提取物复合物及其制备方法与应用”具体公开了由三棱提取物、黄连提取物、光果甘草提取物、基料组成的三棱提取物复合物在抑制皮肤痤疮上的应用。
综上,三棱内酯B作为选择性TLR2和TLR4拮抗剂,可用于治疗动脉粥样硬化、缺血再灌注、肿瘤、慢性炎性肠道疾病、糖尿病、阿尔茨海默氏症、慢性阻塞性肺疾病、脓毒症、系统性红斑狼疮、风湿性关节炎,但尚未发现可用于治疗痤疮;尽管三棱或三棱提取物与其他中药组分复配可用于治疗痰瘀互结型、囊肿性、脾虚湿蕴型痤疮,但因中药组分为多种药物的混合,尚不清楚具体作用机理,三棱或三棱提取物对治疗痤疮具体所起作用不得而知,作为纯化产物的三棱内酯B对痤疮是否具有治疗作用更是无从知晓。因此,目前尚无文献报告,可将三棱内酯B用于痤疮的预防与治疗。
发明内容
有鉴于现有技术的上述缺陷,本发明提供三棱内酯B在制备预防或治疗痤疮药物中的应用,填补三棱内酯B在治疗痤疮方面的空白;另外,本发明还提供了三棱内酯B或含有三棱内酯B的组合物在制备预防或改善痤疮的化妆品中的应用,将三棱内酯B用于化妆品中,用于预防或改善痤疮。
本发明的第一方面,提供三棱内酯B或其药学上可接受的盐或含有三棱内酯B的药物组合物在制备预防或治疗痤疮药物中的应用。
三棱内酯B,其结构式如下:
三棱内酯B,是一种TLR2阻断剂,而产生痤疮是由于痤疮丙酸杆菌的大量繁殖,痤疮丙酸杆菌产生的脂酶分解皮脂生成游离脂肪酸,游离脂肪酸刺激毛囊及毛囊周围发生炎症反应。痤疮丙酸杆菌为革兰氏阳性、无鞭毛的杆菌,其菌体细胞壁成分可被TLR2识别,痤疮丙酸杆菌诱导机体的免疫应答主要是通过TLR2来介导。三棱内酯B,作为TLR2阻断剂,通过抑制TLR2介导的细胞信号通路发挥预防、改善或治疗痤疮的作用。
如下组分可以与三棱内酯B复配,复配的方式可以为将如下组分与三棱内酯B以一定方式混合后,用于皮肤表面或者体内;也可以将如下组分与三棱内酯B先后作用于人体,以提高预防或治疗痤疮的效果。
1)大黄素,化学式为C15H10O5,能够显著抑制皮脂腺斑的增长、皮脂腺细胞的增殖,也能显著抑制皮脂腺细胞脂质合成与分泌,达到抑制皮脂腺分泌旺盛的作用,从而治疗痤疮、脂溢性脱发等皮脂腺分泌旺盛的疾病。
2)雪衣藻寡糖,具有调节菌群作用,具体为抑制有害菌的生长与增殖和促进益生菌的生长与增殖,有害菌除金黄色葡萄球菌外还包括但不限于痤疮丙酸杆菌和马拉色菌等,益生菌除表面葡萄球菌外还包括但不限于双歧杆菌等。雪衣藻寡糖还可以促进皮肤表皮相关细胞的增殖和迁移,舒缓化学刺激物如表面活性剂等引发的皮肤炎症,抑制炎症促进因子TNF-α、IL-1β、IL-8mRNA的表达,促进炎症抑制因子IL-13的表达;通过促进细胞自噬的途径来缓解皮肤炎症。
3)黄连总生物碱和/或川木香挥发油,黄连总生物碱中主要活性成分小檗碱具有调控TLRs表达,抑制炎症因子释放的作用,川木香挥发油是川木香的重要生物活性成分,亦具有抗炎、抗菌等作用,黄连总生物碱与川木香挥发油二者结合,能显著改善肿胀,减轻表皮层角化程度,降低炎症反应,对痤疮具有预防和治疗效果。
4)高车前素,化学名称为4’,5,7-三羟基-6-甲氧基黄酮,是一种黄酮类化合物,广泛存在新疆雪莲、青蒿和大车前等植物中,具有抗炎、抗氧化、抗突变等多种生物活性和药理作用,尤其对于玫瑰痤疮具有优异的抑制作用。
5)视黄酰基植物鞘氨醇,是维A酸与植物鞘氨醇通过缩合得到的产物,在修复皮肤屏障、促进皮肤组织愈合、抗衰老、抗炎、抗痤疮等方面具有优异的效果。
在一些实施方式中,所述药物为抑制TLR2介导的炎症反应的药物。
在一些实施方式中,所述药物为抑制TLR2介导的信号通路,降低炎性介质IL-1β、TLR2和caspase1蛋白表达水平,从而抑制痤疮炎症反应的药物。
在一些实施方式中,三棱内酯B的剂量与抑制痤疮炎症反应的作用呈正相关。
在一些实施方式中,所述预防或治疗痤疮药物以三棱内酯B作为主要成分。
本发明的第二方面,提供一种预防或治疗痤疮的药物,所述药物是由三棱内酯B或其药学上可接受的盐或含有三棱内酯B的药物组合物及药学上可接受的辅料制成的制剂。
在一些实施方式中,所述药物非经胃肠道给药。
在一些实施方式中,所述药物通过硅质海绵骨针给药。
采用申请号202310560808.4中的硅质海绵骨针,将三棱内酯B包裹在硅质海绵骨针的表面,在不过分增加硅质海绵骨针直径的前提下,同样能形成微通道的基础上对相关位置的微环境进行改善。
在一些实施方式中,所述药物为注射针剂、搽剂、纳米粉剂、膏剂或凝胶。
此处的注射针剂为采用水光针注射,水光针作为一种注射类的护肤疗法,借助专门的仪器“水光枪”,将需要的美容针剂注射到紧贴表皮下的真皮层。水光针主要是以注射玻尿酸为主,注射后能让皮肤变得水润、光亮,水光针也可以注射其他营养成分,如Ⅰ型胶原蛋白、Ⅱ型胶原蛋白、Ⅶ型胶原蛋白、生物多糖胶、羊胎素提取液、左旋C原液、葡萄籽提取物等;可以注射氨基酸类物质,如甘氨酸、丙氨酸、脯氨酸、羟赖氨酸、羟脯氨酸等;可以注射辅酶类物质,如Q10、烟酰胺和维生素B2等;可以注射抗敏类物质,如奥亭敏、甘草酸二钾、粉防已提取物、鼠李糖、生物多糖胶-2、积雪草提取物、光果甘草根提取物、母菊花提取物、迷迭香提取物、神经酰胺等;可以注射抗氧化类物质,如花青素、超氧化物歧化酶、水溶性维生素E、茶多酚、视黄醇、谷胱甘肽还原酶、谷胱甘肽过氧化物酶、谷胱甘肽S-转移酶、茶多酚等;可以注射防晒类物质,如甘光草定、芸香叶苷、虎杖苷;可以注射保湿类物质,如丙三醇、海藻糖、泛醇、1,3-丁二醇、1,2-丙二醇、1,2-己二醇、甜菜碱等。
搽剂,是一种在皮肤表面揉搽或用软刷涂抹的外用液体制剂。搽剂也可施于绒布上覆盖皮肤表面,由于揉搽,搽剂中的一些药物成分可产生透皮吸收。不同用途的搽剂分散媒不同,保护和滋润皮肤的搽剂多用油为分散媒,例如骨质宁涤剂;止痛和抗炎的搽剂多用二甲亚砜稀释液为分散媒,可增加穿透作用,例如复方地塞米松搽剂,也有用冰醋酸作为分散媒的搽剂,如米诺地尔搽剂。搽剂中也可以加入助溶剂,如甘油、植物油、甲醇、丙二醇、乙醇等;也可以加入粘合剂,如玉米淀粉、聚维酮、聚乙二醇、甲基纤维素、羟丙甲纤维素、羟丙纤维素、羧甲基纤维素钠、乙基纤维素、明胶、阿拉伯胶、海藻酸钠等;还可以加入稳定剂,如海藻酸钠、枸橼酸、预胶化淀粉、聚维酮、羧甲基纤维素钠、羟丙基纤维素、甘油、羟丙甲纤维素等。本申请中的三棱内酯B可以以二甲亚砜稀释液为分散媒,其中混入助溶剂和/或稳定剂。
纳米粉剂,同样的用量,更多的活性物成分与皮肤的接触面积更广,治疗效果更好。纳米粉剂可以喷涂的方式施用于皮肤表面,也可以加入溶剂分散后,作为搽剂,涂抹于皮肤表面。
膏剂,为基质和药物制成的外用半固体或近似固体的剂型,起保护创面、润滑皮肤和局部治疗作用,也可以透过皮肤或黏膜起全身治疗作用。膏剂分软膏剂和硬膏剂,软膏剂为药物、中药细粉、中药提取物与适宜基质混合制成的半固体外用剂型;硬膏剂,为药物和粘性基质,滩涂于裱背材料形成。软膏剂中的基质有:O/W乳剂基质、W/O型乳剂基质、吸水性软膏基质、动物油脂、植物油、烃类基质。软膏中还加入一些附加剂,如加入表面活性剂,增加药物的溶解度及皮肤的润湿性,帮助药物分散,促进药物穿透;如加入渗透促进剂,二甲基亚砜、氮酮等加速药物穿透皮肤,增加局部用药的渗透性,增加药物的经皮吸收;其他的一些附加剂还有防腐剂、助溶剂、乳化剂、抗氧剂、增稠剂、皮肤渗透促进剂等。本申请中的三棱内酯B与软膏用的基质混合,可以制成软膏剂,同时加以二甲基亚砜,既可以增加三棱内酯B的分散效果,也可以加速药物的穿透效果,增强药物的经皮吸收。
凝胶,或名凝胶制剂,需要将药物成分与载体组装为药物-载体复合物,之后加入赋形成分而制成。常用的药物载体有丝素蛋白、纤维蛋白、球蛋白等,常用的赋形成分包括壳聚糖及其衍生物、纤维素及其衍生物、明胶、透明质酸钠、聚乙烯吡咯烷酮、环糊精、海藻酸钠等。
本发明的第三方面,提供三棱内酯B或含有三棱内酯B的组合物在制备具有预防或改善痤疮的化妆品中的应用。
在一些实施方式中,所述的化妆品选择为护肤品。
作为优选的实施例,所述化妆品包括洁面乳、爽肤水、化妆水、乳液、面膜、面霜、精华液、精油。
与现有技术相比,本发明具有如下有益效果:
(1)本发明中的三棱内酯B,能显著抑制炎性介质IL-1β、TLR2和caspase1蛋白表达水平,减轻痤疮丙酸杆菌诱导的炎症反应,可作为预防或治疗痤疮的可选择性药物,填补了三棱内酯B在治疗痤疮或其他皮肤炎症上的空白。
(2)本发明中的三棱内酯B,来自于中药三棱,安全性高;此外,由于三棱内酯B也可用于化学合成,避免了中药材提取三棱内酯B提取量较少的问题,便于实现工业化生产和三棱内酯B的广泛推广。
(3)本发明中的三棱内酯B,可采用多种制剂形式,比如微针注射、纳米粉剂喷涂等,三棱内酯B进入细胞,抑制痤疮丙酸杆菌的炎症反应,以减轻痤疮症状。多种制剂形式,使得患者可根据自身情况灵活选择给药形式,避免了皮肤患者常规的单一涂抹方式。
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明,以充分地了解本发明的目的、特征和效果。
附图说明
图1是本发明采用western blot法测定不同实验条件下TLR2、IL-1β、Caspase-1蛋白的印迹图;
图2是本发明采用western blot法测定不同实验条件下TLR2蛋白表达水平的柱状统计分析图,其中*指有显著差异(P<0.05),**指有极显著差异(P<0.01);
图3是本发明采用western blot法测定不同实验条件下IL-1β蛋白表达水平的柱状统计分析图,其中ns指无明显差异,*指有显著差异(P<0.05),**指有极显著差异(P<0.01);
图4是本发明采用western blot法测定不同实验条件下Caspase-1蛋白表达水平的柱状统计分析图,其中ns指无明显差异,*指有显著差异(P<0.05),**指有极显著差异(P<0.01)。
具体实施方式
为了使发明实现的技术手段、创造特征、达成目的和功效易于明白了解,下结合具体图示,进一步阐述本发明。但本发明不仅限于以下实施的案例。
须知,本说明书所附图式所绘示的结构、比例、大小等,均仅用以配合说明书所揭示的内容,以供熟悉此技术的人士了解与阅读,并非用以限定本发明可实施的限定条件,故不具技术上的实质意义,任何结构的修饰、比例关系的改变或大小的调整,在不影响本发明所能产生的功效及所能达成的目的下,均应仍落在本发明所揭示的技术内容得能涵盖的范围内。
三棱内酯B作为选择性TLR2和TLR4拮抗剂,可用于治疗动脉粥样硬化、缺血再灌注、肿瘤、慢性炎性肠道疾病、糖尿病、阿尔茨海默氏症等疾病,但尚未发现可用于治疗痤疮;有文献报道三棱或三棱提取物与其他中药组分复配可用于治疗痤疮,但因涉及的组分较多,作用机理不清晰,三棱内酯B所起到的作用无从知晓,三棱内酯B是否对痤疮具有治疗作用不得而知,目前尚无将三棱内酯B用于抗痤疮药物的研究。
本申请的发明人在对三棱内酯B治疗疾病的范围进行研发的过程中,偶然发现三棱内酯B对痤疮丙酸杆菌引起的炎症反应具有抑制作用,可用于抗痤疮药物中。
三棱内酯B抑制痤疮丙酸杆菌引起的炎症反应的测定过程:
1、培养THP-1单核细胞,THP-1单核细胞购自上海碧云天生物技术有限公司,所使用的培养基为含10%FBS(胎牛血清)的1640培养液,其中1640培养液(货号C11875500BT)和FBS(货号10091148)的品牌均为Thermo;
2、将2*106个THP-1单核细胞均分至六孔细胞培养板中,同时加入100ng/ml的佛波酯(PMA),诱导分化24h,弃上清,换新鲜培养基;
3、随机分成6组,(1)正常组、(2)模型组、(3)三棱内酯B低剂量组、(4)三棱内酯B中剂量组、(5)三棱内酯B高剂量组、(6)DMSO组;
4、向(3)三棱内酯B低剂量组、(4)三棱内酯B中剂量组、(5)三棱内酯B高剂量组中分别加入溶解有三棱内酯B(购自sigma,货号为SML-1767)的DMSO溶液,其中(3)、(4)、(5)组的终浓度分别为5μM、50μM、100μM,向(6)DMSO组中加入相同量的DMSO,孵育4h;
5、4h后,向(2)、(3)、(4)、(5)组中分别按照THP-1单核细胞:痤疮丙酸杆菌量为1:100的比例加入高温高压蒸汽灭活的痤疮丙酸杆菌诱导炎症反应,48h后提取细胞总蛋白,采用western blot法测定TLR2、IL-1β、Caspase-1的蛋白表达水平,并计算显著性差异,其结果如图1、2、3、4所示。
如图1,第一行表示不同组中加入DMSO的体积;第二行表示不同组中加入三棱内酯B的浓度;第三行表示是否加入痤疮丙酸杆菌,—表示未加入痤疮丙酸杆菌,+表示加入痤疮丙酸杆菌;第四行表示TLR2蛋白的印迹;第五行表示IL-1β蛋白的印迹;第六行表示Caspase-1蛋白的印迹,第七行(Tublin)表示内参的印迹。图1分别对应六组中TLR2蛋白、IL-1β蛋白、Caspase-1蛋白的印迹,其中模型组(对应第2列)中加入了痤疮丙酸杆菌,其TLR2蛋白、IL-1β蛋白、Caspase-1蛋白印迹对应的灰度均较深,表明了TLR2蛋白、IL-1β蛋白、Caspase-1蛋白含量均较高;三棱内酯B低剂量组(对应第3列,5μM)、三棱内酯B中剂量组(对应第四列,50μM)、三棱内酯B高剂量组(对应第五列,100μM)中因三棱内酯B用量的增加,TLR2蛋白、IL-1β蛋白、Caspase-1蛋白印迹对应的灰度逐渐变浅,表明三棱内酯B的存在,对痤疮丙酸杆菌具有抑制作用,且随着三棱内酯B用量的增加,对痤疮丙酸杆菌的抑制作用逐渐增强,TLR2蛋白、IL-1β蛋白、Caspase-1蛋白的含量依次降低。
如图2、3、4,模型组(P.acnes)对应的TLR2、IL-1β、Caspase-1蛋白含量最高,说明加入痤疮丙酸杆菌后,痤疮丙酸杆菌诱导炎症反应,使得TLR2、IL-1β、Caspase-1的蛋白含量明显升高;而三棱内酯B低剂量组、三棱内酯B中剂量组、三棱内酯B高剂量组中对应的TLR2、IL-1β、Caspase-1的蛋白含量相对于模型组明显降低,表明三棱内酯B对痤疮丙酸杆菌诱导的炎症反应具有抑制作用,且随着三棱内酯B浓度的增加,TLR2、IL-1β、Caspase-1的蛋白含量降低明显,三棱内酯B的用量与抑制痤疮炎症反应的作用在一定范围内呈正相关。
另外,通过计算图2中三棱内酯B低剂量组、三棱内酯B中剂量组、三棱内酯B高剂量组中对应的TLR2蛋白含量相对于模型组的显著性差异水平,及模型组相对于对照组的显著性差异水平可知,模型组相对于对照组的P值为0.0062,三棱内酯B低剂量组相对于模型组的P值为0.031,三棱内酯B中剂量组相对于模型组的P值为0.0118,三棱内酯B高剂量组相对于模型组的P值为0.0085,可见,三棱内酯B低剂量组、三棱内酯B中剂量组、三棱内酯B高剂量组中对应的TLR2蛋白含量相对于模型组均具有显著性差异。
通过计算图3中三棱内酯B低剂量组、三棱内酯B中剂量组、三棱内酯B高剂量组中对应的IL-1β蛋白含量相对于模型组的显著性差异水平,及模型组相对于对照组的显著性差异水平可知,模型组相对于对照组的P值为0.0038,三棱内酯B低剂量组相对于模型组的P值为0.8478,三棱内酯B中剂量组相对于模型组的P值为0.0236,三棱内酯B高剂量组相对于模型组的P值为0.0171,可见,三棱内酯B中剂量组、三棱内酯B高剂量组中对应的IL-1β蛋白含量相对于模型组均具有显著性差异。
通过计算图4中三棱内酯B低剂量组、三棱内酯B中剂量组、三棱内酯B高剂量组中对应的Caspase-1蛋白含量相对于模型组的显著性差异水平,及模型组相对于对照组的显著性差异水平可知,模型组相对于对照组的P值为0.0241,三棱内酯B低剂量组相对于模型组的P值为0.1225,三棱内酯B中剂量组相对于模型组的P值为0.0381,三棱内酯B高剂量组相对于模型组的P值为0.0496,可见,三棱内酯B中剂量组、三棱内酯B高剂量组中对应的Caspase-1蛋白含量相对于模型组均具有显著性差异。
本发明提供了三棱内酯B或其药学上可接受的盐或含有三棱内酯B的药物组合物在制备预防或治疗痤疮药物中的应用。该药物为抑制TLR2介导的炎症反应的药物,通过抑制TLR2介导的信号通路,同时降低炎性介质IL-1β、TLR2、caspase1蛋白表达水平,从而抑制痤疮的炎症反应。
本发明还提供了一种预防或治疗痤疮的药物,该药物是由三棱内酯B或其药学上可接受的盐或含有三棱内酯B的药物组合物及药学上可接受的辅料制成的制剂。
三棱内酯B可单独作为活性成分,加以辅料,制备抗痤疮的药物。该药物可以采用非胃肠道给药的方式,如可以采用水光针将三棱内酯B注入表皮下的真皮层,也可以将三棱内酯B溶于DMSO中制成搽剂,涂抹在皮肤表面,或者将三棱内酯B制成纳米粉剂,喷涂于皮肤表面,此制剂方式下相同用量的三棱内酯B与皮肤的接触面积更广,治疗效果更优。
三棱内酯B也可与其他组分复配,来治疗痤疮。可参与复配的组分包括能够抑制皮脂腺斑增长、皮脂腺细胞增殖,抑制皮脂腺细胞脂质合成与分泌,达到抑制皮脂腺分泌旺盛作用的大黄素;或是具有调控TLRs表达,抑制炎症因子释放的黄连总生物碱;或是具有抗炎、抗菌作用的川木香挥发油;或是具有抗炎、抗氧化、抗突变等多种生物活性和药理作用的高车前素;或是在修复皮肤屏障、促进皮肤组织愈合、抗衰老、抗炎、抗痤疮等方面具有优异效果的视黄酰基植物鞘氨醇。
还提供了三棱内酯B或含有三棱内酯B的组合物在具有预防或改善痤疮的化妆品中的应用。三棱内酯B或含有三棱内酯B的组合物可以用于化妆品中,以预防或改善痤疮。此处的化妆品可以为护肤品,包括洁面乳、爽肤水、化妆水、乳液、面膜、面霜、精华液、精油。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案,皆应在由权利要求书所确定的保护范围内。
Claims (10)
1.三棱内酯B或其药学上可接受的盐或含有三棱内酯B的药物组合物在制备预防或治疗痤疮药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述药物为抑制TLR2介导的炎症反应的药物。
3.如权利要求2所述的应用,其特征在于,所述药物为抑制TLR2介导的信号通路,降低炎性介质IL-1β、TLR2和caspase1蛋白表达水平,从而抑制痤疮炎症反应的药物。
4.如权利要求3所述的应用,其特征在于,三棱内酯B的剂量与抑制痤疮炎症反应的作用呈正相关。
5.如权利要求1所述的应用,其特征在于,所述预防或治疗痤疮药物以三棱内酯B作为主要成分。
6.一种预防或治疗痤疮的药物,其特征在于,所述药物是由三棱内酯B或其药学上可接受的盐或含有三棱内酯B的药物组合物及药学上可接受的辅料制成的制剂。
7.如权利要求6所述的预防或治疗痤疮的药物,其特征在于,所述药物为注射针剂、搽剂、纳米粉剂、膏剂或凝胶。
8.三棱内酯B或含有三棱内酯B的组合物在制备具有预防或改善痤疮的化妆品中的应用。
9.如权利要求8所述的应用,其特征在于,所述的化妆品选择为护肤品。
10.如权利要求8所述的应用,其特征在于,所述的化妆品包括洁面乳、爽肤水、化妆水、乳液、面膜、面霜、精华液、精油。
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