CN116712428A - 三白草酮在制备治疗银屑病的药物中的应用 - Google Patents
三白草酮在制备治疗银屑病的药物中的应用 Download PDFInfo
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Abstract
本发明提供三百草酮在制备治疗银屑病的药物中的应用。属于药物技术领域。三白草酮可有效保护咪喹莫特诱导的小鼠银屑病样皮肤损伤，改善皮肤鳞屑、红斑、增厚和表皮异常分化，同时，三白草酮对皮肤局部和全身炎症也有一定的抑制效果，并抑制外周免疫器官脾脏和淋巴结固有免疫细胞的浸润。在体外细胞水平，三白草酮可抑制角质形成细胞炎症介质、趋化因子、分化等基因的转录，并调节巨噬细胞的M1/M2极化。三白草酮可用于治疗银屑病，可拓展三白草酮其他多种皮肤炎症性疾病上的潜在应用价值。此外，本发明还提供一种可用于银屑病的药物组合物，这种药物组合物含有三白草酮或其药学上可接受盐，可制作成各种剂型以应对不同类型、不同病程发展下的银屑病。
Description
技术领域
本发明涉及医药技术领域，具体涉及三百草酮在制备抗银屑病药物中的应用以及一种治疗银屑病的药物组合物。
技术背景
银屑病是一种常见的慢性难治性炎症性皮肤病，其典型临床表现为边界清楚的红斑、皮疹、斑块、鳞屑等。银屑病的发病机制复杂，病因尚未完全阐明。目前银屑病的治疗多以局部疗法为主，类固醇类激素类药物如丁酸氢化可的松、糠酸莫米松等在治疗银屑病中疗效确切，但长期使用副作用大，限制其广泛应用；激素替代药物如他克莫司、卡波三醇等，由于价格昂贵，也限制了其在临床上的应用。因此，寻找一种疗效好、副作用小的新药对于银屑病的治疗具有重要意义。
三白草(Saururus Chinensis(Lour.)baill)是三白草科多年生草本植物,在中国中南、西南地区均有分布。根据《中国药典》记载，三白草的干燥地上部分具有清热解毒、利尿消肿等功效，内服可用于小便不利，淋浙涩痛，尿路感染，白带，肾炎水肿的治疗；外用可治疮疡肿毒，湿疹。在韩国，三白草在民间也用于治疗水肿、黄疸、淋病等。目前，研究人员已从三白草中分离出黄酮、挥发油、生物碱、木脂素、鞣质等多种成分，并对其生物学活性进行了广泛研究。三白草酮(Sauchinone)是从三白草中分离纯化出的一种木脂素。分子式：C20H20O6，分子量：356，性状：白色晶体。
已有的研究发现三白草酮有抗炎、抗氧化、抗肿瘤等多种药理学活性，并且在溃疡性结肠炎、过敏性气道炎症、骨关节炎、肝癌等多种疾病动物模型中表现出一定的改善作用。然而，三白草酮对银屑病等皮肤炎症性疾病是否有保护作用尚未有报道。同时，三白草酮对巨噬细胞极化的调节作用也不明确。
发明内容
本发明的目的在于填补现有技术存在的缺点和不足，提供三百草酮在制备治银屑病药物中的应用以及一种治疗银屑病的药物组合物。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
三百草酮在制备治疗银屑病的药物中的应用。
三百草酮在制备治疗或改善皮肤鳞屑、红斑、增厚和表皮异常分化的药物中的应用。
三百草酮在制备治疗皮肤局部和全身炎症疾病的药物中的应用。
三百草酮的化学式为：
一种治疗银屑病的药物组合物，该组合物含有三百草酮或三百草酮在药学上可接受的盐类衍生物。
一种治疗银屑病的药物组合物，该组合物含有三百草酮或三百草酮在药学上可接受的盐类衍生物，以及药学上可接受的载体。
根据所述的一种治疗银屑病的药物组合物，其中所述的三百草酮或三百草酮在药学上可接受的盐类衍生物占药物制剂总质量的0.05％-99％，占组合物总质量的1％-5％。
根据所述的一种治疗银屑病的药物组合物，其中所述药物组合物的给药方式为局部给药，消化道给药或非消化道给药。
根据所述的一种治疗银屑病的药物组合物，其中所述的药物组合物的制剂形式为口服制剂、注射剂、栓剂或吸入剂。
根据所述的一种治疗银屑病的药物组合物，其中所述口服制剂为胶囊剂、微囊剂、丸剂、片剂、汤剂、颗粒剂、膏剂、分散粉末、露剂、口服液、滴丸剂、脂质体。
根据所述的一种治疗银屑病的药物组合物，其中所述注射剂为粉针剂或注射液。
优选的，三百草酮或三百草酮在药学上可接受的盐类衍生物。三百草酮可占药物制剂总质量的0.05％-99％，优选的，占组合物总质量的1％-5％。
优选的，药物组合物具有如下制剂形式：软膏剂、膜剂、气雾剂、注射剂、片剂、胶囊剂、滴丸剂、控释或缓释剂和纳米制剂。本发明可以组合物的形式通过经胃肠道给药，注射给药、呼吸道给药、皮肤给药、粘膜给药和腔道给药等方式施用于需要这种治疗的患者。用于口服时，可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等，或制成液体制剂如水、油悬浮剂，或其它液体制剂如糖浆、酏剂等；用于肠胃外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。
三白草酮软膏外用可有效保护咪喹莫特诱导的小鼠银屑病样皮肤损伤，改善皮肤鳞屑、红斑、增厚和表皮异常分化，同时，三白草酮对皮肤局部和全身炎症也有一定的抑制效果，并抑制外周免疫器官脾脏和淋巴结固有免疫细胞的浸润。在体外细胞水平，三白草酮可抑制角质形成细胞炎症介质、趋化因子、分化等基因的转录，并调节巨噬细胞的M1/M2极化。综上，以上研究明确了三白草酮外用乳膏在银屑病模型上有明显的药效，并有助于拓展三白草酮外用制剂其他多种皮肤炎症性疾病上的潜在应用价值，其应用前景广泛，具有较大的推广应用价值。
以下结合附图对本发明进行更进一步详细的说明。
附图说明
图1为局部涂抹三白草酮软膏对咪喹莫特诱导的小鼠银屑病样皮肤损伤愈合的影响；
图2为局部涂抹三白草酮软膏对咪喹莫特诱导的炎症反应的影响；
图3为局部涂抹三白草酮软膏对表皮异常分化的影响；
图4为三百草酮的化学式。
具体实施方式
为了更好地理解本发明的实质，下面用实施例的形式提供三百草酮治疗银屑病的药理实验结果，说明其在制药领域的新用途。同时必须说明，这些实施例仅用于说明本发明而不用于限制本发明的保护范围。
以下提供实施例1至实施例3以说明三百草酮对喹莫特诱导的小鼠银屑病模型皮肤损伤的影响，评价三白草酮对该模型的保护作用，并从巨噬细胞极化的角度，探究三白草酮治疗银屑病的潜在机制。
实施例1
咪喹莫特(IMQ)诱导的小鼠银屑病样皮肤损伤模型的构建及药物活性评价
实验方法：将雌性BALB/c小鼠按体重随机分为3组，包括正常组(Normal)、模型组(Vehicle)和给药组(4％三白草酮软膏)，每组6只小鼠。造模开始前2天，进行备皮。除正常组小鼠外，每日上午在备皮区涂抹62.5mg咪喹莫特，连续7日，诱导银屑病样皮肤损伤。给药组每日下午在备皮处给予药物治疗(62.5mg/只)，连续7日。造模和给药期间，每日监测小鼠体重，并根据“银屑病面积及严重程度指数(PASI)”评分标准，从鳞屑、皮肤增厚和红斑三个方面对小鼠背部皮肤损伤程度进行评分，评分标准如下：0分，无症状；1分；轻微症状；2分，中度症状；3分，中重度症状；4分，重度症状，并计算PASI总分，用以表征银屑病样皮肤损伤的发病情况和药物的治疗效果。实验第8日上午安乐死小鼠，收集血清、皮肤、脾脏、淋巴结。制备脾脏和淋巴结单细胞悬液，用于FACS分析。皮肤样品提取RNA或蛋白，用于后续检测。
实验结果：实验结果如图1所示。咪喹莫特可通过刺激TLR7/8激活天然免疫并进一步激发适应性免疫。小鼠外用咪喹莫特可以较好的模拟临床上银屑病病人皮肤的病理学表现。因此，咪喹莫特诱导的小鼠银屑病模型是临床前评估治疗银屑病药物药效的常用动物模型之一。使用咪喹莫特乳膏涂抹小鼠背部皮肤7天后，可见小鼠背部皮肤出现明显的鳞屑、增厚和红斑样病变，外用4％三白草酮软膏可显著改善这些病变症状，而对小鼠体重无显著性影响。以上结果表明外用三白草酮软膏保护咪喹莫特诱导的小鼠银屑病样皮肤损伤。
实施例2：
.三白草酮对咪喹莫特诱导的炎症反应的影响。
实验方法：实施例1实验结束时取动物皮肤组织匀浆和血清，采用ELISA试剂盒法检测炎症因子水平。按照说明书，用合适PH的稀释液稀释一抗，加入ELISA专用96孔酶标板中，每孔50μl，用封口膜密封酶标板，置于4℃孵育过夜。每孔加入100μl 1％BSA封闭液，密封平板，室温下放置1小时。每孔加入50μl样品或标准品，密封平板，室温下放置2小时。按照推荐的比例用封闭液稀释二抗，倒去标准品和样品，用PBST洗液洗4次，每孔加入50μl二抗溶液，密封平板，室温下放置1小时。按照1：500的比例，用封闭液稀释HRP，倒去二抗溶液，用PBST洗液洗4次，每孔加入50μl HRP溶液，密封平板，室温下放置1小时。每孔加入50μl底物TMB，避光静置适当时间，每孔加入50μl 2NH2SO4终止反应。450nm作为检测波长，570nm作为参比波长，测定吸光度值，根据标准曲线计算样品中所含细胞因子的浓度。
实验结果：实验结果如图2所示。通过ELISA检测咪喹莫特诱导银屑病样皮肤损伤的模型小鼠皮肤匀浆和血清中的细胞因子，结果显示，4％三白草酮软膏可降低皮肤匀浆中IL-6、IL-1β、IL-12、TNF-α、IFN-γ等促炎细胞因子水平，同时降低血清中IL-6、IL-12水平，增加血清中抗炎细胞因子IL-10水平。以上结果表明外用三白草酮软膏对咪喹莫特诱导的皮肤炎症和全身炎症均有一定的保护作用。
实施例3：
三白草酮对表皮异常分化的影响。
实验方法：实施例1实验结束时取动物皮肤组织匀浆，提取RNA。使用RNA simple总RNA提取试剂盒提取组织样品或细胞样品中的RNA，使用Nano Drop分光光度计检测RNA含量，使用HifairTM II 1st Strand cDNASynthesis SuperMix for qPCR试剂盒将RNA反转录为cDNA。配制样品-引物-SYBR Green反应体系，使用QPCR仪扩增目的基因，通过ΔΔCt值法进行相对定量分析。
实验结果：实验结果如图3所示。咪喹莫特诱导表皮基底层角质细胞不完全分化，表皮分化复合体(epidermal differentiation complex)是调控表皮终末分化的蛋白复合物，由loricrin(LOR)、filaggrin(FLG)、involucrin(IVL)等30余个基因编码。通过RT-qPCR检测皮肤组织中分化相关基因表达，结果显示模型组小鼠Lor、Flg、Ivl等基因的转录水平显著下降，而外用三白草酮软膏可促进这些基因转录，表明三白草酮可改善表皮异常分化。
为了更好地说明含有三百草酮的药物组合物的制作方法，以下提供一个实施例4。
实施例4：
三百草酮软膏剂的制备。
配方:
水相：蒸馏水1.9ml、甘油200mg、三乙醇胺10mg、对羟基苯甲酸甲酯10mg；
油相：十八醇50mg、硬脂酸280mg、液体石蜡50mg、主药共制成2500mg
制备:
水相：量取1.9ml蒸馏水，置于烧杯中加热至75℃，在热水中依次加入处方量的甘油、对羟基苯甲酸甲酯和三乙醇胺，搅拌溶解并混合均匀。
油相：量取处方量的十八醇、硬脂酸、液体石蜡置入另一烧杯，加热至85℃，搅拌溶解并混合均匀。将主药三百草酮加入油相介质中，充分搅拌，使主药混匀并溶解分散。不断搅拌水相化合物，同时将油相混合物边搅拌边缓慢地加入水相混合物中，按同一方向搅拌至冷凝，即得制剂。
综上所述，三百草酮在治疗银屑病中具有显著的药用价值。而以三百草酮为有效成分所制作的药物组合物，可以缓解银屑病患者的症状，提高患者的生活质量，从而具有良好的医用价值和市场经济价值。
而本具体实施例仅仅是对本发明的解释，其并不是对本发明的限制。本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本发明的权利要求范围内都受到专利法的保护。
Claims (10)
1.三百草酮在制备治疗银屑病的药物中的应用。
2.三百草酮在制备治疗或改善皮肤鳞屑、红斑、增厚和表皮异常分化的药物中的应用。
3.三百草酮在制备治疗皮肤局部和全身炎症疾病的药物中的应用。
4.一种治疗银屑病的药物组合物，其特征在于，该组合物含有三百草酮或三百草酮在药学上可接受的盐类衍生物。
5.一种治疗银屑病的药物组合物，其特征在于，该组合物含有三百草酮或三百草酮在药学上可接受的盐类衍生物，以及药学上可接受的载体。
6.根据权利要求4或5所述的一种治疗银屑病的药物组合物，其特征在于：所述的三百草酮或三百草酮在药学上可接受的盐类衍生物占药物制剂总质量的0.05％-99％，占组合物总质量的1％-5％。
7.根据权利要求4或5所述的一种治疗银屑病的药物组合物，其特征在于，所述药物组合物的给药方式为局部给药，消化道给药或非消化道给药。
8.根据权利要求4或5所述的一种治疗银屑病的药物组合物，其特征在于，所述的药物组合物的制剂形式为口服制剂、注射剂、栓剂或吸入剂。
9.根据权利要求4或5所述的一种治疗银屑病的药物组合物，其特征在于，所述口服制剂为胶囊剂、微囊剂、丸剂、片剂、汤剂、颗粒剂、膏剂、分散粉末、露剂、口服液、滴丸剂、脂质体。
10.根据权利要求4或5所述的一种治疗银屑病的药物组合物，其特征在于，所述注射剂为粉针剂或注射液。
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