CN117599080A - 一种含有透明质酸或其盐的药物组合物及其应用 - Google Patents
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Abstract
本发明公开了一种含有透明质酸或其盐的药物组合物及其应用,涉及医药技术领域。本发明包括低分子量微生物发酵透明质酸或其盐的组合物、辅料和甘油葡糖苷或其衍生物,低分子量微生物发酵透明质酸或其盐的组合物的添加量为0.001%‑15%,甘油葡糖苷或其衍生物的添加量为0.001%‑15%。本发明的药物组合物中使用的甘油葡糖苷主要来自于沙漠卷柏或耐盐蓝藻等植物,为植物提取物;成份低分子量微生物发酵透明质酸或其盐的组合物,已在医药、日化等领域使用多年;安全有效,对人体无毒副作用,可舒缓皮肤刺激感,可长期并大面积涂抹于皮肤表面使用,能够有效治疗Th2型皮肤炎症、特应性皮炎、银屑病、瘙痒和湿疹,适用范围较为广泛。
Description
技术领域
本发明属于医药技术领域,特别是涉及一种含有透明质酸或其盐的药物组合物及其应用。
背景技术
在免疫学中,根据细胞因子分泌的模式,CD4+T细胞可分为Th1和Th2细胞亚群。Th1细胞介导细胞免疫、细胞独行T细胞(CTL)、巨噬细胞活化及迟发超敏反应。Th2介导体液免疫、B细胞和嗜酸性粒细胞活化以及IgE的生成,其特征是IgE抗体水平升高和嗜酸性粒细胞增多。Th2型细胞主要分泌IL-4、IL-5、IL-6、IL-10、和IL3,称为Th2性细胞因子。正常情况下,Th1/Th2细胞处于相对平衡状态,维持机体正的细胞和免疫功能。但机体发生功能异常时,常表现出平衡偏向其中一方。在一些免疫疾病中,不同的疾病表现出Th1/Th2平衡漂移各不相同。当Th2细胞占优势时会引发Th2型相关疾病。Th2型炎症型皮肤病包括特应性皮炎、银屑病、慢性特发性荨麻疹(湿疹)、大疱性类天疱疮、结节性痒疹、疥疮、慢性特发性瘙痒、嗜酸性粒细胞增多性皮炎、虫咬皮炎等。研究表明TSLP是Th2型疾病的炎症级联反应的上游靶点,胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin,TSLP)是一种上皮源性细胞因子,与TSLP受体TSLPR结合发挥生物学功能。TSLP-TSLPR结合后通过激活树突状细胞使Th2向Th1偏移,使Th2细胞占优势,引发Th2型疾病。由于TSLP是炎症级联反应的上游靶点,因此有机会在其他下游的疾病相关细胞因子(如IL-4、IL-5、IL-13、IL-17和IgE)产生影响之前从源头上解决与此相关的疾病。
目前现有的针对Th2型皮肤疾病的外用药物中,主要是以糖皮质激素为主,其它效果较好的有治疗银屑病的本维莫德、抗人白介素-8单克隆抗体。由于大部分的Th2型皮肤疾病属于长期慢性病,所以需要长期用药。糖皮质激素在长期使用后,副作用大,会引起库欣综合征、消化道症状以及代谢紊乱,并加重炎症反应,对人体健康造成伤害,儿童更甚。由于是糖皮质激素对生长、代谢、以及免疫具有广泛作用,针对Th2型疾病缺乏明确对靶点,因此效果不佳。而其余外用药物,基本都有使用剂量、涂抹面积、累计使用时间等有关副作用限制,并且成本极高。
基于此,我们提出了一种含有透明质酸或其盐的药物组合物及其应用,为解决上述问题提供一种方案。
发明内容
本发明的目的在于提供一种含有透明质酸或其盐的药物组合物及其应用,以解决现有的问题:现有的针对Th2型皮肤疾病的外用药物中,主要是以糖皮质激素为主,其它效果较好的有治疗银屑病的本维莫德、抗人白介素-8单克隆抗体。由于大部分的Th2型皮肤疾病属于长期慢性病,所以需要长期用药。糖皮质激素在长期使用后,副作用大,会引起库欣综合征、消化道症状以及代谢紊乱,并加重炎症反应,对人体健康造成伤害,儿童更甚。由于是糖皮质激素对生长、代谢、以及免疫具有广泛作用,针对Th2型疾病缺乏明确对靶点,因此效果不佳。而其余外用药物,基本都有使用剂量、涂抹面积、累计使用时间等有关副作用限制,并且成本极高。
为解决上述技术问题,本发明是通过以下技术方案实现的:
本发明为一种含有透明质酸或其盐的药物组合物,包括低分子量微生物发酵透明质酸或其盐的组合物、辅料和甘油葡糖苷或其衍生物,所述低分子量微生物发酵透明质酸或其盐的组合物的添加量为0.001%-15%,所述甘油葡糖苷或其衍生物的添加量为0.001%-15%。
进一步地,所述低分子量微生物发酵透明质酸或其盐的组合物分子量为10Da-50KDa。
本发明的另一个目的是提供上述药物组合物的应用,一种含有透明质酸或其盐的药物组合物在制备用于治疗胸腺基质淋巴细胞介导的皮肤疾病药物中的应用。
进一步地,一种含有透明质酸或其盐的药物组合物在制备用于治疗特应性皮炎药物中的应用。
进一步地,一种含有透明质酸或其盐的药物组合物在制备用于治疗银屑病药物中的应用。
进一步地,一种含有透明质酸或其盐的药物组合物在制备用于治疗瘙痒症药物中的应用。
进一步地,一种含有透明质酸或其盐的药物组合物在制备用于治疗湿疹药物中的应用。
进一步地,一种含有透明质酸或其盐的药物组合物在制备用于治疗皮肤过敏药物中的应用。
本发明具有以下有益效果:
本发明的药物组合物中使用的甘油葡糖苷是由一分子甘油及一分子葡萄糖通过糖苷键连接而形成的糖苷类化合物,主要来自于沙漠卷柏或耐盐蓝藻等植物,为植物提取物;成份低分子量微生物发酵透明质酸或其盐的组合物,已在医药、日化等领域使用多年;经长期实践论证,安全有效,对人体无毒副作用,可舒缓皮肤刺激感,可长期并大面积涂抹于皮肤表面使用,能够有效治疗Th2型皮肤炎症、特应性皮炎、银屑病、瘙痒和湿疹,且能够应用于多种剂型中,可配制为液体剂型、凝胶剂型、膏霜剂型或乳液剂型,适用范围较为广泛。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例描述所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明的tslpr基因相对表达量柱形图;
图2为本发明的总运动距离舒缓典型图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
在本实施例中,一种含有透明质酸或其盐的药物组合物包括低分子量微生物发酵透明质酸或其盐的组合物、辅料和甘油葡糖苷或其衍生物;
而且低分子量微生物发酵透明质酸或其盐的组合物的添加量可以为0.001%-15%,甘油葡糖苷或其衍生物的添加量可以为0.001%-15%;
其中,甘油葡糖苷是由一分子甘油及一分子葡萄糖通过糖苷键连接而形成的糖苷类化合物;
在此,低分子量微生物发酵透明质酸或其盐的组合物分子量为10Da-50KDa;
本实施例中采用的甘油葡糖苷是从沙漠卷柏或耐盐蓝藻中提取的,不使用化学酶法催化合成的甘油葡糖苷;
将上述的药物组合物应用在制备用于治疗胸腺基质淋巴细胞介导的皮肤疾病、特应性皮炎、银屑病、瘙痒症、湿疹和皮肤过敏药物中。
经实验论证,本发明的药物组合物能够有效治疗TSLP(胸腺基质淋巴细胞)介导的免疫性皮肤病,或与此类疾病相关的皮肤瘙痒、红肿和皮肤炎症,如特应性皮炎、银屑病、瘙痒症、湿疹、皮肤过敏、肿瘤放化疗后皮肤不良反应等;
且能够应用于多种皮肤外用剂型中,可配制成粉末、凝胶、乳剂、糊剂等软膏剂、薄膜、可再水化冻干糊剂或海绵、可喷涂溶液、局部涂覆的粘合剂和储液槽系统、用于可涂布的中间体(例如薄膜和绷带)、膜基质或作为柔性聚合物基质。
实验一:
实验方法:
1.随机选取斑马鱼于6孔板中,每孔30尾。
2.水溶给予SLS建立斑马鱼皮肤炎症模型。
3.水溶给予本发明的药物组合物,同时设置正常对照组和模型对照组,每孔容量为3mL;三次生物学重复。
4.28℃条件下避光孵育18h。
5.提取各实验组斑马鱼总RNA,合成cDNA,利用q-PCR检测β-actin和目的基因的基因表达。
6.用β-actin作为基因表达的内参,计算目的基因的RNA相对表达量。
RNA相对表达量=2ΔΔC(t)
AC(t)=C(t)目的基因-C(t)β-actin
实验原理:
十二烷基磺酸钠(SLS)作用于机体后可能引发机体产生刺激反应,可导致水肿、红斑、瘙痒、疼痛等症状。对皮肤的刺激表型主要表现为皮肤炎症,炎症早期主要表现为毛细血管扩张、通透性亢进和水肿。刺激物进入斑马鱼体内,诱导炎症反应。TSLP(ThymicStromalLymphopoietin,胸腺基质淋巴细胞生成素)是一种多效性的细胞因子。TSLP发挥生物学作用主要是依赖于与受体的结合。TSLPR(TSLP受体)与TSLP亲和力很低,只有与IL7Rα(IL7受体α链)共同作用时才能形成高亲和力的受体复合物,进而形成三元复合物。这种三元复合物可引起JAK(非受体酪氨酸激酶)和STATs(信号转导和转录激活蛋白)磷酸化,从而启动炎症反应相关信号通路。可见,TSLP-TSLPR及下游信号分子对炎症的发生及发展过程具有重要作用。因此,可通过检测tslpr基因相对表达量来评价本发明的药物组合物是否对TSLPR(TSLP受体)具有抑制功效。
判定依据:
统计学分析p<0.05,判定为有显著性差异。
请参阅图1所示,图中从左至右依次为正常对照组、模型对照组和本发明药物组合物;
观察发现,本发明的药物组合物基因相对表达量与模型对照组相比,明显减少,揭示了本发明的药物组合物对TSLPR(TSLP受体)具有抑制功效;
表1
实验结论:
在本次实验条件下,本发明的药物组合物对TSLP(胸腺基质淋巴细胞生成素)具有抑制功效。
实验二:
实验方法:
1.随机选取斑马鱼于6孔板中,每孔15尾。
2.水溶给予本发明的药物组合物,同时设置正常对照组和模型对照组,每孔容量为3mL。
3.28℃条件下避光孵育24h。
4.每个实验组随机选取10尾斑马鱼转移至96孔板,水溶给予冰醋酸建立斑马鱼疼痛模型。立即利用行为分析仪测定斑马鱼的运动轨迹,分析并采集斑马鱼的总运动距离(D),根据公式计算本发明的药物组合物的舒缓功效,判断其是否具有舒缓功效。
实验原理:
冰醋酸虽然属于弱酸,但有强烈的刺透性和腐蚀性。皮肤接触冰醋酸会有刺痛和灼伤的感觉。选择游泳能力尚未发育完全的斑马鱼,利用冰乙酸刺激斑马鱼引起较大面积和较长时间的炎性疼痛,导致运动轨迹越多,疼痛越严重。应用行为分析仪检测斑马鱼的总运动距离,评价本发明的药物组合物是否具有舒缓功效。
判定依据:
统计学分析p<0.05,判定为有显著性差异。
表2
检测项目 | 检测浓度(%) | 功效(%) | P值 | 检测结果 |
舒缓功效 | 0.5 | 26 | <0.01 | 显著 |
本发明的药物组合物的功效实验请参阅图2所示,图中从左至右依次为正常对照组、模型对照组和本发明药物组合物,其中,红线代表快速运动距离,绿线代表中速运动距离,黑线代表慢速运动距离;
观察发现,本发明药物组合物的总运动距离与模型对照组相比,明显减少,揭示了本发明药物组合物具有舒缓功效;
实验结论:
在本次实验条件下,本发明药物组合物的总运动距离与模型对照组比明显减少,揭示了本发明药物组合物具有舒缓功效。
综上所述,本发明的药物组合物对人体无毒副作用,可快速舒缓皮肤刺激感,可长期并大面积涂抹于皮肤表面使用,能够有效治疗Th2型皮肤炎症、治疗胸腺基质淋巴细胞介导的皮肤疾病、特应性皮炎、银屑病、瘙痒症、湿疹和皮肤过敏,并且作用靶点明确,炎性因子抑制率高。
Claims (8)
1.一种含有透明质酸或其盐的药物组合物,其特征在于,包括低分子量微生物发酵透明质酸或其盐的组合物、辅料和甘油葡糖苷或其衍生物,所述低分子量微生物发酵透明质酸或其盐的组合物的添加量为0.001%-15%,所述甘油葡糖苷或其衍生物的添加量为0.001%-15%。
2.根据权利要求1所述的一种含有透明质酸或其盐的药物组合物,所述低分子量微生物发酵透明质酸或其盐的组合物分子量为10Da-50KDa。
3.如权利要求1或2任一所述的一种含有透明质酸或其盐的药物组合物在制备用于治疗胸腺基质淋巴细胞介导的皮肤疾病药物中的应用。
4.如权利要求1或2任一所述的一种含有透明质酸或其盐的药物组合物在制备用于治疗特应性皮炎药物中的应用。
5.如权利要求1或2任一所述的一种含有透明质酸或其盐的药物组合物在制备用于治疗银屑病药物中的应用。
6.如权利要求1或2任一所述的一种含有透明质酸或其盐的药物组合物在制备用于治疗瘙痒症药物中的应用。
7.如权利要求1或2任一所述的一种含有透明质酸或其盐的药物组合物在制备用于治疗湿疹药物中的应用。
8.如权利要求1或2任一所述的一种含有透明质酸或其盐的药物组合物在制备用于治疗皮肤过敏药物中的应用。
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