CN117919256B - 一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途 - Google Patents
一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途 Download PDFInfo
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Abstract
本发明属于治疗肝炎药物制剂技术领域,具体涉及一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途。所述的组合物由内容物和囊壳组成,其中内容物由蒲公英甾醇、茶氨酸、荆芥内酯和甘油组成;囊壳由明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水组成。经动物实验证实,本发明组合物可使生物机体的葡萄糖耐量性显著提升,并能够显著降低TNF‑αmRNA和IL‑IβmRNA的相对表达量,制备工艺简单,方便口服,且提供了在肝炎方面的用途。
Description
技术领域
本发明属于治疗肝炎药物制剂技术领域,具体涉及一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途。
背景技术
代谢相关脂肪性肝病(MAFLD)曾用名为非酒精性脂肪性肝病(NAFLD),是指在无过量饮酒史及明确的肝损伤因素条件下,以肝脏脂肪变性为主要特征的一组慢性疾病,与胰岛素抵抗和遗传易感性密切相关,常与肥胖、2型糖尿病以及代谢综合征等疾病并存。MAFLD疾病包括非酒精性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化和肝细胞癌。虽然其发生机制至今未完全明确,但在目前广泛接受的“多重打击”学说发病机制中,过度的氧化应激和内质网应激被认为是参与NASH发生发展的重要机制。
蒲公英甾醇是一种具有1,2-环戊烯菲结构的五环三萜类化合物。分子量和熔点分别为426.72克/摩尔和221-222℃。在胃炎、结肠炎、关节炎、肺炎、肿瘤和免疫系统疾病等多种疾病的动物或细胞模型中,蒲公英甾醇已被证明具有显著的预防和治疗效果。
荆芥内酯是一种天然化合物,属于香叶植物的挥发性成分之一。荆芥内酯主要存在于一些草本植物中,如荆芥、白芷、防风等。它具有独特的香味和药用价值,在中医药领域被广泛应用。荆芥内酯在药用上有着多种功效和用途,首先,它具有祛风散寒、理气活血的作用,常用于治疗风寒感冒、风湿关节痛等症状。其次,荆芥内酯还具有抗菌消炎的作用,可用于治疗皮肤感染、炎症等疾病。此外,荆芥内酯还被认为具有舒筋活络、解毒等功效,适用于一些肌肉酸痛、蛇虫咬伤等情况。
在现有技术中,并未发现关于蒲公英甾醇和荆芥内酯联合用于治疗肝炎,尤其是非酒精性肝炎的使用。
发明内容
为克服现有技术的不足,本发明提供了一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途,尤其适用于治疗非酒精性脂肪性肝炎,同时还提供了药用甾醇活性物质组合物的制备方法。
具体而言,本发明技术方案如下:
本发明的第一个目的在于一种含有药用甾醇活性物质的组合物,所述的组合物由内容物和囊壳组成,其中内容物由蒲公英甾醇、茶氨酸、荆芥内酯和甘油组成,以重量比计算,蒲公英甾醇、茶氨酸、荆芥内酯和甘油的比例分别为1.5-3.5:0.3-0.7:0.8-1.2:24.6-27.4。
所述的囊壳由明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水组成,以重量比计算,明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水比例分别为1-2:0.25-0.5:0.05-0.15:0.3-0.7:0.05-0.15:0.05-0.15:26.35-28.3。
本发明的第二个目的在于提供了一种含有药用甾醇活性物质的组合物的制备方法,具体为:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/3-1/2重量的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至70-80℃并与剩下的水混合,混合均匀,加入混合物B,熔化,保温1-2小时,静置得混合物C,保温55-60℃待用;
3)制剂制备:控制混合物C的温度60-65℃;混合物A的温度10-20℃,滴制过程保持10-20℃;滴头温度40-50℃,将内容物包裹于囊壳中,低温干燥,即得。
进一步地,以重量比计算,蒲公英甾醇、茶氨酸、荆芥内酯和甘油的比例分别为2.5:0.5:1:26。
进一步地,以重量比计算,明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水比例分别为1.5:0.4:0.1:0.5:0.1:0.1:27.3。
进一步地,以重量比计算,内容物和囊壳的比为1:1。
进一步地,所述组合物的制备方法为:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/2的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至75℃并与剩下的水混合,混合均匀,加入混合物B,熔化,保温1.5小时,静置得混合物C,保温60℃待用;
3)制剂制备:控制混合物C的温度62.5℃;混合物A的温度15℃,滴制过程保持15℃;滴头温度45℃,将内容物包裹于囊壳中,低温干燥,即得。
进一步地,本发明所述蒲公英甾醇的分子结构为C30H50O,结构式如式(I):
式(I)。
所述的荆芥内酯的分子结构为C10H14O2,结构式如式(II):
式(II)。
本发明的第三个目的在于提供了含有内容物以及囊壳的制剂,进一步地,所述的制剂为软胶囊。
本发明的药物组合物及其制剂可以通过任何途径进入病灶部位,给药途径的包括但不限于静脉内、鼻内、口服、局部或通过吸入给药。
本发明的第四个目的在于所述的组合物在制备治疗肝炎药物中的用途。所述的肝炎为非酒精性脂肪性肝炎。
与现有技术相比,有益技术效果主要体现在以下几个方面:
经动物实验证实,本发明组合物在IPGTT实验中,具体为实施例1-3的组合物可使生物机体的葡萄糖耐量性显著提升与模型组相比具有显著性差异(P<0.05);能够显著降低TNF-α mRNA和IL-Iβ mRNA的相对表达量,这也进一步说明了本发明的组合物的药效,即能显著降低肝脏炎症;最终制备的软胶囊,工艺简单,方便口服,且提供了在非酒精性脂肪性肝炎方面的用途。
附图说明
图1:小鼠葡萄糖耐量实验(IPGTT)。
图2:小鼠TNF-αmRNA和IL-IβmRNA相对表达量。
图3:小鼠血清和肝脏生化参数。
图4:小鼠肝脏氧化应激指标T-SOD的含量。
图5:小鼠肝脏氧化应激指标T-AOC的含量。
图6:小鼠肝脏氧化应激指标丙二醛的含量。
图7:各实施例在第0、1、2、3、6个月时蒲公英甾醇含量的变化。
图8:各实施例在第0、1、2、3、6个月时荆芥内酯含量的变化。
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/3重量的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至70℃并与剩下的水混合,混合均匀,加入混合物C,熔化,保温1小时,静置得混合物B,保温55℃待用;
3)软胶囊制备:控制混合物C的温度60℃,混合物A的温度10℃,滴制过程保持10℃,滴头温度40℃,将内容物包裹于囊壳中,低温干燥,即得。
实施例2:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/2重量的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至75℃并与剩下的水混合,混合均匀,加入混合物C,熔化,保温1.5小时,静置得混合物B,保温60℃待用;
3)软胶囊制备:控制混合物C的温度62.5℃,混合物A的温度15℃,滴制过程保持15℃,滴头温度45℃,将内容物包裹于囊壳中,低温干燥,即得。
实施例3:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/2重量的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至80℃并与剩下的水混合,混合均匀,加入混合物C,熔化,保温2小时,静置得混合物B,保温60℃待用;
3)软胶囊制备:控制混合物C的温度65℃,混合物A的温度20℃,滴制过程保持20℃,滴头温度50℃,将内容物包裹于囊壳中,低温干燥,即得。
对比例1:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
对比例2:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
对比例3:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
对比例4:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
对比例5:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
对比例6:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
对比例7:一种含有蒲公英甾醇的软胶囊,其成分与制备工艺如下:
1000粒
制备工艺同实施例2。
验证实施例
1、本发明实施例在小鼠非酒精性脂肪性肝炎中的药效学实验
1.1动物选取
64只6~8周龄SPF级雄性C57BL/6J小鼠,体质量20~25g,购自济南朋悦实验动物繁育有限公司(SCXK(鲁)20220006)。
1.2实验方法
1)分组、造模与给药
小鼠适应性喂养7d后随机分为8组,每组8只,分别为正常对照组、模型组、实施例1-3组、对比例1-3组。正常对照组小鼠给予正常维持饲料,其他各组小鼠给予28周的高脂高果糖高胆固醇饲料,在第25周开始给予实施例1-3组、对比例1-3组每日1次200mg/(kg·d)的灌胃给药(实施例1-3组、对比例1-3组内容物对应给药),正常对照组和模型组给予同等体积的体积分数为0.5%羧甲基纤维素钠混悬液灌胃,治疗共持续4周。
2)葡萄糖耐量实验(IPGTT)
第3周进行IPGTT以评估小鼠血糖代谢能力。禁食禁水12h后,按照体质量2g/kg给予小鼠腹腔注射葡萄糖溶液,从小鼠尾部采血检测注射后0min、15min、30min、60min、120min的血糖水平。
3)血清和肝脏指标测定
经小鼠眼眶后静脉丛采集全血,室温静置1h后,4℃1000×g离心15min取上层血清,使用全自动生化分析仪检测ALT、AST、甘油三酯、总胆固醇、LDL-C和HDL-C水平;按照检测试剂盒说明书检测其甘油三酯、总胆固醇、丙二醛、T-SOD和T-AOC水平。
4)小鼠肝脏组织炎症因子指标
使用TRIzol试剂提取小鼠肝脏组织总RNA,以总RNA为模板反转录生成cDNA,采用实时荧光定量PCR检测仪进行qPCR。反应体系配制及反应程序设置均按照说明书进行。目的基因的相对表达量结果使用2-ΔΔCt方法进行计算。
1.3数据统计分析
所有数据的统计分析均采用Graphpad Prism 5.0软件进行。各组数据用mean±SD表示。所有数据均采用单因素方差分析进行多重比较或student-t检验和非参数检验。p<0.05认为差异有统计学意义。
2、软胶囊中活性物质含量的验证
2.1、蒲公英甾醇含量照高效液相色谱法(中国药典2020版通则0512)测定。
色谱条件与系统适用性试验:以十八烷基硅烷键合硅胶为填充剂;以甲醇-水(98:2)为流动相;检测波长为283nm。理论板数按蒲公英甾醇峰计算应不低于5000。
对照品溶液的制备:取蒲公英甾醇对照品适量,精密称定,加甲醇制成每1ml含40μg的溶液,作为对照品溶液。
供试品溶液的制备:取本发明实施例的内容物1ml,甘油稀释至10ml,均匀后吸取1ml,置具塞锥形瓶中,精密加入甲醇25ml,取出,放冷,再称定重量,加甲醇补足减失的重量,滤过,取续滤液,即得。
测定法分别精密吸取对照品溶液与供试品溶液各10μl,注入液相色谱仪,测定,即得。
2.2、荆芥内酯含量照高效液相色谱法(中国药典2020版通则0512)测定。
色谱条件与系统适用性试验:以十八烷基硅烷键合硅胶为填充剂;以甲醇-水-冰醋酸(32:68:0.16)为流动相;检测波长为298nm。
对照品溶液的制备:取荆芥内酯对照品适量,精密称定,加甲醇制成每1ml含40mg的溶液,即得。
供试品溶液的制备:取本发明实施例的内容物1ml,甘油稀释为10ml,然后吸取1ml,置具塞锥形瓶中,精密加人70%乙醇50ml,称定重量,加热回流6小时,放冷,再称定重量,用70%乙醇补足减失的重量,摇匀,滤过。精密量取续滤液25ml,置烧瓶中,浓缩至约1ml,加3mol/L盐酸溶液10ml,水浴中加热水解2小时,立即冷却,移入分液漏斗中,用水10ml分次洗涤容器,并入分液漏斗中,加氯化钠2g,用三氯甲烷强力振摇提取5次,每次15ml,合并三氯甲烷液,加无水硫酸钠2g,搅拌,滤过,容器用少量三氯甲烷洗涤,滤过,滤液合并,7℃以下浓缩至近干,立即加甲醇使溶解,转移至10ml量瓶中,并稀释至刻度,摇匀,即得。
测定法分别精密吸取对照品溶液与供试品溶液各10ml,注入液相色谱仪,测定,即得。
2.3、结果。
加速试验条件:温度为(40±2)℃、相对湿度为(75±5)%的条件下进行,持续时间为6个月。在试验期间,在第0、1、2、3、6个月末取样检测考察蒲公英甾醇、荆芥内酯的含量,具体见图7和图8。
Claims (9)
1.一种用于治疗非酒精性脂肪性肝炎的含有药用甾醇活性物质的组合物,其特征在于,所述的组合物由内容物和囊壳组成,其中内容物由蒲公英甾醇、茶氨酸、荆芥内酯和甘油组成,以重量比计算,蒲公英甾醇、茶氨酸、荆芥内酯和甘油的比例分别为1.5-3.5:0.3-0.7:0.8-1.2:24.6-27.4;囊壳由明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水组成,以重量比计算,明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水的比例分别为1-2:0.25-0.5:0.05-0.15:0.3-0.7:0.05-0.15:0.05-0.15:26.35-28.3,所述组合物的制备方法为:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/3-1/2重量的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至70-80℃并与剩下的水混合,混合均匀,加入混合物B,熔化,保温1-2小时,静置得混合物C,保温55-60℃待用;
3)制剂制备:控制混合物C的温度60-65℃;混合物A的温度10-20℃,滴制过程保持10-20℃;滴头温度40-50℃,将内容物包裹于囊壳中,低温干燥,即得。
2.根据权利要求1所述的组合物,其特征在于,以重量比计算,蒲公英甾醇、茶氨酸、荆芥内酯和甘油的比例分别为2.5:0.5:1:26。
3.根据权利要求1所述的组合物,其特征在于,以重量比计算,明胶、鹿角菜胶、西黄蓍胶、甘油、柠檬酸三丁酯、右旋糖酐和水比例分别为1.5:0.4:0.1:0.5:0.1:0.1:27.3。
4.根据权利要求1所述的组合物,其特征在于,以重量比计算,内容物和囊壳的比为1:1。
5.根据权利要求1所述的组合物,其特征在于,所述组合物的制备方法为:
1)内容物制备:取蒲公英甾醇、茶氨酸、荆芥内酯与甘油混合,充分搅拌均匀,得混合物A;
2)囊壳制备:将明胶、鹿角菜胶、西黄蓍胶加入1/2的水膨胀,得混合物B;将甘油、柠檬酸三丁酯、右旋糖酐加热至75℃并与剩下的水混合,混合均匀,加入混合物B,熔化,保温1.5小时,静置得混合物C,保温60℃待用;
3)制剂制备:控制混合物C的温度为62.5℃;混合物A的温度为15℃,滴制过程保持15℃;滴头温度45℃,将内容物包裹于囊壳中,低温干燥,即得。
6.根据权利要求1所述的组合物,其特征在于,所述蒲公英甾醇的分子结构为C30H50O,结构式如式(I):
式(I)。
7.根据权利要求1所述的组合物,其特征在于,所述的荆芥内酯的分子结构为C10H14O2,结构式如式(II):
式(II)。
8.根据权利要求1所述的组合物,其特征在于,所述的制剂为软胶囊。
9.一种含有权利要求1-8任一项所述的组合物在制备治疗非酒精性脂肪性肝炎药物中的用途。
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