CN113143962B - 一种治疗高脂血症的药物组合物及其制备方法 - Google Patents
一种治疗高脂血症的药物组合物及其制备方法 Download PDFInfo
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- CN113143962B CN113143962B CN202110509462.6A CN202110509462A CN113143962B CN 113143962 B CN113143962 B CN 113143962B CN 202110509462 A CN202110509462 A CN 202110509462A CN 113143962 B CN113143962 B CN 113143962B
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- chlorogenic acid
- vitamin
- treating hyperlipidemia
- manganese gluconate
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Abstract
本发明涉及一种治疗高脂血症的药物组合物及其制备方法，所述药物组合物包括绿原酸、维生素、药学上可接受的辅料及任选的微量元素，本发明治疗高脂血症的药物组合物具有优异的降低血清总胆固醇和血清甘油三酯，提升高密度脂蛋白含量的效果，且药物组合物成分明确，组成简单，安全无副作用，可广泛应用于高脂血症的临床治疗。
Description
技术领域
本发明属于药物领域，具体涉及一种治疗高脂血症的药物组合物及其制备方法。
背景技术
高脂血症(Hyperlipoproteinemia)，是指血浆中胆固醇和甘油三酯水平升高、高密度脂蛋白含量降低，是引起动脉粥样硬化、冠心病、高血压、糖尿病、脑卒中等疾病的重要因素之一。目前国内外针对高脂血症尚无统一的诊断标准，一般当血浆总胆固醇浓度＞5.17mmol/L(200mg/dl)可诊断为高胆固醇血症，当血浆甘油三酯浓度＞2.3mmol/L(200mg/dl)可诊断为高甘油三酯血症。
高脂血症可分为原发性高脂血症和继发性高脂血症两种。原发性高脂血症是由脂质和脂蛋白代谢的先天性缺陷引起，继发性高脂血症则多继发于代谢性紊乱疾病如糖尿病、高血压、肝脏疾病、肾脏疾病、甲状腺疾病以及饮酒、吸烟、高脂饮食等。
目前高脂血症的治疗方法包括非药物治疗和药物治疗，其中非药物治疗一般通过控制体重、运动锻炼、戒烟、饮食治疗等方法治疗高血脂，而药物治疗则包括施用可降低血清总胆固醇和低密度脂蛋白水平的他汀类药物或可降低血清甘油三酯水平的贝特类和烟酸类等药物。
绿原酸是植物在进行有氧呼吸的过程，经磷酸戊糖途径中间产物合成的一种苯丙素类物质，其提取技术成熟，亦可少量合成。绿原酸已经被开发应用于食品，保健品，化妆品和药品等多个领域。目前研究结果表明，绿原酸具有保护心血管、抗氧化、抗紫外、抗辐射、抗癌、抗菌、抗病毒、免疫调节以及治疗代谢紊乱等多种药理作用。
现有的研究显示了维生素如维生素E、维生素C，微量元素如锌、铜、锰、铁、铬、硒、钙、镁等均与脂质代谢相关，并有学者基于此提出了通过补充微量元素调节脂质代谢水平，但由于维生素与微量元素的血脂调节效果尚不明确，且过量补充维生素、微量元素还会导致多种健康问题，因此尚未有通过补充维生素和微量元素治疗高脂血症的临床报道。
本发明致力于提供一种具有优异的高脂血症治疗效果的药物组合物。
发明内容
本发明的目的是提供一种治疗高脂血症的药物组合物及其制备方法和用途。
一方面，本发明提供一种治疗高脂血症的药物组合物，包括绿原酸、维生素、药学上可接受的辅料及任选的微量元素。
优选的，所述维生素选自：维生素C、维生素E、维生素B6、维生素 B12或其组合；更优选的，所述维生素选自维生素C；
优选的，所述微量元素选自：锌、锰、硒、铬、铜或其组合；更优选的，所述微量元素选自葡萄糖酸锌、葡萄糖酸锰、氯化铬、葡萄糖酸铜或其组合；最优选的，所述微量元素选自葡萄糖酸锰；
优选的，所述药学上可接受的辅料选自：填充剂、黏合剂、崩解剂、润滑剂、溶剂、抗氧剂、支架剂等；更优选的，所述抗氧剂选自：亚硫酸氢钠、焦亚硫酸钠、L-半胱氨酸盐酸盐中的一种或两种以上的混合，所述支架剂选自：蔗糖、甘露醇、葡萄糖、乳糖、海藻糖、羟乙基淀粉、右旋糖苷20、山梨醇、PEG1000、甘油、甘氨酸、1，2-丙二醇中的一种或两种以上的混合；
优选的，所述治疗高脂血症的药物组合物以绿原酸、维生素及任选的微量元素作为仅有的活性成分；
优选的，所述绿原酸、维生素及任选的微量元素的重量比为100：1-5： 0.01-0.05；更优选的，所述绿原酸、维生素及任选的微量元素的重量比为 100：2-4：0.02-0.04；最优选的，所述绿原酸、维生素及任选的微量元素的重量比为100：3：0.03；
本发明所述治疗高脂血症的药物组合物可经胃肠道或胃肠道外途径施用，更优选的，本发明所述治疗高脂血症的药物组合物经胃肠道外途径施用。
优选的，本发明所述治疗高脂血症的药物组合物可经胃肠道施用的药物剂型包括：片剂、胶囊、颗粒剂、口服液等，可经胃肠道外途径施用的药物剂型包括：注射液、大输液、冻干粉针剂等；
再一个方面，本发明提供了一种治疗高脂血症的药物组合物的制备方法，其包括以下步骤：
(1)按量称取各原料；
(2)按照本领域常规方法制备成经胃肠道或胃肠道外途径施用的药物剂型；
具体的，本发明提供了一种治疗高脂血症的注射液的制备方法，其包括以下步骤：
(1)按量称取各原料；
(2)取注射用水，依次加入绿原酸、抗氧剂、维生素和任选的微量元素，搅拌使充分溶解后定容，pH控制在2-5，加入活性炭，搅拌20-40 分钟后过滤除去活性炭，再用0.22um亲水性微孔滤膜精滤至滤液澄清，无菌灌装即得；
本发明提供了一种治疗高脂血症的冻干粉针剂的制备方法，其包括以下步骤：
(1)按量称取各原料；
(2)取注射用水，依次加入绿原酸、抗氧剂、支架剂、维生素和任选的微量元素，搅拌使充分溶解后定容，pH控制在2-5，加入活性炭，搅拌20-40分钟后过滤除去活性炭，再用0.22um亲水性微孔滤膜精滤至滤液澄清，无菌灌装，冻干即得；
本发明提供了一种治疗高脂血症的片剂的制备方法，其包括以下步骤：
(1)按量称取各原料；
(2)将绿原酸、维生素、任选的微量元素及填充剂、崩解剂过60-100 目筛后混合均匀，取适量黏合剂制软材，过14目筛制粒后干燥，过12目筛整粒，加入润滑剂后混合均匀并压片，即得。
另一个方面，本发明提供了绿原酸、维生素及任选的微量元素的组合在制备治疗高脂血症的药物组合物中的用途；
优选的，所述维生素选自：维生素C、维生素E、维生素B6、维生素B12或其组合；更优选的，所述维生素选自维生素C；
优选的，所述微量元素选自：锌、锰、硒、铬、铜等；更优选的，所述微量元素选自葡萄糖酸锌、葡萄糖酸锰、氯化铬、葡萄糖酸铜或其组合；最优选的，所述微量元素选自葡萄糖酸锰；
优选的，所述药学上可接受的辅料选自：填充剂、黏合剂、崩解剂、润滑剂、溶剂、抗氧剂、支架剂等；更优选的，所述抗氧剂选自：亚硫酸氢钠、焦亚硫酸钠、L-半胱氨酸盐酸盐中的一种或两种以上的混合，所述支架剂选自：蔗糖、甘露醇、葡萄糖、乳糖、海藻糖、羟乙基淀粉、右旋糖苷20、山梨醇、PEG1000、甘油、甘氨酸、1，2-丙二醇中的一种或两种以上的混合；
优选的，所述治疗高脂血症的药物组合物以绿原酸、维生素及任选的微量元素作为仅有的活性成分；
优选的，所述绿原酸、维生素及任选的微量元素的重量比为100：1-5： 0.01-0.05；更优选的，所述绿原酸、维生素及任选的微量元素的重量比为 100：2-4：0.02-0.04；最优选的，所述绿原酸、维生素及任选的微量元素的重量比为100：3：0.03；
本发明所述治疗高脂血症的药物组合物可经胃肠道或胃肠道外途径施用，更优选的，本发明所述治疗高脂血症的药物组合物经胃肠道外途径施用。
优选的，本发明所述治疗高脂血症的药物组合物可经胃肠道施用的药物剂型包括：片剂、胶囊、颗粒剂、口服液等，可经胃肠道外途径施用的药物剂型包括：注射液、大输液、冻干粉针剂等。
本发明的有益效果：
本发明通过将绿原酸与维生素及任选的微量元素进行组合获得了具有优异的治疗高脂血症的药物组合物，尤其以绿原酸、维生素C和葡萄糖酸锰组合的效果最为优异，可显著降低血清总胆固醇和血清甘油三酯水平，提升高密度脂蛋白含量。本发明治疗高脂血症的药物组合物成分明确，组成简单，降血脂效果确切，且安全无副作用，可广泛应用于高脂血症的临床治疗。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
实施例1：一种治疗高脂血症的注射液
绿原酸100g、维生素C 3g、亚硫酸氢钠1g、葡萄糖酸锰0.03g，注射用水适量，按照以下方法制备：
(1)按量称取各原料；
(2)取注射用水，依次加入绿原酸、亚硫酸氢钠、维生素C和葡萄糖酸锰，搅拌使充分溶解，pH控制在3.5，定容至2000mL，加入活性炭，搅拌20-40分钟后过滤除去活性炭，再用0.22um亲水性微孔滤膜精滤至滤液澄清，无菌灌装1000支即得。
实施例2：一种治疗高脂血症的冻干粉针剂
绿原酸100g、维生素C 4g、亚硫酸氢钠2g、葡萄糖酸锰0.05g，甘露醇80g，注射用水适量，按照以下方法制备：
(1)按量称取各原料；
(2)取注射用水，依次加入绿原酸、亚硫酸氢钠、甘露醇、维生素C和葡萄糖酸锰，搅拌使充分溶解，pH控制在4，定容至2000mL，加入活性炭，搅拌20-40分钟后过滤除去活性炭，再用0.22um亲水性微孔滤膜精滤至滤液澄清，无菌灌装1000支，冻干即得。
实施例3：一种治疗高脂血症的片剂
绿原酸100g、维生素C3g、葡萄糖酸锰0.03g，微晶纤维素364g，交联羧甲基纤维素钠30g、硬脂酸镁3g，乙醇适量，按照以下方法制备：
(1)按量称取各原料；
(2)将绿原酸、葡萄糖酸锰、维生素C、微晶纤维素、交联羧甲基纤维素钠过80目筛后混合均匀，取适量乙醇制软材，过14目筛制粒后干燥，过12目筛整粒，加入硬脂酸镁后混合均匀并压片，制得治疗高脂血症的片剂1000片。
效果例1：本发明治疗高脂血症的药物组合物的降脂效果
1.1实验药物
以上药物均按照实施例1方法制备成注射液或乳浊液，其中活性药物的总浓度均调整为0.53％，乳浊液在使用前混合均匀。
1.2实验动物
体重18-20g的雄性昆明种小鼠210只，适应性饲养1d后随机分为21 组，每组10只，分别为正常组、模型组、空白组和药物1-18组，并记为实验第1天，其中正常给予普通饲料，模型组、空白组和药物1-18组小鼠均给予高脂饲料，所述普通饲料的配方为：玉米面60％、麸皮35％、面粉2％、鱼粉1.5％、食盐1％、鱼肝油0.5％，所述高脂饲料的配方为：胆固醇2％、胆酸钠0.5％、猪油7.5％、普通饲料90％，所有小鼠均自由饮水。各组小鼠尾静脉注射相应实验药物，每天两次，每次200μL，其中正常组和空白组尾静脉注射等量的注射用水。连续喂养4周，其中第6天、第13天、第20天和第27天禁止饮水8h后称重。实验第28天，末次给药2h后小鼠眼眶取血，使用ELISA法测定血清总胆固醇、甘油三酯和高密度脂蛋白含量，小鼠断颈处死后取完整肝脏，使用0-4℃生理盐水清洗肝脏，滤纸吸干后称重，计算肝脏指数，具体实验结果参见表1-2，其中：
肝脏指数＝肝脏湿重/体重*100。
1.3实验结果1.3实验结果
应用统计软件SPSS的多因素方差分析模块进行数据分析，P<0.05 表示差异有统计学意义，P<0.01表示差异有显著性差异。
表1本发明药物组合物对高脂饮食小鼠体重的影响
与空白组比较：△，P<0.05.
表2本发明药物组合物对高脂饮食小鼠肝脏指数和血脂的影响
与空白组比较：△，P<0.05,△△，P<0.01；与模型组比较：*，P<0.05,**，P<0.01。
表1-2实验结果显示通过高脂饮食，模型组小鼠相对于食用普通饲料的空白组小鼠体重、肝脏湿重、肝脏指数、血清总胆固醇、甘油三酯水平均明显增高，高密度脂蛋白含量明显降低，表明高脂血症模型造模成功。
绿原酸及其与维生素和/或微量元素的药物组合均显示了一定的抑制高脂饮食所导致的小鼠体重、肝脏重量增加，降低血清总胆固醇、甘油三酯水平的效果，并显示了明显的提升高密度脂蛋白含量的效果，显示了绿原酸及其与维生素和/或微量元素的组合均具有一定的降血脂效果，且绿原酸与维生素和/或微量元素的组合的相应效果普遍优于单独的绿原酸，显示了绿原酸与维生素和/或微量元素的组合具有明显更优的降血脂效果，但实验结果同时显示了并非药物活性成分的种类越多，相应药物组合的降血脂的效果越强，其中原因包括了活性物质水溶性的影响、活性物质间相互作用不同的影响以及随着活性物质种类的增多所导致的单一活性物质药物浓度降低等。经大量的筛选实验显示在给药物浓度相同的情况下，绿原酸与维生素C、葡萄糖酸锰的组合相对于其他药物组合具有明显更优的降血脂效果(注：以上绿原酸及其与维生素和/或微量元素的药物组合的降血脂效果仅为示例性展示，并非本发明筛选绿原酸及其与维生素和/或微量元素药物组合的完整实验过程)。
效果例2：绿原酸与维生素C、葡萄糖酸锰的比例对药物组合物降脂效果的影响
2.1实验药物
2.2实验方法
按照实施例1方法，测定不同比例的绿原酸与维生素C、葡萄糖酸锰组合对小鼠体重、肝脏湿重、肝脏指数、血清总胆固醇、甘油三酯和高密度脂蛋白含量的影响，具体实验结果参见表3-4。
表3绿原酸与维生素C、葡萄糖酸锰组合对高脂饮食小鼠体重的影响
与空白组比较：△，P<0.05,△△，P<0.01；与模型组比较：*，P<0.05.
表4绿原酸与维生素C、葡萄糖酸锰组合对高脂饮食小鼠肝脏指数和血脂的影响
与空白组比较：△，P<0.05,△△，P<0.01；与模型组比较：*，P<0.05,**，P<0.01。
表3-4实验结果显示了绿原酸与维生素C、葡萄糖酸锰的配比对其降血脂效果具有明显的影响，伴随着维生素C与葡萄糖酸锰占比的降低，药物组合降血脂效果逐步增强，其中当绿原酸：维生素C：葡萄糖酸锰＝100： 3：0.03时相应组合显示了最优的降血脂效果，伴随着维生素C与葡萄糖酸锰占比的继续降低，相应组合的降血脂效果逐步降低(注：以上绿原酸与维生素C、葡萄糖酸锰的比例仅为示例性展示，并非本发明筛选绿原酸与维生素C、葡萄糖酸锰比例的完整实验过程)。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (8)
1.一种治疗高脂血症的药物组合物，其特征在于，以绿原酸、维生素C及葡萄糖酸锰作为仅有的活性成分，所述绿原酸、维生素C及葡萄糖酸锰的重量比为100：2-4：0.02-0.04。
2.根据权利要求1所述的治疗高脂血症的药物组合物，其特征在于，所述绿原酸、维生素C及葡萄糖酸锰的重量比为100：3：0.03。
3.根据权利要求1-2任一项所述的治疗高脂血症的药物组合物，其特征在于，所述治疗高脂血症的药物组合物经胃肠道或胃肠道外途径施用。
4.根据权利要求3所述的治疗高脂血症的药物组合物，其特征在于，所述经胃肠道施用的药物剂型包括片剂、胶囊、颗粒剂、口服液，经胃肠道外途径施用的药物剂型包括注射液、冻干粉针剂。
5.根据权利要求4所述的治疗高脂血症的药物组合物，其特征在于，所述注射液选自大输液。
6.权利要求1-5任一项所述的治疗高脂血症的药物组合物的制备方法，其特征在于，包括以下步骤：
(1）按量称取各原料；
(2）按照本领域常规方法制备成经胃肠道或胃肠道外途径施用的药物剂型。
7.绿原酸、维生素C及葡萄糖酸锰的组合在制备治疗高脂血症的药物组合物中的用途，所述绿原酸、维生素C及葡萄糖酸锰的重量比为100：2-4：0.02-0.04。
8.根据权利要求7所述的用途，其特征在于，所述绿原酸、维生素C及葡萄糖酸锰的重量比为100：3：0.03。
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