CN115282201A - 防治糖尿病合并脂肪肝的中药配伍方组合物及其制备方法和应用 - Google Patents
防治糖尿病合并脂肪肝的中药配伍方组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种改善糖尿病合并脂肪肝的中药配伍方组合物及其制备方法和应用，其配方由以下组分组成：黄芪15‑60份、白术6‑24份、茯苓6‑24份、陈皮6‑24份、柴胡5‑20份、黄连3‑12份，丹参5‑20份,虎杖10‑30份，山楂10‑30份。经药理学实验结果表明：中药配伍方组合物具有减轻胰岛素抵抗和慢性炎症，调节体内糖脂代谢，减少肝脏脂质堆积，缓减脂肪肝发展的作用。本发明以我国传统的中医理论为依据，提供一种原料药易得、成本低、易于生产、服用方便、疗效好、提高病人生活质量、副作用小、无耐药性的防治糖尿病合并脂肪肝的中药制剂。
Description
技术领域
本发明属于医药领域，具体是中医药领域，更具体涉及一种改善糖尿病合并脂肪肝的中药配伍方组合物及其制备方法和应用。
背景技术
2型糖尿病(T2DM)和非酒精性脂肪肝（NAFLD，包括单纯性脂肪肝SFL、非酒精性脂肪性肝炎NASH及其相关肝硬化、肝癌）是严重威胁人类健康的重大慢病。近年T2DM发病率呈递增趋势，2019年全球有4.63亿糖尿病，中国达1.3亿人；国际糖尿病联盟(InternationalDiabetes Federation，IDF) 预测到 2040 年，将有 6.42 亿糖尿病患者，中国占1.54 亿。约75%的T2DM患者并发NAFLD（糖尿病合并脂肪肝），然而，与攀升的发病率相对的，是T2DM和NAFLD药物研发面临瓶颈。新研发的T2DM药物不再只是控制血糖，还需控制并发症（如脂肪肝、心血管病、肾病等）、降低体重、加强靶点特异性等。鉴于严峻的患病现状和发展趋势，全球发达国家科研机构、跨国药企纷纷布局糖尿病合并脂肪肝等并发症药物开发。 目前对于糖尿病合并脂肪肝的治疗，饮食和运动指导与干预是基础，但并无明确的特效治疗药物。临床上多使用降糖、降脂与保肝类药物联合使用，虽具有一定的疗效，但多数存在较大的不良反应，如出现胃肠道反应，低血糖，肝肾损害等副作用，治标不治本。中医药治疗糖尿病合并脂肪肝具有其独特的优势，其特点是无明显毒副作用，疗效确切、持久，有一定的应用和开发前景。因中医药在防治糖尿病合并脂肪肝中凸显优势，开发副作用小，效果优的中药配伍方组方药物迫在眉睫。本发明以我国传统的中医理论为依据，提供一种原料药易得、成本低、易于生产、服用方便、疗效好、提高病人生活质量、副作用小、无耐药性的防治糖尿病合并脂肪肝的中药制剂。
发明内容
本发明基于糖尿病的特点研究开发中药配伍方。糖尿病合并脂肪肝，据其临床特点，将其归属于“消渴”“胁痛”“积聚”等范畴。其主要病因为饮食不节、起居无常、不知持满、不时御神、情志失调、久病体虚。“脾不散精，浊毒伤肝”是其基本病机，并贯穿糖尿病合并脂肪肝全过程。“脾不散精”为其本，导致肝脾肾功能失调，从而产生病理产物痰、湿、瘀、浊互结于肝而成脂肪肝。文献认为糖尿病合并脂肪肝为本虚标实之证，脾虚为病机之本，肝郁为发病之关键环节，痰瘀互阻为主要病理因素贯穿疾病始终。治疗上运用中医整体观念，以补虚泻实为基本大法，从调理肝脾两脏入手，根据病机演变，辨证运用疏肝健脾，化痰祛瘀之法。本发明人根据多年文献调研，临床和实验研究，认为糖尿病合并脂肪肝的中医病机为：脾失健运，肝肾阴虚，机体气机失常，肝失疏泄，湿聚成痰，且脾虚不能散精，精微蓄积，郁久则痰、湿、热毒内生，邪毒郁积，阻滞脉络，气滞血瘀，最终郁毒血瘀互结，积于胁下。糖尿病合并脂肪肝的关键病机为脾气亏虚、肝肾阴虚（气阴两虚），湿热内蕴、痰瘀互结（虚、毒、瘀），浊毒攻肝（毒、瘀）。治当疏肝健脾治其本，清热利湿、活血化淤治其标。
本发明中药配伍方组方包括黄芪、白术、茯苓、陈皮、柴胡、黄连，丹参,虎杖，山楂。方中重用黄芪为君药，性温味甘，归脾、肺经，可益气健脾，利水去浊；白术性温味苦、甘，归肝、脾、胃经，可健脾益气，燥湿利水，止汗；茯苓性平味甘淡，归心、肺、脾、肾经，可利水、渗湿、健脾、宁心；陈皮性温味辛、苦，归肺、脾、胃经，可理气健脾，燥湿化痰；柴胡性微寒味苦、辛，归肝、胆经，可疏散退热，疏肝解郁，升举阳气；黄连性寒味苦，归心、脾、胃、肝、胆、大肠经，可清热燥湿，泻火解毒；丹参性微寒味苦，归心、肝经，可活血化瘀，清热凉血解毒；虎杖性微寒味微苦，归肝、胆、肺经，可清热解毒，祛风利湿，活血散瘀止痛；山楂性微温味酸、甘，归脾、胃、肝经，可消食化积，活血散瘀；诸药合用，共奏疏肝健脾，清热利湿、化痰消瘀之功效。
本发明提供一种改善糖尿病合并脂肪肝的中药配伍方组合物，其由黄芪、白术、茯苓、陈皮、柴胡、黄连，丹参,虎杖，山楂组成。
优选地，各组分的配比为：黄芪15-60份、白术6-24份、茯苓6-24份、陈皮6-24份、柴胡5-20份、黄连3-12份，丹参5-20份,虎杖10-30份，山楂10-30份。
更优选地，各组分的配比为：黄芪30g、白术12g、茯苓12g、陈皮12g、柴胡10g、黄连6g，丹参 9g,虎杖15g，山楂15g。
本发明提供一种由所述的组合物制备得到的改善糖尿病合并脂肪肝的中药配伍方的制剂，优选地，其是口服液，薄膜包衣剂，胶囊剂，颗粒剂和粉针剂。
更具体地，所述口服液的制备方法为：将配比称取各组分，经水煎 2-4 次，合并煎液，过滤浓缩至生药 2-3g·mL－1，制成口服液，4 ℃冰箱贮存备用；
所述薄膜包衣剂的制备方法为：各组份打粉过 100 目筛，将细粉混合，100℃水浴提取 3 次，将提取液制成干浸膏；将干浸膏磨成细粉末后加入 95%的乙醇，使药液含醇量为 60%±5%，静置后过滤，与醇提取液真空 70℃混合干燥，得药物细粉，结合颗粒工艺与压片工艺制成薄膜包衣剂；
所述胶囊剂的制备方法为：将各组细粉整粒，然后装胶囊制成胶囊剂；
所述颗粒剂的制备方法为：将各组分的细粉，结合颗粒工艺，整粒，干燥，制成颗粒剂；
所述粉针剂的制备方法为：各组分的细粉，杀菌，制成粉针剂。
本发明还提供所述的组合物在制备预防或治疗糖尿病合并脂肪肝、糖尿病并发高血脂的制剂中的应用。
本发明通过实验验证，结果表明，本发明的中药配伍方能显著降低糖尿病合并脂肪肝小鼠肝指数，血糖，血胰岛素，血脂 TG、TCHO、LDL-C，血清炎症因子hs-CRP和TNF-α、肝组织TG含量和肝功能指标，差异具有统计学意义。本发明的配伍方可使糖尿病合并患者血糖，TG、TCHO和 LDL-C 下降，HDL-C 升高，减少 TG 在肝脏的堆积。说明本中药配伍方可减轻胰岛素抵抗及慢性炎症，调节体内糖脂代谢，减少肝脏脂质堆积，缓减脂肪肝的发展。本发明以我国传统的中医理论为依据，提供一种原料药易得、成本低、易于生产、服用方便、疗效好、提高病人生活质量、副作用小、无耐药性的防治糖尿病合并脂肪肝的中药制剂。
附图说明
图 1中药配伍方对糖尿病合并脂肪肝小鼠肝脏病理变化的影响。
其中：A1. 正常组;B1. 模型组;C1. 中药配伍方组(HE，× 400) ；A2. 正常组;B2. 模型组;C2. 中药配伍方组(油红染色，× 400)；A3. 正常组;B3. 模型组;C3.中药配伍方组(电镜，×9700)。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
实施例一
1材料与方法
1.1 材料
1.1.1 动物 MKR小鼠（采用组织特异性过度表达转基因技术产生），经自然交配后繁殖的子代用于实验观察。C57BL/6野生鼠购自中南大学 （实验动物学部）SPF级生产许可证号 SCXK（湘）2021－2。
1.1.2 饲养条件及环境 实验用小鼠饲养在湖南中医药大学SPF级实验动物中心。饲养笼具、垫料、饲料、饮水均按SPF级实验动物的要求进行制备与消毒。
1.1.3 药物 本实验的配伍组方由黄芪30g，白术12g，茯苓12g，陈皮12g，柴胡10g，黄连6g，丹参 9g，虎杖15g，山楂15g组成。经水煎 2 次，合并煎液，过滤浓缩至生药 2.4g·mL－1，制成口服液，4 ℃冰箱贮存备用。本药剂也可以制成薄膜包衣剂、胶囊剂、颗粒剂和粉针剂。薄膜包衣剂，各组份打粉过 100 目筛，将细粉混合，100℃水浴提取 3 次，将提取液制成干浸膏。将干浸膏磨成细粉末后加入 95%的乙醇，使药液含醇量为 60%±5%，静置后过滤，与醇提取液真空 70℃混合干燥，得药物细粉，结合颗粒工艺与压片工艺制成薄膜包衣剂，为本发明优选剂型；胶囊剂，药物细粉整粒，然后装胶囊制成胶囊剂；颗粒剂，结合颗粒工艺，整粒，干燥，制成颗粒剂；粉针剂，药物细粉，杀菌，制成粉针剂。
1.1.4 高脂饲料 基础饲料加15%猪油，1%胆固醇，0.05%牛黄胆酸纳。
1.1.5 试剂 末端全血葡萄糖测试条（北京怡成生物电子技术有限公司，批号20210424）；小鼠胰岛素ELISA试剂盒（ADL公司，产品号QRCT-301330013013EIA\UTL）；小鼠肿瘤坏死因子α（TNF-α）ELISA试剂盒（ADL公司，产品号QRCT-3013321033221EIA\UTL ）。
1.1.6仪器 怡成超越(JPS-Ⅲ型)血糖测试仪，北京怡成生物电子技术有限公司提供；日立7150全自动生化分析仪，日本日立；奥地利产酶标仪仪器 M1000 型多功能酶标仪( 瑞士 Tecan 公司) ，DIAX600 型 DIAxgoo 型匀浆机(德国 Heidolph公司) ，706型Forma － 80 ℃ 超低温冰箱(美国ThermoScientific 公司)，Neofuge23Ｒ 型台式高速离心机High Speed Bench-topCentrifuge(上海力申科学仪器有限公司) 。
方法
1.2.1中药配伍方组方对糖尿病合并脂肪肝小鼠的干预作用研究
20只经遗传鉴定的MKR鼠8 周时根据性别、体质量分层，随机分为模型组和中药配伍方组；另以10只同龄C57BL/6小鼠作为正常组。模型组、中药配伍方组均以高脂饲料喂养，连续8 周；正常组以基础饲料喂养。试验中无小鼠死亡。高脂饲料喂养4周后，中药配伍方组（前述的口服液）以31.46g生药.kg-1ig给药，正常组和模型组以等体积蒸馏水ig。ig剂量均按人（70kg）和动物体表面积折算的等效剂量比值表换算。实验后各组小鼠分别称重。ig容量为0.2mL/10g。每日定时ig1次，连续给药30d。末次给药后0.5h，心脏取血，分离血清，-20℃冰箱保存备用；肝脏称重，用于计算肝指数。
肝组织形态学观察
取小鼠肝脏最大叶距边缘5mm处肝组织，10%甲醛溶液固定，石蜡包埋，病理切片，HE染色后光镜观察，拍照。同时取一大小约1mm3的肝组织，4%戊二醛溶液固定，用于透射电镜观察肝脏的超微结构。油红 O 染色， 制作冰冻切片，4% 多聚甲醛固定 5min，磷酸盐缓冲液( PBS) 洗 1 次，再置于丙二醇中固定 5min，吸去丙二醇，加入 0.5% 油红 O的丙二醇溶液，置 60 ℃ 烤箱中染色 15min，85% 丙二醇冲洗 5min，PBS 洗 3 次，蒸馏水洗 1次，苏木素复染 2～5min，1% HCl 分色及返蓝后封片。置显微镜下观察并摄像，细胞内脂质为红色。
血指标检测
⑴血糖测定：实验结束前天小鼠禁食不禁水5h 后，以小鼠尾静脉血测血糖浓度。⑵血清肝功能指标天门冬氨酸氨基转移酶（AST）、谷丙转氨酶（ALT）和血脂 （TG、TC、LDL-C和 HDL-C）和hs-CRP：采用全自动生化仪进行测定。⑶血清胰岛素和TNF-α含量测定：ELISA法，操作严格按照试剂盒说明进行。
肝脏TG和FFA的测定
取新鲜肝脏组织，用9g／L的生理盐水4 ℃下制备10%的肝匀浆，3000r／min 离心15min，取上清。严格按照试剂盒要求测定甘油三酯（TG）和脂肪酸（FFA）含量。
统计方法
所有实验数据用SPSS17.0统计软件进行统计分析，结果用“
±S”表示，组间比较采用单因素方差分析，方差不齐采用非参数检验。P<0.05表示有统计学意义。
2结果
2.1病理形态学变化
光镜下可见：C57BL/6正常组小鼠肝小叶结构正常，肝细胞排列规则成条索状，以中央静脉为中心呈放射状分布，肝细胞大小正常，胞核位于细胞中央。糖尿病合并脂肪肝小鼠肝细胞以弥漫性小泡性脂变为主，中药配伍组改善了脂肪性变。油红 O 染色：油红 O 将细胞内出现的脂滴沉积染成红色，细胞内红色显影出现比例越高，提示细胞内脂滴沉积越多。C57BL/6正常组小鼠肝细胞有极少红色脂滴；糖尿病合并脂肪肝小鼠肝细胞内红色脂滴数量显著增加，体积变大；中药配伍组小鼠肝红色细胞脂滴数量和体积均减少。电镜下可见：C57BL/6正常组小鼠肝细胞形态结构正常，有丰富的线粒体；糖尿病合并脂肪肝小鼠肝细胞内堆满大小不一的脂滴，而中药配伍组小鼠肝细胞脂滴明显变小（见图 1）。
2.2中药配伍方对糖尿病合并脂肪肝小鼠血糖及胰岛素的影响
与C57BL/6正常组小鼠比较，模型组小鼠空腹血糖浓度和胰岛素含量均显著升高，差异具有统计学意义（P＜0.01）。中药配伍方能显著降低糖尿病合并脂肪肝小鼠血糖浓度和胰岛素水平，差异具有统计统计学意义（P＜0.01），见表1。
表1中药配伍方对糖尿病合并脂肪肝小鼠血糖及胰岛素含量的影响（
±S，n=10）
| 组别 | 剂量（g.kg<sup>-1</sup>） | 空腹血糖（mmol/L） | 胰岛素(ng/mL) |
| 正常组 | - | 5.86±1.83<sup>**</sup> | 0.73±0.08<sup>**</sup> |
| 模型组 | - | 11.24±2.01 | 20.48±2.01 |
| 中药配伍方组 | 31.46 | 8.23±1.23<sup>**</sup> | 7.21±0.53<sup>**</sup> |
注：与模型组比较：** P＜0.01
2.3中药配伍方对糖尿病合并脂肪肝小鼠肝指数的影响
与C57BL/6正常组小鼠比较，模型组小鼠肝指数显著升高，差异具有统计学意义（P＜0.01）。中药配伍方能显著降低糖尿病合并脂肪肝小鼠肝指数，差异具有统计统计学意义（P＜0.01），见表2。
表2中药配伍方对糖尿病合并脂肪肝小鼠肝指数的影响（
±S，n=10）
| 组别 | 剂量（g.kg<sup>-1</sup>） | 体质量 （ｇ） | 肝质量 （ｇ） | 肝指数 |
| 正常组 | - | 21.64±1.55 | 1.134±0.128<sup>**</sup> | 0.057±0.005<sup>**</sup> |
| 模型组 | - | 22.94±1.83 | 2.232±1.28 | 0.099±0.002 |
| 中药配伍方组 | 31.46 | 22.43±1.58 | 1.769±1.05<sup>**</sup> | 0.078±0.003<sup>**</sup> |
注：与模型组比较：** P＜0.01
2.3中药配伍方对糖尿病合并脂肪肝小鼠肝指数的影响
与C57BL/6正常组小鼠比较，模型组小鼠肝功能指标AST和ALT显著升高，差异具有统计学意义（P＜0.01）。中药配伍方能显著降低糖尿病合并脂肪肝小鼠肝功能指标AST和ALT含量，差异具有统计学意义（P＜0.01），见表3。
表3中药配伍方对糖尿病合并脂肪肝小鼠血清AST、ALT含量的影响（
±S，n=10）
| 组别 | 剂量（g.kg<sup>-1</sup>） | AST （U/L） | ALT（U/L） |
| 正常组 | - | 142.68±53.21<sup>**</sup> | 13.54±6.14<sup>**</sup> |
| 模型组 | - | 289.74±57.24 | 26.85±7.63 |
| 中药配伍方组 | 31.46 | 221.37±41.58<sup>**</sup> | 21.76±6.05<sup>**</sup> |
注：与模型组比较：** P＜0.01
2.2中药配伍方对糖尿病合并脂肪肝小鼠血脂的影响
与C57BL/6正常组小鼠比较，模型组小鼠TG、TCHO、LDL-C、和 LDL-C/HDL-C显著升高，HDL-C显著下降，差异具有统计学意义（P＜0.01）。与模型组比较，中药配伍方组小鼠TG、TCHO、LDL-C和LDL-C/HDL-C显著下降，差异具有统计学意义（P＜0.01），HDL-C升高，但无统计学意义（P＞0.05），见表4。
表4 中药配伍方对糖尿病合并脂肪肝小鼠血脂的影响（
±S，n=10）
注：与模型组比较：** P＜0.01
2.4中药配伍方对糖尿病合并脂肪肝小鼠肝脏TG和FAA含量检测结果
与C57BL/6正常组小鼠比较，模型组小鼠肝脏TG和FAA含量增加，差异具有统计学意义（P＜0.01）。与模型组比较，中药配伍方组小鼠肝脏TG和FAA含量异常增加，差异具有统计学意义（P<0.01），见表5。
表5中药配伍方对糖尿病合并脂肪肝小鼠肝脏TG和FAA含量（
±s，n=10）
| 组别 | 剂量（g.kg<sup>-1</sup>） | TG(µmol/g) | FAA(µmol/g) |
| 正常组 | - | 24.64±2.55<sup>**</sup> | 28.24±4.12<sup>**</sup> |
| 模型组 | - | 52.94±5.73 | 102.23±12.28 |
| 中药配伍方组 | 31.46 | 40.36±3.29<sup>**</sup> | 70.58±8.27<sup>**</sup> |
注：与模型组比较：** P＜0.01。
2.3中药配伍方对糖尿病合并脂肪肝小鼠炎症因子的影响
与C57BL/6正常组小鼠比较，模型组血清hs-CRP和TNF-α含量升高，差异具有统计学意义（P＜0.01）。与模型组比较，中药配伍方组hs-CRP和TNF-α水平均显著下降，差异具有统计学意义（P＜0.01），见表6。
表6中药配伍方对糖尿病合并脂肪肝小鼠血清炎症因子的影响（
±S，n=10）
| 组别 | 剂量（g.kg<sup>-1</sup>） | TNF-α(pg/mL) | hs-CRP (mg/L) |
| 正常组 | - | 265.44±28.26 | 0.14±0.108 |
| 模型组 | - | 731.43±8.84 | 0.19±0.213 |
| 中药配伍方组 | 31.46 | 513.90±4.03 | 0.15±0.325 |
注：与模型组比较：** P＜0.01。
实施例二
为了进一步验证，进行了初步的临床研究。46例糖尿病合并脂肪肝（ 中医辨证为脾气亏虚、肝肾阴虚）患者，随机分为观察组和对照组，各23例，治疗组给予本发明中药配伍方治疗；黄芪30g，白术12g，茯苓12g，陈皮12g，柴胡10g，黄连6g，丹参 9g，虎杖15g，山楂15g，水煎服，每日一剂，分两次，早晚口服各一次，3个月为一疗程。对照组给予二甲双胍合非诺贝特治疗，比较两组各项指标。两组病例治疗前各项检查指标比较无统计学意义（P>0.0 5）；经治疗后，对照组和治疗组空腹血糖、餐后2h血糖、血脂，差异具有统计学意义( P<0.0 5或0.0 1)，除空腹血糖外，治疗组各项检查指标优于对照组，差异具有统计学意义( P< 0.0 5或0.0 1)；治疗组在改善血脂、肝功能方面与对照组相当；在中医症候疗效方面，治疗组优于对照组。如将所取得成果应用于临床,可以满足临床需求,对减轻家庭和社会负担有深远的意义。
两组治疗后空腹血糖，餐后2 h血糖，血脂较治疗前明显降低，差异具有统计学意义( P< 0.05)；治疗组与对照组治疗后比较，空腹血糖差异无统计学意义(P > 0.05)，而餐后2 h血糖、TG、T-CHOL、LDL-C 治疗组下降程度优于对照组，差异具有统计学意义( P<0.05，0.01)，HDL-C治疗组上升优于对照组，差异具有统计学意义( P< 0.01)。 结果见表7。
表7. 两组治疗前后血糖、血脂比较 （
±S ）
治疗前后组内比较，# P<0.05； 治疗组与对照组治疗后比较， *P<0.05，**P<0.0l。
Claims (7)
1.一种改善糖尿病合并脂肪肝的中药配伍方组合物，其由黄芪、白术、茯苓、陈皮、柴胡、黄连，丹参,虎杖，山楂组成。
2.如权利要求1所述的组合物，其特征在于，各组分的配比为：黄芪15-60份、白术6-24份、茯苓6-24份、陈皮6-24份、柴胡5-20份、黄连3-12份，丹参5-20份,虎杖10-30份，山楂10-30份。
3.如权利要求2所述的组合物，其特征在于，各组分的配比为：黄芪30g、白术12g、茯苓12g、陈皮12g、柴胡10g、黄连6g，丹参 9g,虎杖15g，山楂15g。
4.一种由如权利要求1至3任一项所述的组合物制备得到的改善糖尿病合并脂肪肝的中药配伍方的制剂。
5.如权利要求4所述的制剂，其特征在于，所述制剂是口服液，薄膜包衣剂，胶囊剂，颗粒剂和粉针剂。
6.如权利要求5所述的制剂，其特征在于，所述口服液的制备方法为：将配比称取各组分，经水煎 2-4 次，合并煎液，过滤浓缩至生药 2-3g·mL－1，制成口服液，4 ℃冰箱贮存备用；
所述薄膜包衣剂的制备方法为：各组份打粉过 100 目筛，将细粉混合，100℃水浴提取3 次，将提取液制成干浸膏；将干浸膏磨成细粉末后加入 95%的乙醇，使药液含醇量为 60%±5%，静置后过滤，与醇提取液真空 70℃混合干燥，得药物细粉，结合颗粒工艺与压片工艺制成薄膜包衣剂；
所述胶囊剂的制备方法为：将各组细粉整粒，然后装胶囊制成胶囊剂；
所述颗粒剂的制备方法为：将各组分的细粉，结合颗粒工艺，整粒，干燥，制成颗粒剂；
所述粉针剂的制备方法为：将各组分的细粉，杀菌，制成粉针剂。
7.如权利要求1至3任一项所述的组合物在制备预防或治疗糖尿病合并脂肪肝、糖尿病并发高血脂的制剂中的应用。
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