CN100417389C - 一种用于治疗微血管循环障碍疾病的药物组合物及其制备方法 - Google Patents
一种用于治疗微血管循环障碍疾病的药物组合物及其制备方法 Download PDFInfo
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- CN100417389C CN100417389C CNB2006100813055A CN200610081305A CN100417389C CN 100417389 C CN100417389 C CN 100417389C CN B2006100813055 A CNB2006100813055 A CN B2006100813055A CN 200610081305 A CN200610081305 A CN 200610081305A CN 100417389 C CN100417389 C CN 100417389C
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- Prior art keywords
- radix puerariae
- puerariae flavone
- calcium dobesilate
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- flavone
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Abstract
本发明涉及一种用于治疗微血管循环障碍疾病的药物组合物及其制备方法，其特征在于：含有羟苯磺酸钙和葛根黄酮作为药物活性成分，其中羟苯磺酸钙和葛根黄酮的重量配比为：10-1000重量份的羟苯磺酸钙和10-1000重量份的葛根黄酮。
Description
技术领域
本发明涉及一种用于治疗由微血管循环障碍引起的多种疾病的药物组合物及其制备方法。该组合物含有羟苯磺酸钙和葛根黄酮作为药物活性成分，主要用于治疗由微血管循环障碍引起的多种疾病，特别的，主要用于糖尿病引起的视网膜病变，微循环障碍引起的心、脑、肾疾病，如肾小球动脉硬化症以及静脉曲张等综合症的治疗。
背景技术
糖尿病是一组常见的代谢内分泌病，全世界有糖尿病患者1.25亿，我国的糖尿病患者已达4000万。世界卫生组织将糖尿病列为三大疑难病之一，由于糖尿病患者体内血糖浓度较高，过量的葡萄糖经戊糖旁路进行代谢，被醛糖还原酶催化生成山梨醇，而山梨醇可以造成毛细血管细胞和内皮细胞受损；另外患者微血管内皮细胞可生成过多的凝血因子VIII，前列腺环素产生减少，均可促使血小板发生黏附和聚集，促进微血栓形成，另外血糖增高刺激IV型胶质蛋白及粘连蛋白合成增加，硫酸类肝素多糖蛋白构成的负电荷位点数目减少，毛细血管通透性增加。这一系列的原因使糖尿病患者往往伴随较多的并发症，如糖尿病肾病、糖尿病眼病、糖尿病神经病变、糖尿病足、糖尿病心、脑大血管病变等。
同时，其他的一些疾病也直接或间接的导致微血管循环障碍，进而对身体各个器官产生危害，给患者带来了极大的痛苦。
羟苯磺酸钙通过调节微血管壁的生理功能，减低毛细血管的高通透性和减少阻力，降低血浆粘稠度，降低血小板的高聚集性，从而防止血栓形成；通过提高红细胞柔韧性，间接增加淋巴的引流从而减少水肿。羟苯磺酸钙还可以通过抑制血管活性物质(组织胺、5-羟色胺、缓激肽、透明质酸酶、前列腺素)引起的高通透作用，从而改善基底膜胶原的生物合成。因此可以用于微血管循环障碍(毛细血管循环障碍)引起的多种疾病。
中医药在改善血流状态、提高免疫、抗衰老等多途径、多方面、多环节上已经显示出巨大的优势，其毒副作用小，且疗效稳定。
葛根黄酮是从中药葛根中提取的总黄酮，具有降血糖，扩张外周血管，特别是扩张冠状动脉血管、改变高凝聚状态及微循环、抑制血小板聚集等作用。葛根素作为葛根黄酮中的一种，是一个抗氧剂，国外有文献报道，葛根素可有效去除自由基对胰岛细胞的伤害(Puerarin protects rat pancreatic islets from damage byhydrogen peroxide.European Journal of Pharmacology[Eur J Pharmacol]2006Jan 4；Vol.529(1-3)，pp.1-7)。
由于治疗微循环障碍疾病，特别是糖尿病引起的微循环障碍疾病，是一个极其复杂的过程，单一用药难以取得满意的治疗效果。因此，本发明人从中西医结合的角度，通过大量的实验发现：以羟苯磺酸钙组合葛根黄酮，治疗微循环障碍疾病，能够具有协同作用，达到了优势互补，提高疗效的作用。
发明内容
羟苯磺酸钙为国际上广泛使用的微血管循环改善剂，1997年载入欧洲药典，1998年载入英国药典。对微血管循环障碍(毛细血管循环障碍)引起的多种疾病，疗效确切，
葛根黄酮，尤其是葛根素具有抑制血小板聚集，降低血液粘度，改善微循环的作用，对人血清蛋白和大鼠晶状体蛋白的非酶糖基化有明显抑制作用。
本发明将羟苯磺酸钙与葛根黄酮组合应用来治疗微血管循环障碍疾病，特别是由糖尿病引起的视网膜病变等有着较好的协同作用，比单独使用效果更佳。基于上述发现，本发明提供一种用于治疗由微血管循环障碍引起的多种疾病的药物组合物及其制备方法。该组合物含有羟苯磺酸钙和葛根黄酮作为药物活性成分，可用于治疗由微血管循环障碍引起的多种疾病，特别的，主要用于糖尿病引起的视网膜病变，微循环障碍引起的心、脑、肾疾病，如肾小球动脉硬化症以及静脉曲张等综合症的治疗。
本发明所述葛根黄酮是从中药葛根中提取得到的含有黄酮类成分的提取物，该提取物由于提取工艺不同，所含黄酮类成分也不同，该提取物可以是葛根总黄酮，也可以是其中的一种葛根黄酮或其中的几种葛根黄酮的混合物。优选的葛根黄酮是葛根素(8-β-D-葡萄吡喃糖-4′，7-二羟基异黄酮)。
葛根黄酮作为药物应用有多年，可以从市场上买到，已经列入药典或国家药品标准，其制备方法有多种，在专利文献或其他文献中有大量的报道，属于现有技术，如：葛根黄酮通过粉碎、压榨、研磨、过筛、渗漉、萃取、水提、醇提、酯提、层析等方法对葛根进行加工得到、所得葛根黄酮可以是浸膏形式的物质，可以是干浸膏也可以是流浸膏，根据制剂的不同需要决定制成不同的浓度。
本发明也提供了葛根黄酮的制备方法，具体见实施例。
根据本发明，所述葛根黄酮是符合药物标准的产品，只要符合药物标准，能够作为药物应用，不管用什么方法制备的葛根黄酮都属于本发明的保护范围。
本发明的组合物，其中羟苯磺酸钙和葛根黄酮的重量配比为10-1000重量份的羟苯磺酸钙和10-1000重量份的葛根黄酮。
优选的羟苯磺酸钙和葛根黄酮的重量配比为100-500重量份的羟苯磺酸钙和100-500重量份的葛根黄酮。
最优选的羟苯磺酸钙和和葛根黄酮的重量配比为250重量份的羟苯磺酸钙和250重量份的葛根黄酮。
以上组成是按重量作为配比的，如大规模生产可以以kg为单位，或以t(吨)为单位；小规模制剂也可以以g为单位。重量可以增大或者减小，但各组成之间的重量配比的比例不变。
以上重量配比的比例是经过科学筛选得到的，对于特殊病人，如重症或轻症，肥胖或瘦小的病人，可以相应调整组成的量的配比，增加或减少不超过100％，药效不变。
本发明的组合物，以药物制剂形式存在，优选的是单位剂量的药物制剂形式，在制成药物制剂时可以制成任何可药用的剂型，这些剂型选自：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、丸剂、散剂、膏剂、丹剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂。优选的是口服制剂形式，最佳优选的是片剂，胶囊剂，颗粒剂。
本发明的药物制剂，根据需要可以加入一些药物可接受的载体，可以采用制剂学常规技术制备该药物制剂，如将药物活性物质与药物可接受的载体混合。所述药物可接受的的载体选自：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物制剂在使用时根据病人的情况确定用法用量。
本发明的药物制剂，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
本发明最优选的配方列在本发明实施例中。
本发明的组合物主要用于治疗由微血管循环障碍引起的多种疾病，特别用于糖尿病引起的视网膜病变，微循环障碍引起的心、脑、肾疾病，如肾小球动脉硬化症以及静脉曲张等综合症的治疗。
以下通过实验数据说明本发明的有益效果：
试验例1：羟苯磺酸钙和葛根黄酮组合物对大鼠血流动力学的影响
取大鼠，禁食12h后，快速尾静脉注射链脲霉素50mg·kg-1，72h后测定血糖值。选择血糖水平13mmol·L-l以上者，按体重随机分五组，模型组，正常组，葛根黄酮治疗组(A组)，羟苯磺酸钙治疗组(B组)，实施例6中所得羟苯磺酸钙和葛根黄酮组合物治疗组(A+B组)，每组8只，灌胃给药，给药量l00mg·kg-1，qd，连续30d，动物分组及实验方法同上，摘大鼠眼球取血4ml，(肝素体外抗凝)，测定以下指标：(1)全血粘度(ηb)，(2)血浆粘度(ηb)，(3)红细胞压积(HCT)，(4)血沉(ESR)，试验结果如表1所示。
表1葛根提取物对STZ大鼠血流动力学的影响(x±s，n＝8)
结论：由以上试验结果可知，与单独用药及模型组相比羟苯磺酸钙和葛根黄酮组合物治疗组，可明显降低大鼠全血高切粘度、低切粘度及血浆粘度，红细胞压积。由于高切血液粘度主要反映红细胞的变形能力，低切血液粘度主要反映红细胞的聚集能力，表明羟苯磺酸钙和葛根黄酮具有降低血液粘稠度、改善局部血液循环的协同药理作用，因此可用于治疗微血管循环障碍疾病，如糖尿病引起的视网膜病变等。
试验例2：羟苯磺酸钙和葛根素组合物治疗糖尿病视网膜病变疗效观察
II型糖尿病患者60例，符合WHO糖尿病诊断和分型标准，临床诊断为糖尿病视网膜病变，除外其他原因所致眼底改变。随机分为4组，分别为葛根素治疗组(A组)，羟苯磺酸钙治疗组(B组)，羟苯磺酸钙和葛根素组合物治疗组(A+B组)。
四组患者给予常规降血糖药物治疗的同时，治疗组A给予葛根素500mg，每日2次；治疗组B给予羟苯磺酸钙500mg，每日2次；治疗组A+B给予葛根素和羟苯磺酸钙各250mg，每日2次，以上药物均口服给药；对照组予弥克保500μg，每日1次，肌肉注射，3周为1个疗程，连用2个疗程。
4组患者均于治疗前后用彩色多普勒测定视网膜中央动静脉血流参数，治疗前后视网膜中央动脉的收缩峰值血流速度(PSV)、加速度(A)、舒张末期血流最大速度(EDV)以及视网膜中央静脉回流速度(CRV)结果如下表所示。
表2治疗前后视网膜中央动静脉血液流变学血参数比较(cm/s)
由试验结果可知，各治疗组治疗前后视网膜中央动脉的收缩峰值血流速度(PSV)、加速度(A)、舒张末期血流最大速度(EDV)均增加，视网膜中央静脉回流速度(CRV)减慢。与羟苯磺酸钙和葛根素单独用药相比，复方给药组对视网膜中央动静脉血液流变学血参数的改变更加显著，揭示复方给药对视网膜微循环改善作用较单独给药为佳，说明两种药物具有很好的协同微循环改善作用，可以使用两药的复方来治疗糖尿病视网膜病变等微循环障碍疾病。
具体实施方式
下面通过具体实施方式对本发明做进一步说明，但并不意味着对本发明保护范围的限定。
实施例1
将原辅料分别过100目筛，取羟苯磺酸钙5g，葛根黄酮500g，加入微晶纤维素、羧甲基淀粉钠混合均匀，加入15％PVP适量制成软材，用16-24目筛制粒，湿颗粒于50-80℃干燥，16-24目筛整粒，加入硬脂酸镁混匀，测定颗粒中主药含量合格后，压片，制成2000片。
其中，葛根黄酮的提取方法如下：取葛根10kg，加6倍量水煎煮三次，第一次1.0小时，第二、三次为0.5小时，分别滤过，合并滤液，浓缩成相对密度为1.08～1.14(55℃)的清膏，将清膏搅拌下加入2.8倍的乙醇，搅匀，加热至60℃，静置24h，滤过，减压回收乙醇，浓缩成稠膏状，85℃以下真空干燥得干膏1.25kg，将干膏研细备用。通过紫外分光光度法测定，干膏中葛根黄酮所占的百分比约为40％，干膏中葛根黄酮的量约为500g。
实施例2
将原辅料分别过100目筛，取羟苯磺酸钙500g，葛根黄酮5g，加入微晶纤维素、羧甲基淀粉钠混合均匀，加入15％PVP适量制成软材，用16-24目筛制粒，湿颗粒于50-80℃通风干燥，16-24目筛整粒，加入硬脂酸镁混匀，测定颗粒中主药含量合格后，上胶囊分装机包封，制成1000粒。
其中，葛根黄酮的提取方法如实施例1所述。
实施例3
将原辅料分别过100目筛，取羟苯磺酸钙100g，葛根素500g，加入微晶纤维素、羧甲基淀粉钠混合均匀，加入15％PVP适量制成软材，用16-24目筛制粒，湿颗粒于50-80℃通风干燥，16-24目筛整粒，加入硬脂酸镁混匀，测定颗粒中主药含量合格后，压片，制成2000粒。
实施例4
将原辅料分别过100目筛，取羟苯磺酸钙500g，葛根素100g，加入微晶纤维素、羧甲基淀粉钠混合均匀，加入15％PVP适量制成软材用16-24目筛制粒，湿颗粒于50-80℃通风干燥，16-24目筛整粒，加入硬脂酸镁混匀，测定颗粒中主药含量合格后，上胶囊分装机包封，制成1000粒。
实施例5
将原辅料分别过100目筛，取羟苯磺酸钙250g，葛根素250g，加入微晶纤维素、羧甲基淀粉钠混合均匀，加入15％PVP适量制成软材，用16-24目筛制粒，湿颗粒于50-80℃通风干燥，16-24目筛整粒，加入硬脂酸镁混匀，测定颗粒中主药含量合格后，压片，制成2000粒。
实施例6
将原辅料分别过100目筛，取羟苯磺酸钙250g，葛根黄酮250g，加入微晶纤维素、羧甲基淀粉钠混合均匀，加入15％PVP适量制成软材，用16-24目筛制粒，湿颗粒于50-80℃通风干燥，16-24目筛整粒，加入硬脂酸镁混匀，测定颗粒中主药含量合格后，上胶囊分装机包封，制成1000粒。
其中，葛根黄酮的提取方法如实施例1所述。
Claims (10)
1. 一种用于治疗由微血管循环障碍引起的多种疾病的药物组合物，其特征在于：含有羟苯磺酸钙和葛根黄酮作为药物活性成分，其中羟苯磺酸钙和葛根黄酮的重量配比为：10-1000重量份的羟苯磺酸钙和10-1000重量份的葛根黄酮。
2. 根据权利要求1所述的组合物，其特征在于：其中羟苯磺酸钙和葛根黄酮的重量配比为：100-500重量份的羟苯磺酸钙和100-500重量份的葛根黄酮。
3. 根据权利要求1所述的组合物，其特征在于：其中羟苯磺酸钙和和葛根黄酮的重量配比为：250重量份的羟苯磺酸钙和250重量份的葛根黄酮。
4. 根据权利要求1-3任何一项组合物，其特征在于：其中葛根黄酮可以是从葛根中提取得到的葛根总黄酮，也可以是一种葛根黄酮或几种葛根黄酮的混合物。
5. 根据权利要求1-3任何一项组合物，其特征在于：其中葛根黄酮是葛根素。
6. 根据权利要求1-3任何一项组合物，其特征在于：选自如下药物剂型，片剂、胶囊剂、口服液、口含剂、颗粒剂、丸剂、散剂、膏剂、丹剂、注射剂、栓剂、霜剂、喷雾剂、贴剂。
7. 根据权利要求6的组合物，其特征在于：是片剂或胶囊剂。
8. 根据权利要求1所述的组合物，其特征在于：还含有微晶纤维素、羧甲基淀粉钠、淀粉、糊精、PVP或硬脂酸镁。
9. 权利要求1的组合物在制备治疗由微血管循环障碍引起的疾病的药物中的应用。
10. 权利要求9的应用，其特征在于：由微血管循环障碍引起的疾病是糖尿病引起的视网膜病变，微循环障碍引起的心、脑、肾疾病。
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Effective date of registration: 20090213 Address after: No. 1, one heart road, Shuangyang Economic Development Zone, Jilin, Changchun: 130616 Patentee after: Jilin Yixin pharmaceutical Limited by Share Ltd. Address before: Tianchuang Technology Building No. 8 Beijing Haidian District color charge Fang Lu room 720 zip code: 100080 Co-patentee before: Jilin Yixin pharmaceutical Limited by Share Ltd. Patentee before: Beijing Guodan Medicine Technology Development Co.,Ltd. |
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| ASS | Succession or assignment of patent right |
Owner name: JILIN YIXIN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: BEIJING GUO DAN DRUG TECHNOLOGY DEVELOPMENT CO., LTD. Effective date: 20090213 |
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| C56 | Change in the name or address of the patentee |
Owner name: JILIN A-THINK PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: JILIN YIXIN PHARMACEUTICAL CO., LTD. |
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| CP01 | Change in the name or title of a patent holder |
Address after: 130616 Jilin province Changchun Shuangyang Economic Development Zone on the road No. 1 Patentee after: SINOPHARM A-THINK PHARMACEUTICAL Co.,Ltd. Address before: 130616 Jilin province Changchun Shuangyang Economic Development Zone on the road No. 1 Patentee before: Jilin Yixin pharmaceutical Limited by Share Ltd. |
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| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Guoyao Yixin Pharmaceutical Co.,Ltd. Person in charge of patentsThe principal of patent Document name: Notice of termination of patent right |
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080910 |