CN108057102B - 预防或治疗痛风性关节炎的药物组合物、制备方法和用途 - Google Patents
预防或治疗痛风性关节炎的药物组合物、制备方法和用途 Download PDFInfo
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Abstract
本发明提供一种用于预防或治疗痛风性关节炎的药物组合物,其以秦皮、土茯苓和牛膝为原料经10%v/v~90%v/v的乙醇水溶液提取制成。本发明还提供了所述药物组合物的制备方法和用途,以及含有所述药物组合物的药物制剂及其制备方法。本发明的药物组合物具有较好的抗炎抑菌作用,可有效预防或治疗痛风性关节炎。本发明药物组合物的原料药味虽少,但三者联合使用具有较好的减毒增效作用。本发明药物组合物原料来源易得,易于产业化,可根据需要制成各种剂型,为临床提供更加方便、更加有效、质量更加可控的现代中药。
Description
技术领域
本发明属于中药领域,涉及一种用于预防或治疗痛风性关节炎的药物组合物及其制备方法和用途,本发明还涉及含有所述药物组合物的药物制剂及其制备方法。
背景技术
痛风是由于嘌呤代谢紊乱,导致血尿酸水平增高,和/或尿酸排泄减少而导致尿酸盐在组织沉积的疾病,尿酸盐沉积在关节部位可导致急慢性关节炎,即称痛风性关节炎。
急性痛风性关节炎是尿酸钠盐微结晶引起的炎症反应,其临床症状表现为关节肿胀,疼痛难忍,且易反复发作。尿酸在体液中的溶解性较低,pH=7.4时,尿酸最高溶解度是380μmol/L,超过溶解度时形成过饱和状态,并以尿酸盐的形式沉积在关节软骨、滑膜和其他组织,因为这些组织中血管较少,组织液pH较低,基质中含粘多糖和结缔组织较丰富,使尿酸盐容易沉积,微结晶引起非特异性炎症反应,造成关节软骨的溶解和软组织的损伤。因此,抗炎镇痛和加速尿酸盐的排泄是治疗痛风性关节炎的重要方法。
目前,急性痛风性关节炎需要药物治疗,而且治疗最好在起病后24h之内开始,越早治疗,效果越好。临床上常用药物包括非甾体类抗炎药、前列腺素抑制剂、秋水仙碱或类固醇药物、降尿酸药物等。但是,秋水仙碱有胃肠道、肾脏以及骨髓抑制等副作用;非甾体类抗炎药具有明显的胃肠道副作用如消化不良、出血、糜烂和溃疡等;皮质醇激素易造成体内激素水平紊乱,发胖,停药后反弹等不良反应;别嘌醇易产生超敏反应等,从而大大限制了其临床应用。
痛风性关节炎属于中医学“痹证、痛风、历节”范畴,热毒壅盛是痛风急性期关节疲阻的重要原因,湿邪化热,湿热之邪灼伤津液,血受熏蒸,凝结癖塞,加重受累关节气血运行不畅。目前临床上已有较多采用中药复方治疗急性痛风性关节炎的报道,如息痛散,四妙散加味,白虎加桂枝汤加减等,收到了良好的临床疗效。
秦皮为木犀科植物苦枥白蜡树Fraxinus rhynchophylla Hance,白蜡树Fraxinuschinensis Roxb.,尖叶白蜡树Fraxinus chinesisvar.acuminata Lingelsh.,宿柱白蜡树Fraxinus stylosa Lingelsh.的干燥枝皮或干皮,具有清热燥湿、收涩、明目的功效。秦皮中主要抗炎镇痛作用的化学成分是香豆素类化合物,包括秦皮苷、鸢尾苷、野鸢尾苷、次野鸢尾黄素和鸢尾黄素等成分。
土茯苓为百合科植物光叶菝契(Smilax glabra Roxb.)的干燥根,是具有除湿、清热、通利关节功效的一味传统中药。已有研究表明,天然药物土茯苓中具有利尿、清热、泻火、解毒的有效组分为土茯苓总黄酮类成分,主要包括落新妇苷、黄杞苷、花旗松素等。对于土茯苓,目前在临床上已有多种形式的口服和注射型药物被广泛使用。
牛膝为苋科植物牛膝(Achyranthese bidentata B)的干燥根,性苦、甘、酸、平,归肝肾经,具有活血祛瘀、补肝肾、强筋骨、利尿通淋、引血下行功效,药材主要包括甾酮、黄酮、三萜皂苷、多糖类成分。
需要进一步开发一种疗效好、使用方便的用于预防或治疗痛风性关节炎的药物组合物。
发明内容
本发明的一个目的是提供一种疗效好、使用方便的用于预防或治疗痛风性关节炎的药物组合物。
本发明的另一个目的是提供一种制备上述药物组合物的方法。
本发明的又一个目的是提供一种包含本发明所述的药物组合物的药物制剂。
本发明的再一个目的是提供上述药物制剂的制备方法。
本发明的又一个目的是提供本发明所述的药物组合物的用途。
本发明的目的是通过以下技术方案来实现的。
一方面,本发明提供一种用于预防或治疗痛风性关节炎的药物组合物,其以秦皮、土茯苓和牛膝为原料经10%v/v~90%v/v的乙醇水溶液提取制成。
优选地,所述药物组合物以1重量份的秦皮、0.1~10重量份的土茯苓和0.1~10重量份的牛膝为原料提取制成;更优选地,所述药物组合物以1重量份的秦皮、0.2~5重量份的土茯苓和0.2~5重量份的牛膝为原料提取制成;进一步优选地,所述药物组合物以1重量份的秦皮、2重量份的土茯苓和1重量份的牛膝为原料提取制成。
优选地,所述的药物组合物以秦皮、土茯苓和牛膝为原料经10%v/v~90%v/v的乙醇水溶液回流提取、浓缩而制成。
另一方面,本发明提供一种制备上述药物组合物的方法,所述方法包括以下步骤:
1)取秦皮、土茯苓和牛膝,加入10%v/v~90%v/v的乙醇水溶液加热提取,优选在常压回流温度下加热提取,得到提取液;
2)减压浓缩步骤1)所得提取液即得。
优选地,其中步骤1)中所述乙醇水溶液的重量为秦皮、土茯苓和牛膝总重量的6-20倍;优选地,所述提取进行1~4次。
优选地,其中步骤2)中的减压浓缩在50~75℃的温度下进行;优选地,所述减压浓缩进行至相对密度为1.10~1.20;更优选地,所述减压浓缩继续进行至得到稠浸膏。
又一方面,本发明提供一种用于预防或治疗痛风性关节炎的药物制剂,其包含本发明所述的药物组合物和药学上可接受的辅料。
优选地,所述药学上可接受的辅料选自赋形剂、填充剂、粘合剂、稀释剂、润滑剂、湿润剂、崩解剂、表面活性剂、增溶剂、乳化剂、消泡剂、防腐剂、甜味剂和芳香剂等中的一种或多种。具体的,所述辅料例如为淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、低取代羟丙基纤维素、交联聚维酮、羧甲基淀粉钠、聚乙二醇、硬脂酸镁、微粉硅胶、葡萄糖、甘露醇、木糖醇、甘氨酸、柠檬酸、富马酸、酒石酸、苹果酸、蛋白糖、糖精钠、苹果香精、菠萝香精、桔子香精、滑石粉、可溶性淀粉、十二烷基硫酸镁等。
根据需要,本发明的药物组合物可制成适于各种途径用药的药物制剂。优选地,所述的药物制剂为口服制剂、注射剂或外用制剂。
优选地,所述口服制剂为片剂、颗粒剂、胶囊剂、滴丸剂或适当形式的缓释剂、控释剂等固体口服制剂等,更优选地,所述口服制剂为软胶囊剂、分散片、缓释片、控释片、泡腾片或口腔崩解片等;所述注射剂为粉针剂或水针剂等;所述外用制剂为喷雾剂或滴鼻剂等。
再一方面,本发明提供一种制备上述药物制剂的方法,其包括以下步骤:将本发明所述的药物组合物与药学上可接受的辅料混合,再进一步制备成所述药物制剂。
又一方面,本发明提供所述药物组合物在制备用于预防或治疗痛风性关节炎的药物中的用途。本发明的药物组合物具有抗炎、抑制尿素酶活性、消肿止痛等作用,可用于治疗痛风性关节炎。
本发明的药物组合物是在秦皮、土茯苓这一治疗痛风经典药对的基础上组合牛膝而成的,本发明的药物组合物不但药效物质较为清楚(秦皮香豆素、土茯苓黄酮、牛膝三萜皂苷及甾醇类成分),药理作用较为突出,符合现代医学的抗炎镇痛、降低尿酸水平的治疗理念,而且符合传统中医的从肝脾肾综合而治和清热解毒、活血通络的治法治则,并具有较好的协同增效减毒作用,获得了较好的疗效。
本发明药物组合物具有明显的抗炎、镇痛、促进尿酸排泄作用,可有效预防或治疗痛风性关节炎,尤其是痛风性关节炎急性发作期。本发明药物组合物的原料为秦皮、土茯苓和牛膝,药味虽少,但三者联合使用具有较好的减毒增效作用。本发明药物组合物原料来源易得,易于产业化,可根据需要制成各种剂型,为临床提供更加方便、更加有效、质量更加可控的现代中药,既提高了传统中药的药理作用和临床疗效,同时通过提取分离纯化降低了杂质含量,实现了现代中药复方安全、有效、稳定、可控、方便的目的。
具体实施方式
下面结合如下实施例对本发明做更进一步的详细说明,其并不意味着限制本发明。
除非另外说明,本文所用的术语“QTNF浸膏”是指本发明的以秦皮、土茯苓和牛膝为原料制成的浸膏。
实施例1 QTNF浸膏的制备
取秦皮药材1kg,土茯苓2kg,牛膝1kg,用重量为药材总重量10倍的70%v/v乙醇回流提取三次,每次2小时,收集提取液,60℃下减压回收溶剂至相对密度1.20,即得QTNF浸膏。
实施例2 QTNF浸膏的制备
取秦皮药材1kg,土茯苓5kg,牛膝0.5kg,用重量为药材总重量8倍的50%v/v乙醇回流提取2次,每次1小时,收集提取液,75℃下减压回收溶剂至相对密度1.15,即得QTNF浸膏。
实施例3 QTNF浸膏的制备
取秦皮药材1kg,土茯苓10kg,牛膝0.1kg,用重量为药材总重量20倍的30%v/v乙醇回流提取1次,每次3小时,收集提取液,65℃下减压回收溶剂至相对密度1.10,即得QTNF浸膏。
实施例4 QTNF浸膏的制备
取秦皮药材1kg,土茯苓0.5kg,牛膝2kg,用重量为药材总重量12倍的90%v/v乙醇回流提取3次,每次1.5小时,收集提取液,50℃下减压回收溶剂至相对密度1.15,即得QTNF浸膏。
实施例5 QTNF浸膏的制备
取秦皮药材1kg,土茯苓0.2kg,牛膝5kg,用重量为药材总重量16倍的10%v/v乙醇回流提取2次,每次2小时,收集提取液,70℃下减压回收溶剂至相对密度1.18,即得QTNF浸膏。
实施例6 QTNF浸膏的制备
取秦皮药材1kg,土茯苓0.1kg,牛膝10kg,用重量为药材总重量15倍的60%v/v乙醇回流提取2次,每次1小时,收集提取液,60℃下减压回收溶剂至相对密度1.16,即得QTNF浸膏。
实施例7 QTNF浸膏的制备
取秦皮药材1kg,土茯苓1kg,牛膝0.2kg,用重量为药材总重量20倍的20%v/v乙醇回流提取一次,每次3小时,收集提取液,65℃下减压回收溶剂至相对密度1.12,即得QTNF浸膏。
实施例8 胶囊剂的制备
用实施例1所得到的QTNF浸膏,取QTNF浸膏14g和淀粉40g,混合均匀,用85%v/v乙醇制粒,60℃干燥,整粒,装胶囊,即制得含有1重量份秦皮、2重量份土茯苓和1重量份牛膝的提取物的胶囊剂。
实施例9 泡腾片剂的制备
将实施例2得到的QTNF浸膏,减压干燥,得到干膏粉,取QTNF干膏6g、乳糖23g、枸橼酸20g、碳酸氢钠22g、碳酸钠3g、滑石粉2g,将上述原辅料过80目筛,混合均匀,压片,即制得含有1重量份秦皮、5重量份土茯苓和0.5重量份牛膝的提取物的泡腾片剂。
实施例10 泡腾片剂的制备
将聚乙二醇(PEG6000)10g水浴加热熔融,加入36g碳酸氢钠混合均匀,冷却粉碎过80目筛;将实施例3得到的QTNF浸膏,减压干燥,得到干膏粉,取所述干膏粉10g、乳糖20g和枸橼酸32g,过80目筛混匀;将以上粉末混匀,用10%淀粉浆制粒,60℃以下干燥,整粒,硬脂酸镁1g,混合均匀,压片,即制得含有1重量份秦皮、10重量份土茯苓和0.1重量份牛膝的提取物的泡腾片剂。
实施例11 泡腾片剂的制备
用实施例4所得到的QTNF浸膏,取QTNF浸膏4g、乳糖20g、枸橼酸30g过80目筛混匀,用聚乙烯吡咯烷酮乙醇溶液制粒,颗粒在60℃以下干燥,整粒,分别加入碳酸氢钠36g、硬脂酸镁2g,混合均匀,压片,即制得含有1重量份秦皮、0.5重量份土茯苓和2重量份牛膝的提取物的泡腾片剂。
实施例12 滴丸的制备
用实施例5所得到的QTNF浸膏,取QTNF浸膏20g,混合均匀,加入40g熔融的聚乙二醇6000中,搅拌均匀,保温90℃状态下倒入滴丸装置中,以30d/min的滴速滴入10℃的液体石蜡中,制成滴丸,即制得含有1重量份秦皮、0.2重量份土茯苓和5重量份牛膝的提取物的滴丸剂。
实施例13 软胶囊剂的制备
用实施例6所得到的QTNF浸膏,取QTNF浸膏6g和植物油60g,混匀,用明胶作囊壳材料,压制成软胶囊,即制得含有1重量份秦皮、0.1重量份土茯苓和10重量份牛膝的提取物的软胶囊剂。
实施例14 颗粒剂或片剂的制备
用实施例7所得到的QTNF浸膏,取QTNF浸膏8g和蔗糖40g,混合均匀,制粒,干燥,即制得含有1重量份秦皮、1重量份土茯苓和0.2重量份牛膝的提取物的颗粒剂;或将制得的颗粒经进一步压片,即制得含有1重量份秦皮、1重量份土茯苓和0.2重量份牛膝的提取物的片剂。
实施例15 缓释片剂的制备
用实施例1所得到的QTNF浸膏,取QTNF浸膏2g和羟丙甲纤维素(HPMCK 100M,美国Colocon公司)50g,卡波普(934FPN,美国古立德公司)30g,混合均匀,制粒,干燥,压片,即制得含有1重量份秦皮、2重量份土茯苓和1重量份牛膝的提取物的缓释片剂。
实施例16 分散片剂的制备
用实施例3所得到的QTNF浸膏,取QTNF浸膏5g、柠檬酸10g、阿司帕坦20g、甘露醇12g、微晶纤维素40g、羧甲基淀粉钠15g、低取代羟丙基纤维素12g,将以上原辅料过100目筛,混匀,75%v/v乙醇溶液制粒,60℃低温干燥,加入聚乙二醇6000 4g和低取代羟丙基纤维素8g,混合均匀,压片,即制得含有1重量份秦皮、10重量份土茯苓和0.1重量份牛膝的提取物的分散片剂。
药效学试验
为了更好地说明本发明对预防或治疗痛风性关节炎的作用,设计和安排了如下药效学试验。
1、试验试剂及动物
QTNF:本发明按照实施例1制得的药理样品。棕褐色浸膏,3.25g生药/g浸膏,批号140820。
样品2:按照与实施例1相同的土茯苓和秦皮的重量比称取土茯苓和秦皮药材,并按照实施例1的制备方法制得的药理样品。棕褐色浸膏,4.67g生药/g浸膏,批号140821。
苯溴马隆片(立加利仙):白色片剂,50mg/片,批号1208247,德国赫曼大药厂产品。
秋水仙碱片:白色片剂,0.5mg/片,批号130323,西双版纳版纳药业有限责任公司产品。
次黄嘌呤:批号305A042,Solarbio公司产品。
尿酸钠:批号SM0305GA14,上海源叶生物科技有限公司产品。
生理盐水:批号2A12110905,山东齐都药业有限公司产品。
羧甲基纤维素钠:批号20110520,上海科丰化学试剂有限公司产品。
尿酸测定试剂盒:批号20140818,南京建成生物工程研究所产品。
黄嘌呤氧化酶(XOD)测定试剂盒:批号20140821,南京建成生物工程研究所产品。
小鼠尿酸酶(Uricase)酶联免疫试剂盒:批号201408,武汉基因美生物工程有限公司产品。
KM小鼠,SPF级,北京维通利华实验动物技术有限公司提供,许可证号:SCXK(京)2012-0001。
Wistar大鼠,SPF级,北京维通利华实验动物技术有限公司提供,许可证号:SCXK(京)2012-0001。
2、实验方法
2.1对次黄嘌呤致小鼠高尿酸血症的影响
选用健康雄性KM小鼠,体重25-28g,按体重随机分为正常对照组、模型对照组、阳性药苯溴马隆:39mg/kg剂量组、QTNF:3.58、7.15g生药/kg剂量组,样品2:7.15g生药/kg剂量组,共6组,每组10只。灌胃给药,每日一次,连续5天,灌胃容积为20ml/kg体重,正常对照组、模型对照组给予等容量0.5%CMC-Na。末次给药后30min,除正常对照组腹腔注射等容量生理盐水外,其余各组腹腔注射次黄嘌呤1000mg/kg,30min后小鼠摘眼球取血,分离血清,测定血清尿酸、黄嘌呤氧化酶活力、尿酸酶活性,结果见表1。
2.2对尿酸钠(MSU)诱导大鼠急性痛风性关节炎的影响
选用健康雄性Wistar大鼠,体重160-185g,按体重随机分为正常对照组、模型对照组、阳性药秋水仙碱:0.81mg/kg剂量组、QTNF:2.48、4.95g生药/kg剂量组,样品2:4.95g生药/kg剂量组,共6组,每组10只。灌胃给药,每日一次,连续5天,灌胃容积为10ml/kg体重,正常对照组、模型对照组给予等容量0.5%CMC-Na。末次给药后1h,正常对照组大鼠右侧踝关节背侧注射生理盐水0.2ml,其它各组大鼠右踝关节的背侧(关节伸直45度进针)将0.2ml(50mg/mL)尿酸钠(MSU)混悬液注入到关节腔造模。分别于造模前、造模后6h、24h、48h测定大鼠关节肿胀度,观察肿胀度的变化,肿胀度变化=(造模后关节容积-造模前关节容积),并记录大鼠步态分级。结果见表2、表3。
大鼠步态分级:
0级:正常行走;
1级:轻微跛行,受试下肢略有弯曲;
2级:中度跛行,受试下肢刚触及地面;
3级:重度跛行,受试下肢离开地面,三足着地行走。
3、实验结果与分析
3.1QTNF对次黄嘌呤致小鼠高尿酸血症的影响
表1结果显示,给药5次,与正常对照组相比,模型对照组血清尿酸含量明显升高、尿酸酶活性增强,造模成功。与模型对照组相比,QTNF7.15g生药/kg剂量组能明显抑制血清尿酸的升高、增强尿酸酶活性,且优于同等剂量的样品2(秦皮-土茯苓药对)。
与正常对照组比较:ΔΔP<0.01;与模型对照组比较:*P<0.05**P<0.01
3.2对尿酸钠(MSU)诱导大鼠急性痛风性关节炎的影响
表2结果显示,给药5次,与正常对照组比较,模型对照组大鼠注射MSU溶液6h后关节明显肿胀,24h肿胀达高峰,造模成功。与模型对照组比较,QTNF 4.95g生药/kg剂量组能明显减轻造模6h后的关节肿胀度,阳性药秋水仙碱0.81mg/kg也有明显作用,且优于同等剂量的样品2(秦皮-土茯苓药对)。
表3结果显示,给药5次,与正常对照组相比,模型对照组大鼠注射MSU溶液后,活动减少,右后肢肿胀弯曲,有的行走时后肢间断抬起,有的始终抬起,三足着地行走。与模型组比较,QTNF 4.95g生药/kg剂量组能改善造模后24h大鼠步态,阳性药秋水仙碱0.81mg/kg)也有明显作用,且优于同等剂量的样品2(秦皮-土茯苓药对)。
与正常对照组比较:△△P<0.01;与模型对照组比较:*P<0.05**P<0.01
注:不同分级下的数为各剂量组达到此分级的动物数。
试验结果显示,QTNF能明显抑制次黄嘌呤所致高尿酸血症小鼠血清尿酸的升高、增强尿酸酶活性;对尿酸钠(MSU)诱导的大鼠急性痛风性关节炎,能明显减轻大鼠关节肿胀,表明QTNF对高尿酸血症及痛风性关节炎有明显的预防和治疗作用。此外,联合使用秦皮、土茯苓和牛膝作为原料提取制成的浸膏的治疗效果要显著优于使用土茯苓和秦皮作为原料提取的浸膏的治疗效果,这表明向秦皮和土茯苓中加入牛膝共同提取,取得了预料不到的协调作用效果。
Claims (16)
1.一种用于预防或治疗痛风性关节炎的药物组合物,其以秦皮、土茯苓和牛膝为原料经10%v/v~90%v/v的乙醇水溶液提取制成,其中所述药物组合物以1重量份的秦皮、0.2~5重量份的土茯苓和0.2~5重量份的牛膝为原料提取制成。
2.根据权利要求l所述的药物组合物,所述药物组合物以1重量份的秦皮、2重量份的土茯苓和1重量份的牛膝为原料提取制成。
3.一种制备权利要求1或2所述的药物组合物的方法,所述方法包括以下步骤:
1)取秦皮、土茯苓和牛膝,加入10%v/v~90%v/v的乙醇水溶液加热提取,得到提取液;
2)减压浓缩步骤1)所得提取液即得。
4.根据权利要求3所述的方法,其中步骤1)中在常压回流温度下加热提取。
5.根据权利要求3所述的方法,其中步骤1)中所述乙醇水溶液的重量为秦皮、土茯苓和牛膝总重量的6-20倍。
6.根据权利要求3所述的方法,其中步骤1)中所述提取进行1~4次。
7.根据权利要求3至6中任一项所述的方法,其中步骤2)中的减压浓缩在50~75℃的温度下进行。
8.根据权利要求3至6中任一项所述的方法,其中步骤2)中所述减压浓缩进行至相对密度为1.10~1.20。
9.根据权利要求3至6中任一项所述的方法,其中步骤2)中所述减压浓缩继续进行至得到稠浸膏。
10.一种用于预防或治疗痛风性关节炎的药物制剂,其包含权利要求1或2所述的药物组合物和药学上可接受的辅料。
11.根据权利要求10所述的药物制剂,其中,所述药学上可接受的辅料选自填充剂、粘合剂、润滑剂、湿润剂、崩解剂、表面活性剂、增溶剂、消泡剂、防腐剂、甜味剂和芳香剂中的一种或多种。
12.根据权利要求10或11所述的药物制剂,其中,所述的药物制剂为口服制剂、注射剂或外用制剂。
13.根据权利要求12所述的药物制剂,其中,所述口服制剂为片剂、颗粒剂、胶囊剂或滴丸剂;所述注射剂为粉针剂或水针剂;所述外用制剂为喷雾剂或滴鼻剂。
14.根据权利要求12所述的药物制剂,其中,所述口服制剂为软胶囊剂、分散片、缓释片、控释片、泡腾片或口腔崩解片。
15.一种制备权利要求10~14中任一项所述的药物制剂的方法,其包括以下步骤:将权利要求1或2所述的药物组合物与药学上可接受的辅料混合,再进一步制备成所述药物制剂。
16.权利要求1或2所述的药物组合物在制备用于预防或治疗痛风性关节炎的药物中的用途。
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