CN108938760A - 一种中药组合物在制备治疗骨性关节炎药物中的应用 - Google Patents
一种中药组合物在制备治疗骨性关节炎药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种中药组合物在制备治疗骨性关节炎药物中的应用,该中药组合物由如下重量份的原料药制成:三七100‑400份,川芎200‑500份,延胡索200‑500份,白芍200‑500份,牛膝200‑500份,狗脊100‑400份,熟大黄100‑400份,独活100‑400份。该中药组合物可用于治疗骨关节软骨退变及炎症疾病。
Description
技术领域
本发明总地涉及中药领域,具体涉及一种中药组合物在制备治疗骨 性关节炎药物中的应用。
背景技术
骨性关节炎(OA)在中医上被称为“骨痹”或“痹证”,认为是随 着人体衰老,外邪入侵,肝肾静脉气血失调,导致机体逆乱,骨节不利, 易发生骨性关节炎。现代西医认为骨性关节炎是主要发生于骨关节软骨 的慢退行性变,病理下主要表现为软骨软化、糜烂等。目前其发病机制 研究还尚无定论。多见于中老年人,膝关节和髋关节最易受累,严重影 响患者的生存质量,给病人家庭也带来了沉重负担。
细胞因子在骨关节软骨退变的过程中起重要作用。其中白细胞介素 1β(IL-1β),可由软骨细胞和滑膜细胞分泌产生,能刺激软骨细胞分 泌基质金属蛋白酶,而金属蛋白酶是软骨基质降解最主要的酶。此外, IL-1β同时可促进滑膜细胞释放前列腺素E2(PGE2),促进胶原酶的生成, 产生强大的促炎症作用,进一步促使软骨降解。白细胞介素-8(IL-8) 是另一种重要的炎症介质,软骨细胞也可分泌。该炎症介质能增加细胞 表面白细胞粘附因子,促使白细胞聚集及组织损伤。肿瘤坏死因子(TNF- α)可刺激滑膜细胞分泌PGE2,刺激软骨细胞分泌白细胞介素1β(IL-1 β)、PGE2和多种胶原酶。P38MAPK的磷酸化会促进含上述多种因子的产 生和分泌,加重了炎症损伤,最终导致软骨损伤及软骨基质的降解。一 氧化氮(NO)过量分泌可导致各种慢性炎症。软骨细胞受损后,诱发NO 合成酶蛋白表达,导致NO大量释放,进一步促进炎症细胞因子释放, 抑制软骨细胞增殖,最终导致软骨质量的退行性病变。
本发明所使用的中药组合物由三七、延胡索、牛膝、熟大黄、白芍、 川芎、狗脊和独活组成。现代药理学研究表明,三七有扩血管和降压作 用,并具有改善血管内皮细胞功能,降低血黏稠度,抑制血小板活化和 聚集,从而有抗血栓形成作用;川芎有降低骨内压、扩血管、抗瘀作用, 其所含川芎嗪能明显扩张冠脉血管、降低动脉压和冠脉阻力、抗血小板 聚集;延胡索能改善红细胞变形指数,显著降低红细胞压积,显著降低 血黏稠度,从而保持正常微循环灌注;独活、牛膝有明显镇静、镇痛作 用;白芍能明显降低小鼠毛细血管通透性,减少炎性渗出。本发明使用 的中药组合物含有上述多种药物成分,并进行合理配伍应用,故能促进 受损局部组织血液循环,改善血液流变状态,降低毛细血管通透性,减 轻炎性反应,继而减轻神经根水肿,从而达到抗炎镇痛作用。全方具有 活血化瘀、祛风除湿、行气止痛之功效,用于血瘀气滞、脉络闭阻所致 腰痛,临床用于治疗腰椎间盘突出症具有良好的效果(详见专利 CN1276760C)。
发明内容
本发明的目的在于提供一种由三七、延胡索、牛膝、熟大黄、白芍、 川芎、狗脊和独活组成的中药组合物的新用途,即在制药中的新应用。在 背景技术的基础上,申请人对该中药组合物在预防和治疗骨性关节炎中 的作用进行了研究,研究结果证明其具有良好的作用。
本发明提供了一种中药组合物在制备治疗骨性关节炎药物中的应 用,其中,所述中药组合物由如下重量份的原料药制成:三七100-400 份,川芎200-500份,延胡索200-500份,白芍200-500份,牛膝200-500 份,狗脊100-400份,熟大黄100-400份,独活100-400份。
优选地,根据前述的应用,其中,所述中药组合物由如下重量份的 原料药制成:三七335份,川芎445份,延胡索445份,白芍445份, 牛膝445份,狗脊335份,熟大黄335份,独活335份。
更优选地,根据前述的应用,其中,所述中药组合物为片剂、胶囊 剂、颗粒剂、丸剂、注射剂、煎膏剂、悬浮剂、分散剂、糖浆剂、栓剂、 凝胶剂、气雾剂、贴剂或口服液。
还优选地,根据前述的应用,其中,所述中药组合物的制备方法包 括:
(1)三七100-400重量份,川芎200-500重量份,延胡索200-500 重量份,白芍200-500重量份,牛膝200-500重量份,狗脊100-400重 量份,熟大黄100-400重量份,独活100-400重量份,以上八味,取一 半三七粉碎成细粉,另一半三七粉碎成粗粉;
(2)取延胡索、川芎、独活粉碎成粗粉,与三七粗粉合并,用4-8 倍量65-85%乙醇渗漉,制成流浸膏;
(3)白芍、牛膝、狗脊及熟大黄加水浸透后煎煮1-2次,每次30-90 分钟,提取液浓缩至在50℃时相对密度为1.15~1.20,加入乙醇使含醇 量达60-90%,冷藏24小时以上,滤过,滤液回收乙醇并浓缩至相对密 度为1.15~1.20,加入乙醇使含醇量达60-90%,冷藏24小时以上,滤 过,滤液回收乙醇并浓缩至适宜体积;
(4)在步骤(3)制成产物中加入步骤(2)所述流浸膏,回收乙 醇并浓缩至稠膏状,干燥,加入三七细粉混匀制成中药组合物。
再优选地,根据前述的应用,其中,所述制备方法步骤(2)为: 取延胡索、川芎、独活粉碎成粗粉,与三七粗粉合并,用6倍量75% 乙醇渗漉,制成流浸膏。
再优选地,根据前述的应用,所述制备方法步骤(3)为:白芍、 牛膝、狗脊及熟大黄加水浸透后煎煮60分钟,提取液浓缩至50℃相对 密度为1.15~1.20,加入乙醇使含醇量达60%,冷藏24小时以上,滤 过,滤液回收乙醇并浓缩至50℃相对密度为1.15~1.20,加入乙醇使含 醇量达80%,冷藏24小时以上,滤过,滤液回收乙醇并浓缩至适宜体 积。
再优选地,根据前述的应用,其中,所述制备方法还包括:
(5)向步骤(4)的中药组合物中加入常规辅料制成临床接受的剂 型。
再优选地,根据前述的应用,所述制备方法步骤(5)为:粉碎步 骤(4)的中药组合物后,加入适量淀粉,以10%的聚丙烯酸4号树脂 制粒,装胶囊。
本发明所用药材具有改善血管内皮细胞、扩张动脉、抑制血小板聚 集、降低骨内压、镇静阵痛等作用,可用于治疗骨关节软骨退变及炎症 疾病。
药理实验表明,本发明的中药组合物对关节软骨细胞、大鼠实验性关 节软骨炎症均具有明显抑制作用;本发明的组合物可降低IL-1β诱导的软 骨细胞IL-1β、NO、iNOS、PGE2、COX1、MMP-9、TNF-α、NF-κB的分泌以 及P38MAPK磷酸化,可降低大鼠创伤性关节炎骨关节NO、TNF-α分泌,还 可降低大鼠骨性关节炎COX2、NO和iNOS的表达,与骨关节炎传统治疗方 法合用可提升疗效。
具体实施方式
以下结合实施例,对本发明的具体实施方式进行更加详细的说明, 以便能够更好地理解本发明的方案以及其各个方面的优点。然而,以下 描述的具体实施方式和实施例仅是说明的目的,而不是对本发明的限制。
如本文所使用的,术语“治疗”指任何在治疗或改善损伤、病状、 病症或症状(例如,疼痛)上的成功指标,包括任何客观或主观的参数, 诸如消除;好转;症状减少或使患者更能忍受症状、损伤、病状或病症; 降低症状或病症频率或持续时间;或者,在一些情况下,预防症状或病 症的发作。症状的治疗或改善可以基于任何客观或主观参数,包括,例 如身体检查的结果。
此外,本发明引用公开文献,例如专利CN1276760C和CN1552414A, 这些文献是为了更清楚地描述本发明,它们的全文内容均纳入本文进行 参考,就好像它们的全文已经在本文中重复叙述过一样。
下述实施例所用原料及试剂均可由市场购得。
下述实施例所用的本发明中药组合物胶囊剂根据CN1276760C实施 例,由江苏康缘药业股份有限公司制备,商品名称为腰痹通胶囊。每粒 胶囊装量为0.42g,相当于原药材3.12g。
实施例1本发明中药组合物对IL-1β诱导的软骨细胞炎症的影响
1实验材料及方法
1.1药物
腰痹通胶囊内容物。
1.2材料
AL104电子天平,梅特勒-托利多仪器有限公司;离心机,Eppendorf 5804R;酶标仪,Flex station3(MD);二氧化碳培养箱(Thermo); ChemiDoc XRS(Bro-rad)。
一氧化氮(NO)、一氧化氮合成酶(iNOS)、白介素1β(IL-1β)、 前列腺素E2(PGE2)、环氧酶1(COX1)、基质金属蛋白酶9(MMP-9)、 肿瘤坏死因子(TNF-α)和核转录因子κB(NF-κB)检测试剂盒(南 京建成)。
动物:SD大鼠,雄性,100-120g,购自维通利华。
高糖DMEM培养基,胎牛血清购自Gibco;p-P38MAPK抗体购自Abcam, HRP标记二抗购自美国Santa cruz公司;P38MAPK抑制剂购自Sigma。
1.3方法
(1)原代软骨细胞分离、培养
无菌条件下取4周龄SD大鼠膝关节软骨,剪碎至1mm3以下,0.25% 胰酶37℃震荡消化1h,加入终浓度为0.02%的II型胶原酶37℃震荡 消化2h,经200目细胞筛过滤,1000rpm离心5min,含10%FBS高 糖DMEM培养基吹匀后置细胞培养基培养,II型胶原酶细胞免疫组化鉴 定。
(2)造模与给药
取第三代软骨细胞铺于96孔板培养过夜后分为5组:正常组、模 型组、腰痹通高、中、低剂量组,正常组使用100μL高糖DMEM,模 型组为终浓度含10ug/L IL-1β的100μL高糖DMEM,腰痹通高、中、 低剂量分别使用含50、25和12.5mg/L腰痹通胶囊内容物和10μg/L IL-1β的100μL高糖DMEM,各组按以上方法给药后培养6h。
另取第三代软骨细胞接种至75cm2培养皿,设置正常组、模型组、 腰痹通组和P38抑制剂组,正常组使用100μL高糖DMEM,模型组为 终浓度含10μg/L IL-1β的100μL高糖DMEM,腰痹通组给予含50 mg/L腰痹通胶囊内容物和10μg/L IL-1β的100μL高糖DMEM,P38抑制剂组给予50μM的P38MAPK抑制剂和10ug/L IL-1β的100μL高 糖DMEM,各组给药10min后进行蛋白检测。
(3)检测方法
96孔板给药6h后各孔取50μL上清,ELISA测定其中IL-1β、 NO、iNOS、PGE2、COX1、MMP-9、TNF-α、NF-κB含量;培养皿给药10 min后使用细胞蛋白提取试剂盒提取出各组蛋白,使用western blot 检测p-P38表达,使用ImageJ分析灰度值,计算蛋白相对表达量。
2结果处理与分析
2.1对模型大鼠软骨细胞IL-1β、NO、iNOS、PGE2、COX-1、MMP-9、 TNF-α、NF-κB分泌的影响
与正常对照组相比,模型组IL-1β、NO、iNOS、PGE2、COX-1、MMP-9、 TNF-α、NF-κB分泌均显著升高(P<0.001),不同剂量的腰痹通可降 低这些因子的分泌(P<0.05,P<0.01,P<0.001),具有一定的量效关 系。
表一 腰痹通胶囊对IL-1β诱导的 膝关节软骨细胞IL-1β、NO、iNOS、PGE2分泌的影响
###P<0.001,与正常组比较;*P<0.05,**P<0.01,***P<0.001,与模 型组比较
表二 腰痹通胶囊对IL-1β诱导的 膝关节软骨细胞COX-1、MMP-9、TNF-α、NF-κB分泌的影响
##P<0.001,###P<0.001;与正常组比较,*P<0.05,**P<0.01,***P<0.001, 与模型组比较
2.2腰痹通胶囊对P38MAPK磷酸化的影响
实验发现经IL-1β刺激,软骨细胞P38MAPK磷酸化都显著升高 (P<0.001),腰痹通组可显著降低p-P38MAPK表达,提示腰痹通胶囊 可能通过抑制P38MAPK磷酸化降低软骨炎症损伤。
表三 腰痹通胶囊对IL-1β诱导的膝关节软骨细胞P38MAPK磷酸化的 影响
###P<0.001,与正常组比较;***P<0.001,与模型组比较
以上结果显示,腰痹通胶囊可显著降低软骨细胞炎症因子的释放, 降低软骨细胞凋亡,抑制P38MAPK通路磷酸化可能是腰痹通胶囊抗炎机 制之一。
实施例2本发明中药组合物对创伤性骨关节炎大鼠模型抗炎作用的影 响
1材料与方法
1.1药品及试剂
腰痹通胶囊内容物。
NO、TNF-α检测试剂盒,购自南京建成。
1.2动物
健康SD大鼠30只,雌雄各半,180-220g,购自维通利华。
1.3创伤性骨关节炎大鼠模型的建立
动物常规饲养1周后进行称重,将SD大鼠分为正常组、模型组、 腰痹通高、中、低剂量组,每组6只。除正常组外,其余4组将10%的 水合氯醛(3mg/kg)注射入SD大鼠腹腔以进行麻醉,打开关节腔,手 术切断内侧副韧带,摘除半月板,切除前后交叉韧带,缝合内外皮层。 术后连续3d每日注射青霉素2×105U以预防感染。术后1周,高、 中、低剂量组分别以20、10、5mg/kg剂量灌胃,每日一次,正常组、 模型组分别给予等量生理盐水灌胃,连续8周。
1.4指标检测
末次给药后1h处死大鼠,取同部位病变膝关节,大体观察后小心 切取小块同部位病变膝关节,仔细去除骨头和皮肤称重,在冰浴下以电 动研磨器制作20%匀浆液,2000r/min离心10min取上清液,采用 ELISA法测定NO、TNF-a含量。
2结果
SD大鼠创伤性骨关节炎损伤部位NO和TNF-α释放显著升高 (P<0.001),不同剂量腰痹通胶囊可显著降低NO和TNF-α的释放 (P<0.05,P<0.01)。
表四 腰痹通胶囊对大鼠创伤性骨关节炎损伤部位NO和TNF-α的影响
###P<0.001,与正常组比较;*P<0.05,**P<0.01,***P<0.001,与模 型组比较
以上结果表明,创伤性骨关节炎NO和TNF-α释放显著上升,会加 剧炎症以及软骨细胞凋亡,腰痹通胶囊可降低它们的产生和释放。
实施例3本发明中药组合物对膝骨性关节炎大鼠炎症抗炎作用影响
1材料与方法
1.1药品及试剂
腰痹通胶囊内容物。
COX-2、NO、iNOS检测试剂盒,购自南京建成。
1.1动物
健康SD大鼠30只,雌雄各半,180-220g,购自维通利华。
1.3大鼠造模、分组及给药
动物常规饲养1周后进行称重,将SD大鼠分为正常组、模型组、 腰痹通高、中、低剂量组,每组6只。
Murat法:4%木瓜蛋白酶溶液与0.3mol/L半胱氨酸溶液1:1混 置0.5h制成混合液,将除正常组以外的其余大鼠固定于操作台,用剃 须刀片剃除大鼠左后膝及其周围绒毛,碘伏消毒。术者微屈大鼠左膝, 以1ml注射器由髌骨内侧下方斜向上刺入关节腔,注入混合液20μL。 造模第1、4、7天分别配制新鲜混合液并进行注射。造模成功后高、中、 低剂量组分别按21、10.5、5.25mg/kg灌胃给药4周,每日一次,正 常组和模型组给予相同体积生理盐水。
1.4检测
膝关节韧带外侧注入1.5ml生理盐水,反复活动关节20次,缓慢 抽取关节液置1.5ml离心管中,3000rpm 4℃离心30min,取上清进 行ELISA检测;
2结果
模型组环氧酶2(COX-2)、NO和iNOS的表达显著升高(P<0.001), 腰痹通胶囊可显著降低这些因子的表达(P<0.01,P<0.001)。
表五 腰痹通胶囊对膝骨性关节炎大鼠COX-2、NO和iNOS表达的影响
###P<0.001,与正常组比较;**P<0.01,***P<0.001,与模型组比较
以上结果表明腰痹通胶囊可通过降低炎症因子的释放降低骨性关 节炎损伤。
实施例4本发明中药组合物对膝盖骨关节炎的治疗疗效
1材料与方法
1.1药品及试剂
腰痹通胶囊。
1.2方法
选取98例2016年2月-2018年1月期间在连云港中医院接受治疗 的骨关节炎患者,所有患者均符合《中医病证诊断疗效标准》及美国风 湿病学会1995年膝关节炎临床分型诊断标准。
患者按1:1随机分为对照组(接受常规治疗)和实验组(接受腰 痹通胶囊治疗)各49例,对两种不同方式的治疗效果进行对照研究。 对照组患者采用常规治疗方法,口服非甾体类镇痛消炎药扶他林,口服 氨基葡萄糖,局部推拿按摩,让患者注意休息,对关节进行保护,防止 出现过度活动;给予患者针灸、TDP照射30min每天。实验组接受上 述治疗外还加口服腰痹通胶囊3.78g/天。本研究将2周设置为一个疗 程,共治疗三个疗程。
1.3疗效判断标准
痊愈:症状及体征完全消失,关节功能恢复正常;显效:症状及体 征明显改善,关节功能基本恢复正常;有效:症状及体征有所改善,活 动后疼痛又明显加剧;无效:症状及体征无好转,关节功能受限。按照 膝OA严重性指数(ISOA)对两组患者的关节功能进行评价并对比,为 1-14分,分数越高表示患者的病情越严重,关节功能越差。
2.结果
2.1两组患者治疗效果比较
经过治疗,实验组总有效率为89.8%,对照组为79.6%,两组相 比有显著学差异(P<0.05);两组膝关节严重指数(ISOA)均较治疗前 显著改善(P<0.05),实验组较对照组改善更为明显
表六 两组患者治疗效果比较
*P<0.05,与对照组比较
表七两组患者膝关节严重指数比较
*P<0.05,与治疗前比较
西医认为,膝关节骨关节炎可能由多种原因引起,一是由于长期姿 势不良,负重用力,体重过重导致关节慢性劳损,软组织损伤;二是由 外伤如骨折、软骨、韧带的损伤等引起;三是长期关节面受力不平衡。 其发病缓慢,活动时疼痛加剧,膝关节活动受限,劳累或夜间症状更为 明显。西医在治疗上没有特效方法,以止痛消炎为主,但存在一定副作用,患者耐受性不强。中医认为,膝关节骨关节炎属“痹症”“鹤膝风” 等范畴,以中老年人多见,其病机以中老年人肝肾亏虚、筋骨失养为本, 外感病邪、痹阻骨节为标,为本虚标实证。中医认同肾主骨,肝主筋, 故以肝肾亏虚为本,而膝关节周围气血流动不畅,血停为瘀,湿凝为痰, 痰瘀互结,阻闭经络,为常见诱因。本病的治疗可补益肝肾、壮筋活络, 配合针灸、推拿、按摩,形成独有的治疗体系,结合中西医疗效更为优 越。
最后应说明的是:显然,上述实施例仅仅是为清楚地说明本发明所 作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来 说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里 无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的 变化或变动仍处于本发明的保护范围之中。
Claims (8)
1.一种中药组合物在制备治疗骨性关节炎药物中的应用,其特征在于,所述中药组合物由如下重量份的原料药制成:三七100-400份,川芎200-500份,延胡索200-500份,白芍200-500份,牛膝200-500份,狗脊100-400份,熟大黄100-400份,独活100-400份。
2.根据权利要求1所述的应用,其特征在于,所述中药组合物由如下重量份的原料药制成:三七335份,川芎445份,延胡索445份,白芍445份,牛膝445份,狗脊335份,熟大黄335份,独活335份。
3.根据权利要求1或2所述的应用,其特征在于,所述中药组合物为片剂、胶囊剂、颗粒剂、丸剂、注射剂、煎膏剂、悬浮剂、分散剂、糖浆剂、栓剂、凝胶剂、气雾剂、贴剂或口服液。
4.根据权利要求3所述的应用,其特征在于,所述中药组合物的制备方法包括:
(1)三七100-400重量份,川芎200-500重量份,延胡索200-500重量份,白芍200-500重量份,牛膝200-500重量份,狗脊100-400重量份,熟大黄100-400重量份,独活100-400重量份,以上八味,取一半三七粉碎成细粉,另一半三七粉碎成粗粉;
(2)取延胡索、川芎、独活粉碎成粗粉,与三七粗粉合并,用4-8倍量65-85%乙醇渗漉,制成流浸膏;
(3)白芍、牛膝、狗脊及熟大黄加水浸透后煎煮1-2次,每次30-90分钟,提取液浓缩至在50℃时相对密度为1.15~1.20,加入乙醇使含醇量达60-90%,冷藏24小时以上,滤过,滤液回收乙醇并浓缩至相对密度为1.15~1.20,加入乙醇使含醇量达60-90%,冷藏24小时以上,滤过,滤液回收乙醇并浓缩至适宜体积;
(4)在步骤(3)制成产物中加入步骤(2)所述流浸膏,回收乙醇并浓缩至稠膏状,干燥,加入三七细粉混匀制成中药组合物。
5.根据权利要求4所述的应用,其特征在于,所述制备方法步骤(2)为:取延胡索、川芎、独活粉碎成粗粉,与三七粗粉合并,用6倍量75%乙醇渗漉,制成流浸膏。
6.根据权利要求4所述的应用,其特征在于,所述制备方法步骤(3)为:白芍、牛膝、狗脊及熟大黄加水浸透后煎煮60分钟,提取液浓缩至50℃相对密度为1.15~1.20,加入乙醇使含醇量达60%,冷藏24小时以上,滤过,滤液回收乙醇并浓缩至50℃相对密度为1.15~1.20,加入乙醇使含醇量达80%,冷藏24小时以上,滤过,滤液回收乙醇并浓缩至适宜体积。
7.根据权利要求4-6任一所述的应用,其特征在于,所述制备方法还包括:
(5)向步骤(4)的中药组合物中加入常规辅料制成临床接受的剂型。
8.根据权利要求7所述的应用,其特征在于,所述制备方法步骤(5)为:粉碎步骤(4)的中药组合物后,加入适量淀粉,以10%的聚丙烯酸4号树脂制粒,装胶囊。
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