CN111671841B - 一种抗骨关节炎药物组合物及其制备方法和应用 - Google Patents
一种抗骨关节炎药物组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种抗骨关节炎药物组合物及其制备方法和应用,所述组合物包括以下组份:贯众、土茯苓、黄柏、黄芩、大黄、草河车、胡黄连和黑矾。本发明根据中医药理论和骨关节炎疾患的发病机制选取原料,遵循互相配伍原则,各组份配比科学合理,在骨性关节炎动物模型与临床观察研究中表明,本发明提供的药物组合物有平补肝肾,祛邪蠲痹的功效,具有预防和治疗骨关节炎疾病的作用,且长期使用毒副作用。
Description
技术领域
本发明涉及中医药领域,具体涉及一种抗骨关节炎药物组合物及其制备方法和应用。
背景技术
骨关节炎(Osteoarthritis,OA)是指由多种因素引起关节软骨纤维化皲裂溃疡脱失而导致的以关节疼痛为主要症状的退行性疾病,是最常见的一种慢性进行性关节病。临床症状主要表现为关节疼痛、肿胀、晨僵、关节积液、关节肥大,运动过程中伴有骨摩擦、功能障碍或畸形。特别地,关节肿胀表现为关节早期局部肿胀,包括关节弥漫性肿胀、滑膜囊增厚或关节积液。其病因可能与年龄、肥胖、炎症、创伤及遗传因素有关,病理特点为关节软骨变性破坏、软骨下骨硬化或囊性变、关节边缘骨质增生、滑膜增生、关节囊挛缩、韧带松弛或挛缩、肌肉萎缩无力等。骨关节炎分为原发性和继发性。原发性OA多发于中老年人群,无明显全身或局部诱因,与遗传和体质因素有一定的关系。继发性OA可发生于青壮年,继发于创伤、炎症、关节不稳定、积累性劳损或先天性疾病等。
骨关节炎的发病部位主要在关节软骨、软骨下骨及滑膜。关节软骨的成分包含软骨细胞和细胞外基质(Extracellular matrix,ECM)。目前普遍认为健康的软骨细胞外基质主要有II型胶原蛋白(Collagen II,COL2)和蛋白聚糖(Aggrecan,ACAN)组成,它们为组织提供了拉力支撑,并在负载状态下为软骨提供抗压和减震能力,有助于维持软骨细胞外环境和软骨结构的稳态。在OA的发病过程中,软骨的组成结构发生改变,如:软骨细胞发生死亡、软骨细胞受到炎性细胞因子的刺激从而导致细胞外基质降解;细胞外基质的合成与分解失衡、基本结构被破坏,如ACAN含量降低、胶原蛋白的类型从II型胶原变为I型胶原。另外,有研究显示,炎性细胞因子,如白细胞介素-1β(Interleukin-1β,IL1β)、肿瘤坏死因子-α(Tumor Necrosis Factor-α,TNF-α)和白细胞介素-6(Interleukin 6,IL-6)等,可刺激软骨细胞分泌一种蛋白水解酶:基质金属蛋白酶(Matrix metalloproteinase,MMPs),从而引发软骨基质的改变,导致软骨炎症或病变。此外,研究表明,骨性关节炎的软骨细胞可分泌白细胞介素-18(IL-18)和白细胞介素-21(IL-21),且关节组织内受破坏的软骨组织及其降解产物可诱导滑膜分泌更多的IL-18和IL-21,这两种因子可激活T淋巴细胞和自然杀伤细胞(NK细胞)并促进γ-干扰素(INF-γ)的分泌,间接诱导骨关节炎软骨的破坏。因此,在许多研究中,治疗OA的主要方式为通过抑制这些炎性细胞因子的表达来促进软骨基质的表达。目前OA的发病机理仍多有不清,正处于探索阶段,有待进一步的详细研究。
临床上对于骨关节炎的治疗目标是缓解疼痛,延缓疾病进展,矫正畸形,改善或恢复关节功能,提高患者生活质量。目前,针对骨关节炎的治疗包括非药物治疗、药物治疗以及手术治疗。《2018年骨关节炎临床治疗指南》提出对OA的治疗采取阶梯化治疗。对于早期OA患者,通常建议使用非药物手段进行治疗,如:物理治疗以及适当的锻炼,肥胖患者应进行减肥,使用拐杖以减轻关节的负荷等。对于终末期OA,目前只有通过手术的方法进行治疗,如:人工关节置换术,通常需要花费高昂的治疗费用且可能出现并发症。而对于处于中期OA的患者通常采取药物治疗,包括非甾体类抗炎药(Nonsteroidal anti-inflammatorydrugs,NSAIDS)、对乙酰氨基酚、曲马多和阿片类药物、硫酸软骨素和氨基葡萄糖等,这些药物仅可起到缓解症状的作用,但有很少证据表明这些药物可延缓疾病的进展;进一步地,上述药物大多会产生多种副作用,长期使用是有毒的。还有一些防止OA的新型药物或制剂,如阿达木单抗(抗TNF-a单抗)、托珠单抗(IL-6受体单抗)和MOR-103(抗粒细胞-巨噬细胞集落刺激因子单抗),这些新型药物或制剂仍存在一些问题:一方面,有临床试验结果表明,单抗类药物并不能有效地缓解严重骨关节炎的疼痛;另一方面,因治疗费用昂贵,使得诸多患者难以承受,药物难以推广和普及。迄今为止,上述多数治疗骨关节炎的潜在药物都具有一定的局限性,一般仅能达到减缓关节疼痛的效果,而未能达到根本减轻退变。该领域对能提供有效疼痛缓解的、能有效延缓关节结构进展的、无毒副作用的、潜在防滥用的非阿片类止痛药物存在着真真切切的需求。
中医药在防治膝关节骨关节炎方面具有疗效确切、副作用小且价格低廉等优点,日益得到广大患者的认可。OA在中医学中属于“骨痹”、“痹证”范畴。多数现代中医学者认为骨关节炎乃“本虚标实”、“本痿标痹”之证。现代中医学有关OA的研究主要集中在对其病机的探讨以及各种治法、验方对其干预的研究。虽然中医药学者利用现代临床病理、生化药理研究的成果,进行了一系列的中医药治疗OA的实验研究,初步揭示了中医药治疗本病的疗效机制,但治疗效果仍然不让人满意。
发明内容
本发明目的在于克服现有技术的上述不足,提供一种抗骨关节炎药物组合物及其制备方法和应用,本发明依据中医中药原理及骨关节炎尤其是膝骨关节炎的发病机制,科学进行组方,研制出具有抗骨关节炎作用的药物组合物。该药物组合物在动物实验中能够显著提高抗炎效果,在临床实验中能够显著提高痊愈率和总显效率。
为了实现上述发明目的,本发明采用以下技术方案:
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
在其中一些实施方案中,所述药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
在其中一些实施方案中,所述药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
OA在中医学中属于“骨痹”、“痹证”范畴。《黄帝内经》阐述痹症的外因为“风、寒、湿三气杂至,合而为痹也。”《景岳全书》认为与气血不通有关:“盖痹者闭也,以气血为邪所闭,不得通行而病也。”《张氏医通》则提出“膝者筋之府,屈伸不能,行则偻俯,筋将惫矣,故膝痛无有不因肝肾虚者,虚者风寒湿气袭之。”此病多为本虚标实、虚实夹杂,以肝肾不足为虚,风寒湿气血凝滞为实。肝虚者无以藏血,血虚则无以荣筋,筋不荣则拘挛疼痛,名曰筋痹;肾者主骨生髓,肾脏衰则见骨节酸软空痛名曰骨痹;此两者为不荣则痛。实者多为风寒湿等邪气外犯人体经络,诛邪流连内阻,经络不通,发为痹病,此为不通则痛。
本发明药物组方由贯众、土茯苓、黄柏、黄芩、大黄、草河车、胡黄连和黑矾共8味中药组成。方中贯众和土茯苓二者为君药,贯众苦微寒,入肝脾经,能清热解毒;土茯苓甘淡平,入肝胃经,能驱湿解毒,合以清除肝胃湿热邪毒。黄柏、黄芩、大黄、草河车、胡黄连五味合为臣药,具有补肝肾、袪风湿、益肝血、强筋骨、除酸痛之功效,黑矾作为佐药,用以增强组方效力。特别是,草河车和胡黄连归经皆入肝经,且因二药均具有保肝利胆、强筋骨、壮腰膝之功,参合搭配,配伍更彰力。以上八味药材来源清晰,均为药典收载品种,且安全性高,组方重在平补肝肾、填精养血,以平补为主导,未入温阳、滋阴药物,扶正不助邪,适用于年高体衰患者;且兼顾标本,祛邪蠲痹不伤正,配药重在治本,未用峻猛毒烈之品,无辛燥风药耗伤精气、毒烈伤正之弊。本发明从从肝肾虚络痹辨治,强调补肝养血、蠲痹通络,寓补于通,以平补为要。治病求本,故可缓解关节软骨的退行性病变。
进一步地,本发明还涉及所述药物组合物的制备方法,包括以下步骤:土茯苓、黑矾粉碎成细粉;将贯众、黄柏、黄芩、大黄、草河车、胡黄连六味药材煎煮,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,干燥即得。
进一步地,所述煎煮次数为两次;
进一步地,所述第一次煎煮时间为3-5小时,优选的为4小时;所述第二次煎煮时间为2-3小时,优选的为2.5小时;
进一步地,所述煎煮加6-20倍的水,优选10-15倍。
进一步地,所述干燥的温度为50-100℃;优选地,还包括对干燥的产物进行粉碎的步骤。
本发明的另一个方面还涉及一种药物组合物,由上述的药物组合物和药学上可接受的辅料制备而成。
进一步地,所述医药辅料包括崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种。
优选地,所述崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种;
优选地,所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤维素中的至少一种;
优选地,所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种;
优选地,所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种;
优选地,所述湿润剂选自十二烷基硫酸钠;
优选地,所述矫味剂可以为阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种;
优选地,所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素或硬脂酸铝凝胶中的至少一种;
优选地,所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种;
优选地,所述防腐剂选自对羟苯甲酸甲酯或对羟苯甲酸丙酯中的至少一种。
在其中一些实施例中,所述药物组合物的给药剂量为1-12g/天。
优选地,所述药物组合物的给药剂量为:2-5g/天。
此用量是以50Kg成人体重计算的用量,儿童减半。
在其中一些实施例中,所述药物组合物的剂型为固体、半固体或液体的形式;
优选地,所述药物组合物的剂型为液体时,其为水溶液、非水溶液或混悬液;
更优选地,所述药物组合物的剂型为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、干混悬剂、滴丸剂或干浸膏剂。
本发明的另一个方面还涉及上述药物组合物的应用,具体而言,所述药物组合物用于制备抗骨关节炎的药物。
所述抗骨关节炎包括治疗、缓解或预防骨关节炎。
本发明提供的抗骨关节炎药物组合物及其制备方法和应用与现有技术/产品相比,至少具有如下有益效果:
1.本发明根据中医药理论和骨关节炎疾患的发病机制选取原料,遵循相互配伍原则,各组份配比科学合理,其中关键成分贯众、土茯苓等相互作用,协同增效,可以显著抑制IL-1β、IL-18、TNF-α、MMP-1的表达,从根本上减轻骨关节的退变;通过动物实验从分子机理角度出发,证明了本发明药物组合物具有预防和治疗骨关节炎疾病的作用,对抗骨性关节炎的效果优于市面上一般药物;通过临床观察,从中医和西医诊断标准出发,本发明提供的药物组合物有平补肝肾,填精养血、祛邪蠲痹而不伤正的功效,对OA的疗效强于市面上非甾体类抗炎药。
2.安全性检测结果表明本发明提供的药物组合物安全性好,长期服用无不良反应。
3.本发明提供的药物组合物制备方法的工艺设计简单,制备过程中未使用有机溶剂,制备过程无高温高压过程,流程环保无污染,易于实现工业化规模生产。
4.本发明提供的药物组合物可以单独使用,也可以与其它活性成分复配使用,也可方便的和药学上可接受的载体制备成各种剂型的药物,方便服用。
具体实施方式
为了更好的解释本发明,现结合以下具体实施例做进一步说明。然而,本领域的技术人员容易理解,实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明,而非旨在限制本发明。
实施例1
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述的药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将贯众、黄柏、黄芩、大黄、草河车、胡黄连六味药材加12倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
实施例2
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将贯众、黄柏、黄芩、大黄、草河车、胡黄连六味药材加15倍的水煎煮两次,第一次4小时,第二次2.5小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于90℃干燥,粉碎成粉末,过100目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成胶囊剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素、蔗糖、甘露醇、硬脂酸、滑石粉、糊精、麦芽糖醇、柠檬酸、山梨糖醇酐单油酸酯和对羟苯甲酸丙酯。
实施例3
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将贯众、黄柏、黄芩、大黄、草河车、胡黄连六味药材加13倍的水煎煮两次,第一次5小时,第二次2小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于85℃干燥,粉碎成粉末,过200目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成软胶囊剂。其中,步骤(1)中所述的医药辅料为:交联聚乙烯吡咯烷酮、玉米淀粉、硬脂酸镁、明胶、十二烷基硫酸钠、阿斯巴甜和羧甲基纤维素钠。
对比例1
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将板蓝根、黄柏、黄芩、大黄、草河车、胡黄连等七味药材加12倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
对比例2
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
黑矾粉碎成细粉;将贯众、连翘、黄柏、黄芩、大黄、草河车、胡黄连等七味药材加14倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
对比例3
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将贯众、龙胆草、黄芩、大黄、草河车、胡黄连等七味药材加15倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
对比例4
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将黄柏、黄芩、大黄、草河车、胡黄连六味药材加12倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
对比例5
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
黑矾粉碎成细粉;将贯众、黄柏、黄芩、大黄、草河车、胡黄连六味药材加12倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
对比例6
一种药物组合物,其是由按重量份计,包括以下组分的原料药制得的:
所述药物组合物的制备方法,包括以下步骤:
土茯苓、黑矾粉碎成细粉;将贯众、黄芩、大黄、草河车、胡黄连六味药材加12倍的水煎煮两次,第一次3小时,第二次3小时,合并煎液,滤过,滤液浓缩成稠膏,加入上述细粉,混匀,于100℃干燥,粉碎成粉末,过60目筛即得。
一种抗骨关节炎药物组合物,其制备方法包括以下步骤:
(1)将上述药物组合物与医药辅料混合;
(2)根据《中国药典(2015版)》四部所述制剂制备方法制成片剂。
其中,步骤(1)中所述的医药辅料为:羧甲基纤维素钙、藻酸、乳糖、蔗糖、甜菊甙、甘露醇、微粉硅胶、阿拉伯胶、明胶、十二烷基硫酸钠和卵磷脂。
实施例4:动物实验
1.实验设计
1.1骨性关节炎动物模型的制备
60只雄性新西兰大耳兔,普通级,10~12月龄,体重2.0~2.5kg,由广州中医大学实验动物中心提供,实验动物质量合格证号SCXK(粤)2003-0001。适应性喂养1周,无不适反应后随机分为正常组、模型组、阳性对照组、实施例1、2、3组、对比例1-6组,每组5只。除正常组外,将其它白兔分别在第1,3,5天用戊巴比妥钠(90mg/kg,静脉注射)麻醉后,向双后膝关节腔注射2%(w/v)木瓜蛋白酶和0.03mol/LL-半胱氨酸比例为2:1的混合溶液,注射剂量按0.1ml/kg。注射完造模试剂后正常饲养2周,膝关节出现肿胀,功能活动障碍为造模成功。
1.2实验方法
造模后,进行相应的药物治疗,阳性对照组予壮骨关节丸;给药剂量为0.2g/d),实施例1、2、3组予本发明实施例相应药物组合物(给药剂量均为0.2g/d),对比例1-6组予对比例相应的药物组合物(给药剂量均为0.2g/d),用蒸馏水配制相应浓度的药物混悬液,通过灌胃给药,每只兔给药容积为10ml,正常组和模型组分别给予等量的蒸馏水,每天一次,连续灌胃4周。
所述壮骨关节丸购自华润三九医药股份有限公司,批准文号:国药准字Z44023377,适应症/功能主治:补益肝肾,养血活血,舒筋活络,理气止痛,用于肝肾不足,气滞血瘀,经络痹阻;各种退行性骨关节痛,腰肌劳损等。
给药4周后全部耳缘静注空气处死动物,处死后对其双后膝关节周围消毒,用1ml注射器(内置有1ml注射用水)经膝关节两侧进针,通过髌上韧带插入关节腔内,反复进行抽注,最终取出关节积液,经2000r/min离心15min,取上清液置-20℃保存,备用。上清液制作病理标本,比较关节液中主要炎症因子,包括IL-1β、IL-18、TNF-α、MMP-1、IL-13和TIMPs含量的变化。
2.实验结果
实验的结果如表1所示。从表格数据可以看出,与模型组相比,对照组、实施例组、对比例组均有显著性差异(P<0.05),表现为对照组和实施例组都呈现出较好的抗炎效果,而且实施例组的抗炎效果显著好于对照组和对比例组,提示本发明的药物组合物获得了意想不到的抗炎效果,并且各组分之间具有协同增效作用,缺一不可。
表1各试验组关节液中IL-1β、IL-18、TNF-α、MMP-1、IL-13和TIMPs含量的比较(n=5)
注:*与正常组比较,P<0.05;△与模型组比较,P<0.05;○与阳性对照组比较,P<0.05。
3.实验结论
在现代医学作用机理中,OA主要表现为IL-1β、TNF-α和MMPs表达水平的显著升高。这些炎性成分又可作用于软骨细胞、滑膜细胞及其周围组织进一步促进致炎因子的产生,终至出现软骨破坏。另一方面,OA患者软骨基质中金属蛋白酶组织抑制物(TIMPs)明显减少,软骨细胞及滑膜的IL-13等抑制性细胞因子产生水平降低,使这些细胞因子抑制致炎性细胞因子IL-1的作用减弱。因此,OA患者的关节病变进展与致炎性因子的增高和炎性抑制因子的水平减低两方面的因素有关。
本发明以新西兰大耳兔骨性关节炎动物模型实验测试药物的抗炎效果,兔模型的骨性关节炎症状与人类OA临床症状表现类似,具有可参照性。从试验数据可以看出,相比于模型组,给予实施例所述药物组合物能显著降低兔模型中IL-1β、IL-18、TNF-α、MMP-1的浓度,提示实施例药物具有抗模型动物骨性关节炎的作用,从根本上减轻退变,适用于OA的预防和治疗;相比于阳性对照组,给予实施例药物组合物能显著降低兔模型中IL-1β、IL-18、TNF-α、MMP-1的浓度,提示实施例药物有平补肝肾,填精养血、祛邪蠲痹而不伤正的功效,且其抗骨性关节炎的效果要优于市面上壮骨关节丸的效果;相比于对照组,给予实施例药物能显著降低兔模型中IL-1β、IL-18、TNF-α、MMP-1的浓度,另外,软骨基质中金属蛋白酶组织抑制物(TIMPs)明显减少,软骨细胞及滑膜的IL-13等抑制性细胞因子产生水平降低,提示实施例药物成分中的关键成分贯众、土茯苓、黄柏具有协同增效作用,缺一不可。
实施例5:临床研究
1.患者资料
1.1西医诊断标准
符合2007年膝骨关节炎的国际分类诊断标准:
(1)近1个月内反复膝关节疼痛;
(2)X线片(站立或负重位)示关节间隙变窄、软骨下骨硬化和(或)囊性变、关节缘骨赘形成;
(3)关节液检查符合骨关节炎,即关节液(至少2次)清亮、黏稠,WBC<2000个/ml;
(4)年龄≥40岁;
(5)晨僵≤30min;
(6)活动时有骨摩擦音(感);
综合临床、实验室及X线检查,满足(1)+(2)条或(1)+(3)+(5)+(6)条,或(1)+(4)+(5)+(6)条者可诊断膝骨关节炎。
在此基础上结合目前国际公认的治疗膝OA的临床观察指标如视觉模拟评分(Visual Analog Scale,简称VAS)、西安大略与麦克马斯特大学骨关节炎指数(WesternOntario and McMaster Universities Osteoarthritis Index,简称WOMAC),强调量化、细化指标从而有利于疗效的观察统计。具体方案从疼痛、活动与疼痛的关系及功能障碍三方面进行评分,其中3个疼痛亚类,2个僵直,4个关节功能问题采用WOMAC骨关节指数,用5分Liket评分标准(无为0分,轻度为1分,中度为2分,重度为3分,极重为4分),第1个疼痛问题采用VAS。具体指标如下:
患者对关节疼痛的评估(VAS);
(1)夜间卧床休息时疼痛或不适(0为无,4为极度疼痛);
(2)平地行走时疼痛或不适(0为无,4为极度疼痛);
(3)上下楼梯时疼痛或不适(0为无,4为极度疼痛);
(4)早晨醒后第一次活动时关节僵直的严重程度(0为无,4为极度疼痛或不适);
(5)在稍后的坐、躺和休息时僵直的严重程度(0为无,4为极度疼痛或不适);
(6)下楼出现的困难程度(0为无,4为极度疼痛或不适);
(7)上楼出现的困难程度(0为无,4为极度疼痛或不适);
(8)在不平地上行走的困难程度(0为无,4为极度疼痛或不适);
(9)蹲下或弯曲膝盖的困难程度(0为无,4为极度疼痛或不适)。
注:以上情况均以过去48h来记录;除第1项以100mm标尺目测记分外,其余9个问题共36分,根据总分按下列标准评估膝OA的轻重程度:轻度<10分;中度10~18分;重度>18分。
1.2中医诊断标准
OA的中医证候诊断标准参考2002年《中药新药治疗骨关节病的临床研究指导原则》,其症候表现为:(1)主症:关节疼痛,动则疼痛明显,性质为酸痛或刺痛,痛处固定,胫软膝酸。(2)次症:活动受限,屈伸不利,腰脊酸痛。偏于肾阴虚者见潮热,盗汗,口干,低热心烦,或午后潮热,目眩,耳鸣。(3)舌脉:舌红少津,脉细数。
中医临床证候分级量化标准参照“膝关节骨关节炎II期临床试验方案:“高益民,膝关节骨关节炎Ⅱ期临床试验方案[J].中药新药与临床药理,1998,(1):15-17,60.”制定。中医证候评分对病情的判断:轻度:综合评分在11分以下;中度:综合评分在12-22分之间;重度:综合评分在23-34分之间。
共纳入80例OA患者,临床观察了对照组和实施例组治疗前后中医症候及WOMAC指数的变化。
一般资料:80例OA患者,随机分为实施例组1、2、3各20例,对照组20例。实施例中,男28例,女22例;年龄45~78岁,平均61.2岁,单侧29例,双侧31例;病程1~15年,平均5.8年。对照组中,男11例,女9例;年龄44~77岁,平均60.3岁,单侧10例,双侧10例;病程1~16年,平均5.9年。经统计,实施例各组与对照组的临床资料具有可比性(P>0.05)。
纳入病例标准:①符合OA诊断标准;②VAS疼痛评估诊断和中医证候评分诊断在轻度和中度级别;③能按疗程接受治疗者。
排除有下列疾病者:①膝关节肿瘤、结核、感染及关节严重畸形的晚期膝关节骨性关节炎。②合并其他风湿病如系统性红斑狼疮、干燥综合征。③合并有心脑血管、肝、肾和造血系统等严重疾病患者。④妊娠期及哺乳期患者。⑤过敏体质或对多种药物过敏者。
1.2治疗方法
所有患者戒除烟酒、合理饮食、适量运动。实施例1、2、3分别对应服用所述实施例中的药物组合物,每日两剂,每剂2g(以药物组合物计),分早晚两次服用。对照组采用非甾体抗炎药美洛昔康片,用药剂量每天2次,每次2片,每片7.5mg。3个月为一疗程。
所述非甾体抗炎药美洛昔康片购自修正药业集团四川制药有限公司,批准文号:国药准字H20040011。
1.3观察指标
按照2002年《中药新药临床研究指导原则》骨关节炎疗效评定标准。
1.3.1疾病疗效判定标准
(1)临床痊愈:膝关节疼痛、肿胀消失,活动功能恢复正常,压痛或浮髌试验阴性,实验室检查正常,积分值为零;
(2)显效:膝关节疼痛、肿胀消失或明显减轻,活动明显改善,压痛或浮骸试验阴性,积分值下降>2/3者;
(3)有效:膝关节疼痛、肿胀减轻,活动有所改善,压痛或浮骸试验弱阳性,积分值下降>1/3者;
(4)无效:症状、体征改善未达到上述标准者,积分值下降<1/3者。
1.3.2中医临床证候疗效判定标准
(1)临床痊愈:中医临床症状、体征消失或基本消失,证候积分减少≥95%。
(2)显效:中医临床症状、体征明显改善,证候积分减少≥70%。
(3)有效:中医临床症状、体征均有好转,证候积分减少≥30%。
(4)无效:中医临床症状、体征均无明显改善,甚或加重,证候积分减少不足30%。
注:计算公式(尼莫地平法):疗效率=(治疗前分值-治疗后分值)/(治疗前分值)×100%。
1.3.3主要指标疗效判定
根据临床观察目的对主要的疗效观测指标,采用中医症候疗效指标和WOMAC指数进行疗效判定。
2.结果
2.1中医症候疗效指标
所有患者均完成一个疗程的治疗,无脱落。中医症候疗效指标结果统计于表2。
表2各组患者临床中医症候疗效指标比较(n=20)
2.2西医WOMAC指数
各组患者治疗前后的西医WOMAC指数变化情况统计于表3:
表3各组患者治疗前后的西医WOMAC指数变化情况(n=20)
注:与本组治疗前比较,*P<0.05;与对照组比较,△P<0.05。
2.3安全性检测
各组均未出现肝肾功能和血、尿常规等指标的异常。安全性检测结果表明本发明提供的药物组合物安全性好,长期服用无不良反应。
3.实验结论
从各组患者的中医症候疗效指标来看,由表2统计结果可见,实施例1、2、3组的显效率(%)和总有效率(%)均明显大于对照组(两组有显著性差异(P<0.05)),特别地,实施例1的中医证候疗效显效率为45%,总有效率为100%,显著优于对照组的15%和80%。由此表明从中医诊断标准出发,本发明药物组合物对OA的疗效强于市面的非甾体抗炎药美洛昔康片。
由表3统计结果可见,治疗前,实施例和对照组的WOMAC总指数、疼痛指数、功能指数、僵硬指数无显著性差异(P>0.05);治疗后,实施例和对照组WOMAC总指数及疼痛指数、功能指数、僵硬指数较治疗前均显著下降,进一步比较可得,实施例的WOMAC总指数、疼痛指数、功能指数、僵硬指数治疗前后的比较差值要大于对照组,结果更显著(P<0.05)。由此表明从西医诊断标准出发,本发明药物组合物对OA的疗效强于市面的非甾体抗炎药美洛昔康片。
以上所述仅为本发明的具体实施例,所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,并非因此限制本发明的专利范围,凡是这些技术特征的组合不存在矛盾,利用本发明作的等效变换,或直接或间接运用在其它相关的技术领域,均同理包括在本发明的专利保护范围之中。
Claims (4)
1.一种药物组合物在制备治疗/预防骨关节炎的药物中的应用;所述药物组合物是由按重量份计,由以下组分的原料药制得的:
贯众 90~200份,
土茯苓 50~150份,
黄柏 40~80份,
黄芩 20~50份,
大黄 10~40份,
草河车 10~35份,
胡黄连 10~20份,
黑矾 1~10份。
2.根据权利要求1所述的应用,其特征在于,所述药物组合物的制备方法包括以下步骤:
称取配方量的原料药;
土茯苓、黑矾粉碎成细粉;
将贯众、黄柏、黄芩、大黄、草河车、胡黄连六味药材加水煎煮,合并煎液,滤过,滤液浓缩成稠膏;
加入上述细粉,混匀,干燥。
3.根据权利要求2所述的应用,其特征在于,所述干燥的温度为50-100℃。
4.根据权利要求2所述的应用,其特征在于,所述制备方法还包括对干燥的产物进行粉碎的步骤。
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