CN114306292A - 买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用 - Google Patents
买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用 Download PDFInfo
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Abstract
本发明公开了买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,所述的买麻藤醇制备工艺简单易行,成本低,产出率高,适合工业化生产。所述的买麻藤醇是少数几个能够通过抑制PDK1这一新兴药物靶点来治疗骨质疏松性骨缺损的药物,其对治疗骨质疏松性骨缺损有明显效果,本发明将为骨质疏松性骨缺损的中医药治疗提供一种新的有效药物。
Description
【技术领域】
本发明属于治疗骨质疏松性骨缺损药物技术领域,涉及买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用。
【背景技术】
骨质疏松症是一种以骨量低下、骨微结构破坏,导致骨脆性增加、易发生骨折为特征的系统性、全身性代谢性骨病。骨质疏松性骨缺损是指骨质疏松症患者骨的结构完整性遭到破坏,常见于创伤、感染、肿瘤切除等。由于骨质疏松症患者体内成骨细胞介导的骨形成作用明显低于破骨细胞介导的骨吸收,易导致骨折且经常伴随骨缺损。骨质疏松性骨缺损具有骨质差、骨折愈合慢、再骨折发生率高等特点。
骨质疏松性骨缺损的再生修复是目前临床治疗难点之一。现在对于骨质疏松性骨缺损的治疗主要是常规假体植入、异体骨移植及全身性抗骨质疏松药物治疗,但是这些治疗方法往往不能有效解决缺损部位的组织重建与修复。由于骨质疏松性骨缺损患者存在骨微结构改变、骨质量差、新骨再生潜力低下等基础病情,常规假体植入、异体骨移植容易出现骨与植入物整合不佳、免疫排斥反应强烈、局部及全身性感染、二次缺损等问题。全身性抗骨质疏松药物治疗,如双磷酸盐类、锶盐等虽能一定程度改善骨质疏松性骨缺损患者的基础病情,但不能有效解决缺损部位组织重建,而且昂贵的价格、并发症和有限的生物利用度也是一个障碍。这些传统疗法的局限性促使研发更有效和更安全的策略来治疗骨质疏松骨缺损。
从中药材中寻找治疗骨损伤的原料是一个很好的方向,目前已有相关的研究,例如中国专利申请号201810732960.5一种治疗股骨头坏死和乳腺增生的中药组合物及其乳膏剂,所述中药组合物包括曼陀罗、癞蛤蟆草、细辛、葛根、狼毒、朱砂根、九龙根、海风藤、土鳖虫、皂角、香加皮、莪术、买麻藤、过江龙、豆豉姜、香樟、徐长卿、降香、两面针、青皮木、羊耳菊、虎杖、五味藤、千斤拔、横经席、山萩、鹰不扑、草乌、薄荷脑、樟脑、冰片、马钱草,通过配伍辅料十六十八醇、凡士林、硬脂酸、单双硬脂酸甘油酯、丙二醇、三乙醇胺,制备成乳膏剂,用于股骨头坏死及乳腺增生的外敷治疗。但是该研究是关注于股骨头坏死和乳腺增生,并没有着眼于骨质疏松性骨缺损的研究。
【发明内容】
为了克服现有治疗骨质疏松性骨缺损药物的不足,本发明提供了买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,买麻藤醇针对治疗骨质疏松性骨缺损新兴药物靶点PDK1起作用,疗效明显,副作用小、安全方便、价格低廉。
本发明的目的通过以下技术方案来实现:
买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用。
所述的买麻藤醇,通过以下步骤制备得到:
1)乙醇提取:取买麻藤药材,藤茎切斜片,粉碎成粗粉,加体积浓度50%的乙醇于55-60℃提取两次,每次2小时,第一次加10倍量,第二次加8倍量,滤过,合并滤液,回收乙醇至滤液无醇味,得乙醇提取物;
2)树脂纯化:用等量水稀释上步骤得到的乙醇提取物,通过D101大孔吸附树脂柱,依次用水、20%乙醇、40%乙醇、60%乙醇及无水乙醇进行梯度洗脱,收集相应的洗脱液,回收乙醇,浓缩至相对密度约1.10的清膏,喷雾干燥,即得买麻藤醇。
进一步的,所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,是买麻藤醇在制备通过抑制PDK1药物靶点来治疗骨质疏松性骨缺损药物中的应用。
更进一步的,所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,是买麻藤醇在制备降低PDK1(3-磷酸肌醇依赖性蛋白激酶1)基因表达水平的治疗骨质疏松性骨缺损药物中的应用,PDK1是通过NF-κB这个通路来抑制炎症反应,COX-2是检测炎症反应的一个指标,买麻藤醇针对PDK1这个基因这个靶点。
进一步的,所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,所述药物是药物组合物,是以买麻藤醇为主要活性成分,加上药学中可接受的辅料或辅助性成分制备成临床上可接受的药物制剂,所述的买麻藤醇在药物组合物中的含量通常为0.01-95.0%(w/w)。
通常而言,作为药物,均是在制备成制剂后才临床应用。本发明所述的药物,作为药物组合物可根据本领域公知的方法制备,可通过将本发明药物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。
进一步的,所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,所述药物制剂包括口服制剂和注射制剂两种剂型。
进一步的,所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,所述口服制剂为口服胶囊,所述注射制剂为静脉注射液。
本发明所述药物或药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明药物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。为了将本发明药物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等;黏合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明药物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明药物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明药物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明药物的胶囊剂。
为将本发明药物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
和现有技术相比,本发明具有如下优点:
1、本发明所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,所述的买麻藤醇制备工艺简单易行,成本低,产出率高,适合工业化生产。
2、本发明所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,所述的买麻藤醇是少数几个能够通过抑制PDK1这一新兴药物靶点来治疗骨质疏松性骨缺损的药物,其对治疗骨质疏松性骨缺损有明显效果,尤其是在制备使得PDK1,NF-κB,COX-2这三个基因表达水平下降药物中的应用,本发明将为骨质疏松性骨缺损的中医药治疗提供一种新的有效药物。
【附图说明】
图1是本发明实验例中与骨缺损组小鼠相比,买麻藤醇治疗组小鼠的骨体积分数、骨小梁厚度、骨小梁数目增加,骨小梁分离度减少的图(A为通过Micro-CT扫描不同组小鼠骨组织标本;B为骨组织形态学分析,不同组小鼠骨组织中骨松质参数,包括BV/TV,Tb.Sp,Tb.N,Tb.Th(*P<0.05,**P<0.01,***P<0.001));
图2是本发明实验例中各组小鼠骨髓组织中各相关炎症因子的表达水平的统计分析的图(与正常组比较,骨缺损组的骨髓组织中的抗炎因子(IL-10、IL-13、TGF-β1)明显下降,促炎因子(IL-1β、IL-17、TNF-α)明显增加,买麻藤醇治疗后,抗炎因子则明显升高,促炎因子不同程度下降的图,模型组与正常组比较,##p<0.05,##P<0.01,###P<0.001;买麻藤醇组与骨缺损组比较,*P<0.05,**P<0.01,***P<0.001);
图3是本发明实验例中小鼠骨髓组织中PDK1的表达水平的统计分析的图(与正常组比较,骨缺损组的骨髓组织中的PDK1明显增加,买麻藤醇治疗后,PDK1表达不同程度下降,买麻藤醇组与正常组比较,*P<0.05,**P<0.01,***P<0.001);
图4是本发明实验例中小鼠破骨细胞分化中PDK1、NF-κB、COX-2的表达水平的统计分析的图(在买麻藤提取物买麻藤醇干预后,破骨细胞分化过程中PDK1、NF-κB、COX-2表达降低,买麻藤醇组与正常组比较,*P<0.05,**P<0.01,***P<0.001)。
【具体实施方式】
以下结合实施例对本发明的具体实施方式做进一步说明。
实施例:
买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用。
所述的买麻藤醇,通过以下步骤制备得到:
1)乙醇提取:取买麻藤药材,藤茎切斜片,粉碎成粗粉,加体积浓度50%的乙醇于55-60℃提取两次,每次2小时,第一次加10倍量,第二次加8倍量,滤过,合并滤液,回收乙醇至滤液无醇味,得乙醇提取物;
2)树脂纯化:用等量水稀释上步骤得到的乙醇提取物,通过D101大孔吸附树脂柱,依次用水、20%乙醇、40%乙醇、60%乙醇及无水乙醇进行梯度洗脱,收集相应的洗脱液,回收乙醇,浓缩至相对密度约1.10的清膏,喷雾干燥,即得买麻藤醇。
实验例1:体内探究买麻藤醇对骨质疏松性骨缺损小鼠的影响。
通过切除雌性小鼠双侧卵巢来构建骨质疏松模型,然后以此为基础分别设立正常组、骨缺损组、买麻藤醇治疗组。买麻藤醇治疗组在使用买麻藤醇进行治疗后,通过Micro-CT扫描,ELISA分析及蛋白免疫印迹检测等技术手段对买麻藤提取物买麻藤醇的治疗效果进行评估。
结果:
首先与正常组小鼠相比,骨缺损组小鼠的骨量明显下降,证实骨缺损小鼠模型构建成功;与骨缺损组小鼠相比,买麻藤醇治疗组小鼠的骨体积分数、骨小梁厚度、骨小梁数目增加,骨小梁分离度减少(图1:A为通过Micro-CT扫描不同组小鼠骨组织标本;B为骨组织形态学分析,不同组小鼠骨组织中骨松质参数,包括BV/TV,Tb.Sp,Tb.N,Tb.Th(*P<0.05,**P<0.01,***P<0.001))。
发明人在前期的研究中发现骨质疏松症患者体内炎症因子表达均异常增高,这些炎症因子(白细胞介素17、肿瘤坏死因子α、补体蛋白分子等)不间断的攻击、损害骨组织细胞,打破骨代谢平衡,造成骨密度持续下降,进而加重骨质疏松性骨缺损,因此发明人也检测了小鼠模型的炎症因子水平,与正常组比较,骨缺损组的骨髓组织中的抗炎因子(IL-10、IL-13、TGF-β1)明显下降,促炎因子(IL-1β、IL-17、TNF-α)明显增加,买麻藤醇治疗后,抗炎因子则明显升高,促炎因子不同程度下降(图2为各组小鼠骨髓组织中各相关炎症因子的表达水平的统计分析:模型组与正常组比较,##p<0.05,##P<0.01,###P<0.001;买麻藤醇组与骨缺损组比较,*P<0.05,**P<0.01,***P<0.001)。
与正常组比较,骨缺损组的骨髓组织中的PDK1明显增加,买麻藤醇治疗后,PDK1表达不同程度下降(图3为小鼠骨髓组织中PDK1的表达水平的统计分析,买麻藤醇组与正常组比较,*P<0.05,**P<0.01,***P<0.001)。
实验例2
体外探究买麻藤对小鼠破骨细胞分化过程的影响。
发明人分别提取小鼠的骨髓巨噬细胞分别进行诱导分化,并分别设立了对照组、买麻藤醇低、高浓度组。在诱导分化5天后,提取相关蛋白,使用蛋白免疫印迹技术检测PDK1、NF-κB、COX-2等表达。
结果提示,在买麻藤提取物买麻藤醇干预后,破骨细胞分化过程中PDK1、NF-κB、COX-2表达降低(图4为小鼠破骨细胞分化中PDK1、NF-κB、COX-2的表达水平的统计分析,买麻藤醇组与正常组比较,*P<0.05,**P<0.01,***P<0.001)。
发明人一直致力于探讨骨质疏松性骨缺损的发病机理及中草药的干预机制,在PDK1调控破骨细胞在骨质疏松症发病中的分子机制研究中,通过构建条件性破骨细胞中PDK1基因敲除小鼠证实了抑制PDK1基因的表达可减弱破骨细胞活性和骨的吸收能力,能有效促进骨质疏松性骨缺损的再生修复,防治骨质疏松症这些研究成果强烈提示了PDK1是潜在的促进骨组织再生修复的药物靶点。但目前临床上没有有效的PDK1抑制剂,为此,申请人一直在寻找针对PDK1药物靶点治疗骨质疏松性骨缺损的药物以实现临床转化。
上述说明是针对本发明较佳可行实施例的详细说明,但实施例并非用以限定本发明的专利申请范围,凡本发明所提示的技术精神下所完成的同等变化或修饰变更,均应属于本发明所涵盖专利范围。
Claims (7)
1.买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用。
2.根据权利要求1所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,其特征在于:所述的买麻藤醇,通过以下步骤制备得到:
1)乙醇提取:取买麻藤药材,藤茎切斜片,粉碎成粗粉,加体积浓度50%的乙醇于55-60℃提取两次,每次2小时,第一次加10倍量,第二次加8倍量,滤过,合并滤液,回收乙醇至滤液无醇味,得乙醇提取物;
2)树脂纯化:用等量水稀释上步骤得到的乙醇提取物,通过D101大孔吸附树脂柱,依次用水、20%乙醇、40%乙醇、60%乙醇及无水乙醇进行梯度洗脱,收集相应的洗脱液,回收乙醇,浓缩至相对密度1.10的清膏,喷雾干燥,即得买麻藤醇。
3.根据权利要求1或2所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,其特征在于:买麻藤醇在制备降低PDK1基因表达水平的治疗骨质疏松性骨缺损药物中的应用。
4.根据权利要求3所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,其特征在于:买麻藤醇在制备使得PDK1、NF-κB或COX-2三个基因表达水平下降的治疗骨质疏松性骨缺损药物中的应用。
5.根据权利要求1或2所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,其特征在于:所述的药物是药物组合物,是以买麻藤醇为主要活性成分,加上药学中可接受的辅料或辅助性成分制备成临床上可接受的药物制剂,所述的买麻藤醇在药物组合物中的含量通常为0.01-95.0%w/w。
6.根据权利要求5所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,其特征在于:所述药物制剂包括口服制剂和注射制剂两种剂型。
7.根据权利要求6所述的买麻藤醇在制备治疗骨质疏松性骨缺损药物中的应用,其特征在于:所述口服制剂为口服胶囊,所述注射制剂为静脉注射液。
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