CN114948981A - 有效成分哈巴俄苷在制备治疗骨质疏松药品中的应用 - Google Patents
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Abstract
本发明涉及有效成分在制备治疗骨质疏松药品中的应用，有效成分为哈巴俄苷，哈巴俄苷也可以为唯一有效成分，有效成分可以添加药用辅料制备成制剂，制剂剂型为片剂、胶囊、颗粒剂、口服液中的一种,能升高去卵巢骨质疏松大鼠模型血清中无机钙、磷含量,降低去卵巢骨质疏松大鼠模型血清中碱性磷酸酶(ALP)含量和抗酒石酸酸性磷酸酶(TRAP)含量。
Description
技术领域
本发明属于医药技术领域，具体涉及有效成分在制备治疗骨质疏松药品中的应用，有效成分为哈巴俄苷。
背景技术
骨质疏松症(OP)是以骨量减少、骨的微观结构退化为特点的，使骨脆性增加且易于发生骨折的一种全身代谢性骨病。通常根据发病原因，将其分为两类：一是原发性骨质疏松症，约有90％以上的骨质疏松症属此类，又分为高转换型的绝经后骨质疏松症、低转换型的老年性骨质疏松症和发于青少年、妊娠、哺乳期女性等人群的不明原因的特发性骨质疏松症；另一种是由于药物或影响骨代谢的某些疾病等导致的继发性骨质疏松症。随着我国老年人口的逐年增多，因年龄增长而发生骨退行性病变患骨质疏松症的人数也随之增加，这使骨折、致残、致死率大大提升。为提高患者生活质量，缓解经济和精神压力，寻求有效的骨质疏松症防治方法的研究与应用刻不容缓。
Wnt/β-catenin通路对骨量和强度有积极的调节作用。Wnt信号转导途径通过β-catenin调控下游Cyclin D1、C-myc等众多基因表达，从而参与调节干细胞的分化和增殖。而Wnt信号通路的激活受到不同家族蛋白的调控，包括Dickkopfs和分泌卷曲相关蛋白(secreted frizzled related proteins,sFRPs)，sFRP是一种糖蛋白，含有类半胱氨酸结构域，该结构域使s FRPs既能与细胞外室中的可溶性Wnt 蛋白结合，也能与Fz受体结合，从而对Wnt信号进行强有力的调控，维持骨稳态。
发明内容
本发明的目的在于：(1)有效成分在制备治疗骨质疏松药品中的应用。(2)有效成分为哈巴俄苷。(3)有效成分哈巴俄苷添加药用辅料制备成制剂。
为达到上述目的，本发明提供如下技术方案：有效成分在制备治疗骨质疏松药品中的应用，有效成分为哈巴俄苷。
所述有效成分在制备治疗骨质疏松药品中的应用，哈巴俄苷为唯一有效成分。
所述有效成分在制备治疗骨质疏松药品中的应用，将有效成分添加药用辅料，制备成剂型。
所述有效成分在制备治疗骨质疏松药品中的应用，剂型为片剂、胶囊、颗粒剂、口服液中的一种。
所述有效成分在制备治疗骨质疏松药品中的应用，有效成分哈巴俄苷能升高去卵巢骨质疏松大鼠模型血清中无机钙、磷含量。
所述有效成分在制备治疗骨质疏松药品中的应用，有效成分哈巴俄苷能降低去卵巢骨质疏松大鼠模型血清中碱性磷酸酶(ALP)含量和抗酒石酸酸性磷酸酶(TRAP) 含量。
哈巴俄苷，CAS：19210-12-9，分子式为：C24H30O11，分子量为494.488，购于上海源叶生物科技有限公司。
具体实施方式
下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：取哈巴俄苷10g,加淀粉，制备成片剂。
实施例2：取哈巴俄苷10g,加糊精，制备成颗粒剂。
实施例3：取哈巴俄苷10g,加淀粉，制备成胶囊剂。
实施例4：哈巴俄苷对骨密度的影响
4.1实验药物与动物：实验药物为实施例1制备的哈巴俄苷片剂。清洁级SD大鼠,雄性，体重240～310g,由上海西普尔必凯实验动物有限公司提供。
4.2模型的制备：大鼠适应性喂养1周后，随机分为假手术组(Sham，8只)和去卵巢组(32只)。腹腔注射质量分数为10％的水合氯醛(0.3mL/100g·bw)麻醉大鼠，修剪腹部毛发，75％酒精消毒后剖开腹腔，找到并切除双侧卵巢，喷洒少量青霉素后按顺序缝合伤口。Sham组切除腹腔内少量脂肪后缝合伤口。术后大鼠恢复30天，然后将去卵巢组按体重随机分为4组：模型对照组(OVX)、阳性药物对照组(E2，0.3mg/kg， 1mL/100g·BW)、本发明低剂量组(1000mg/kg·BW，1mL/100g·BW)和本发明高剂量组 (2000mg/kg·BW，1mL/100g·BW)，每组8只。Sham组和OVX组以1mL/100g·BW灌胃生理盐水。每天灌胃一次，灌胃90天。其间，每隔30天，眼眶采血一次，分析E2水平，当去卵巢非阳性药物组E2水平显著小于Sham，TRACP水平显著小于OVX时，去卵巢造模成功。最后一次灌胃后，所有大鼠禁食10-12h，期间可自由饮水，5％水合氯醛麻醉后眼眶取大鼠血液，室温静置40min，待血液凝固后，于4℃放置1小时，采用4℃， 3000rpm，离心20min收集血清，存于-80℃备用。大鼠处死后，迅速取出大鼠股骨和胫骨，剥离筋膜，大鼠左股骨远心端，置于10％中性***溶液中固定，用于组织学分析；大鼠右股骨远心端用于Micro-CT分析；剩余部分迅速置入液氮，置于 -80℃保存备用。
4.3血清骨代谢指标检测：分别按试剂盒说明书上步骤测定血中无机钙、磷、碱性磷酸酶(ALP)含量。碱性磷酸酶(ALP)试剂盒原理：磷酸苯二钠被碱性磷酸酶分解，产生磷酸和游离酚，游离酚在碱性溶液条件下与4－氨基安替吡啉作用，后经铁***氧化，生成红色醌衍生物，红色深浅表示酶活力的高低。抗酒石酸酸性磷酸酶 (TRAP)试剂盒：TRAP催化底物水解，产生游离酚，后与重氮盐反应生成有色偶氮化合物，通过比色测定酶的活力。
表1本发明对去卵巢骨质疏松大鼠血清生化指标的影响
| 组别 | 钙(mmol·L<sup>-1</sup>) | 磷(mmol·L<sup>-1</sup>) | ALP/(金氏单位100ml<sup>-1</sup>) | TRAP(U/L) |
| 假手术组 | 1.898±0.453 | 1.986±0.341 | 5.576±1.564 | 11.314±2.325 |
| 模型组 | 1.723±0.364 | 1.664±0.325 | 12.124±2.425 | 16.763±2.566 |
| 阳性药组 | 2.033±0.442 | 2.124±0.552 | 7.946±1.657* | 11.086±2.463* |
| 高剂量组 | 2.447±0.345* | 2.326±0.542* | 6.852±1.536* | 8.425±1.478* |
| 低剂量组 | 1.978±0.442 | 1.929±0.402 | 8.809±1.879* | 9.841±1.566* |
注:与模型组比较:*<0.05,**P<0.01。
骨骼的更新是一个动态平衡的过程，骨骼为供骨形成的需要而不停摄入血中游离钙的同时，又将骨吸收产生的钙释放入血中。测定血清钙、磷这两种骨代谢的一般生化标志物，可以考察抗骨松颗粒对钙、磷的影响，来研究其能否促进骨基质合成和骨矿沉积。骨矿化过程中，成骨细胞所分泌的骨特异性碱性磷酸酶(bALP)可水解单憐酸酯，生成无机憐，增加了局部无机磷的浓度，有利于骨形成过程，同时又能将抑制矿化结晶的焦磷酸盐水解，发挥出类似钙结合蛋白或Ga2+－ATP酶的作用。骨碱性磷酸酶是总碱性磷酸酶的重要部分，总碱性磷酸酶在骨碱性磷酸酶发生变化时，也会相应变化，故可作为骨形成标志物中的一种，来部分反映骨形成状态。抗酒石酸酸性磷酸酶(TRAP)是一种糖基化的含金属蛋白酶，在破骨细胞和破软骨细胞中大量表达，另外在活化的巨噬细胞和神经元也有，TRAP大部分被破骨细胞释放入血，与骨吸收呈正相关，并且其含量不受昼夜变化、饮食与肝、肾疾病等因素的影响，特异性高，己成为第二代骨吸收的生化标志物，能反映骨吸收状态和破骨细胞活性。去卵巢骨质疏松模型中模型组与假手术组比较，模型组ALP及TRAP含量均显著增高，而股骨骨密度又降低，说明模型俎大鼠骨量严重丢失并且骨形成与骨吸收均显著增强，骨代谢变得活跃起来，提示高转换型骨质疏松发生。股骨骨密度显著升高，并且 ALP及TRAP含量均显著降低，说明本发明能抑制成破骨活性，显著提高骨质疏松大鼠的骨量，抑制骨的高转换状态，有治疗骨质疏松症作用。
4.4骨密度分析：骨密度与骨质疏松症密切相关，是诊断骨质疏松症的标准之一。用显微CT对大鼠股骨头骨密度进行分析。
表2对骨密度的影响(x±s,n＝10)
| 组别 | 骨密度(g/kg) |
| 假手术组 | 875.872±40.237 |
| 模型组 | 492.526±52.683 |
| 阳性药组 | 897.451±44.431* |
| 高剂量组 | 902.730±46.514* |
| 低剂量组 | 887.525±47.452* |
注:与模型组比较:*<0.05,**P<0.01。
骨密度是测定骨质疏松症的金标准，又因双能X线骨密度仪全自动化程度高，使用方便，并且性能先进，扫描快捷，结果准确可靠，故本实验用其测定大鼠股骨密度 E2、本发明显著提高了骨质疏松大鼠骨密度，能治疗骨质疏松。
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。
Claims (7)
1.有效成分在制备治疗骨质疏松药品中的应用，其特征在于，有效成分为哈巴俄苷。
2.如权利要求1所述有效成分在制备治疗骨质疏松药品中的应用，其特征在于，哈巴俄苷为唯一有效成分。
3.如权利要求1所述有效成分在制备治疗骨质疏松药品中的应用，其特征在于，将有效成分添加药用辅料，制备成剂型。
4.如权利要求3所述有效成分在制备治疗骨质疏松药品中的应用，其特征在于，剂型为片剂、胶囊、颗粒剂、口服液中的一种。
5.如权利要求1所述有效成分在制备治疗骨质疏松药品中的应用，其特征在于，有效成分哈巴俄苷能升高去卵巢骨质疏松大鼠模型血清中无机钙、磷含量。
6.如权利要求1所述有效成分在制备治疗骨质疏松药品中的应用，其特征在于，有效成分哈巴俄苷能降低去卵巢骨质疏松大鼠模型血清中碱性磷酸酶(ALP)含量和抗酒石酸酸性磷酸酶(TRAP)含量。
7.如权利要求1所述有效成分在制备治疗骨质疏松药品中的应用，其特征在于，有效成分哈巴俄苷能提高骨密度。
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Citations (3)
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|---|---|---|---|---|
| US20020183264A1 (en) * | 2000-11-29 | 2002-12-05 | Shin Joon Shik | Use of harpagid-related compounds for prevention and treatment of osteoporosis, arthritis and ruptured disc and pharmaceutical composition containing the same |
| KR20170011403A (ko) * | 2015-07-22 | 2017-02-02 | 원광대학교산학협력단 | 하파고사이드를 유효성분으로 하는 파골세포 분화 억제를 통한 염증관련 골 질환 치료제 |
| WO2021222298A1 (en) * | 2020-04-29 | 2021-11-04 | The Board Of Trustees Of The Leland Stanford Junior University | Mechanical and biochemical activation and control of skeletal stem cells for cartilage regeneration |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020183264A1 (en) * | 2000-11-29 | 2002-12-05 | Shin Joon Shik | Use of harpagid-related compounds for prevention and treatment of osteoporosis, arthritis and ruptured disc and pharmaceutical composition containing the same |
| KR20170011403A (ko) * | 2015-07-22 | 2017-02-02 | 원광대학교산학협력단 | 하파고사이드를 유효성분으로 하는 파골세포 분화 억제를 통한 염증관련 골 질환 치료제 |
| WO2021222298A1 (en) * | 2020-04-29 | 2021-11-04 | The Board Of Trustees Of The Leland Stanford Junior University | Mechanical and biochemical activation and control of skeletal stem cells for cartilage regeneration |
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| HWA-JIN CHUNG ET AL.: "Anti-Osteoporotic Activity of Harpagoside by Upregulation of theBMP2 and Wnt Signaling Pathways in Osteoblasts and Suppressionof Differentiation in Osteoclasts", J. NAT. PROD., vol. 80, pages 434 - 442 * |
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