CN101259133A - 唑来磷酸用于制备预防及治疗骨质疏松症的药物 - Google Patents
唑来磷酸用于制备预防及治疗骨质疏松症的药物 Download PDFInfo
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Abstract
本发明公开了唑来磷酸在防治骨质疏松症的应用,动物实验研究发现唑来磷酸对骨质疏松症具有较好的预防及治疗作用。唑来磷酸可制成临床可接受的片剂、胶囊剂、颗粒剂、混悬剂、干混悬剂、口服液等口服制剂中的任何一种,供临床预防和治疗骨质疏松症。
Description
技术领域
骨质疏松症是以骨组织显微结构受损,骨矿成分和骨基质等比例不断减少,骨质变薄,骨小梁数量减少,骨脆性增加和骨折危险度升高的一种全身骨代谢障碍的疾病。骨质疏松是老年人最常见的疾病。本发明涉及唑来磷酸在防治骨质疏松症的应用。唑来磷酸是第一个被批准用于治疗多发性骨髓瘤、乳腺癌、前列腺癌、肺癌及其它实体瘤的各种肿瘤骨转移相关并发症的双磷酸盐。它通过与骨结合来阻断破骨细胞对骨和软骨的吸收,抑制破骨细胞活性,诱导破骨细胞凋亡,抑制肿瘤释放的各种刺激因子所诱发的骨骼的钙释放,从而降低血清钙水平,达到减少骨破坏,缓解骨痛和降低血钙的目的。本课题组研究发现口服唑来磷酸对骨质疏松具有较好的预防及治疗作用。
背景技术
骨质疏松是老年人最常见的疾病。一般来说,骨头因疏松而变薄、变脆弱、容易造成骨折,特别是腕骨、股骨及脊椎骨。而骨质疏症最明显的症状,就是脊椎压迫性骨折,它会引起背部酸痛、身高变矮及驼背现象。在美国和西方国家中,在年龄超过55岁绝经后的女性中,有一半的人患程度不同的骨质疏松症。据统计我国目前65岁以上的老年人已达1.2亿,而患有骨质疏松的患者在这些人群中约占90%。
产生骨质疏松的根本原因就是骨吸收与骨形成作用失衡,大量的骨吸收使骨量减少、质量下降。目前所用治疗骨质疏松症的疗法(如维生素D、激素替代)都只能防止骨被吸收而不能促使骨形成。雌激素替代疗法,因其具有潜在的致癌危险性及不良反应,故临床应用受到限制;甲状旁腺激素虽能刺激骨形成,但缺点之一是必须注射给药;降钙素可以短期改善骨质疏松患者的疼痛,但在预防密质骨的丢失和骸部骨折效果不好。
随着科学的发展和人类的进步,人均寿命不断延长,老年人口迅速增加,骨质疏松的发病率也随着出现迅速的增加。因此防治骨质疏松是保证人民生活质量的一个十分迫切的研究课题。
唑来磷酸是继骨鳞、博宁后新一代(第三代)的双磷酸盐类药物。骨转移是恶性肿瘤常见并发症之一,它大多以溶骨性破坏为主,主要表现为骨痛、高钙血症、脊髓压缩及病理性骨折等,严重影响患者的生活质量。有研究表明,唑来磷酸比同类传统药物博宁有更高的安全性。本课题组研究发现口服唑来磷酸对骨质疏松具有较好的预防及治疗作用。
发明内容
本发明的目的是提供了口服唑来磷酸在治疗骨质疏松症中的预防及治疗作用。
唑来磷酸分子式:C5H10N2O7P2·H2O;英文名:Zoledronic acid;分子量:290.10;熔点:230℃;化学结构式:
具体实施方式:
实例1:唑来磷酸对维甲酸造成骨质疏松的大鼠骨密度的影响
大鼠(250-320g),雌雄各半,共50只。随机分为5组:正常对照组,模型对照组,唑来磷酸0.4932mg/kg、1.5364mg/kg、4.8761mg/kg三个剂量组。除正常对照组外,其他各组均灌服维甲酸65mg/kg,每日一次,连续2周。造模同时各给药组依所设剂量灌胃给药0.15ml/kg,每日一次,对照组给予等量溶媒,模型对照组正常饲养,连续4周。最后一次给药后次日,以10%水合氯醛(350mg/kg,i.p.)麻醉大鼠,置于双能线骨密度测定仪探头下,仰位固定于检测台上,头与身体呈直线,线球管对准身体纵轴中点,选择大鼠骨质疏松敏感区域单侧(左侧)股骨中点的皮质骨和第三腰椎骨测定骨密度。实验结果经统计学处理,作t检验判断显著性,结果见表1。
表1唑来磷酸对骨质疏松大鼠骨密度的影响(n=10,x±SD)
模型组与正常组比较:*P<0.05,**P<0.01
样品组与模型组比较:△P<0.05,△△P<0.01
由表1可见,与正常组相比模型组大鼠股骨密度和椎骨密度显著下降(P<0.01),唑来磷酸高、中、低剂量组均能显著提高骨质疏松大鼠股骨密度和椎骨密度(P<0.01)。
实例2:唑来磷酸对维甲酸造成骨质疏松大鼠的股骨长度、重量和骨钙含量的影响
大鼠(250-320g),雌雄各半,共50只。随机分为5组:正常对照组,模型对照组,唑来磷酸0.4932mg/kg、1.5364mg/kg、4.8761mg/kg三个剂量组。除正常对照组外,其他各组均灌服维甲酸65mg/kg,每日一次,连续2周。造模同时各给药组依所设剂量灌胃给药0.15ml/kg,每日一次,对照组给予等量溶媒,模型对照组正常饲养,连续4周。最后一次给药后次日处死并解剖大鼠,剥离左侧股骨,用游标卡尺测量股骨的长度,将股骨烤干至恒重,称量骨干重。
骨钙测定:依据国家标准GB12398-90进行测定。称取样品于小三角烧瓶中,加5mlHNO3;HCLO4(4∶1),加上漏斗,置于电热板上加热消化,如消化不完全,补加硝酸继续加热至无色透明为止,加2ml去离子水,加热以除去多余的硝酸。取下冷却,用2%氧化镧溶液定容至100ml容量瓶中。实验结果经统计学处理,作t检验判断显著性,结果见表2。
表2唑来磷酸对骨质疏松大鼠股骨长度、重量和骨钙的影响(n=10,x±SD)
模型组与正常组比较:*P<0.05,**P<0.01
样品组与模型组比较:△P<0.05,△△P<0.01
由表2可见,各组大鼠的股骨长度均无显著差异,与正常组相比模型组大鼠股骨重量和骨钙含量显著下降(P<0.01),唑来磷酸高、中、低剂量组均能显著提高骨质疏松大鼠股骨重量和骨钙含量(P<0.01)。
实例3:唑来磷酸对卵巢切除大鼠的股骨长度、重量和骨钙含量的影响
绝经伴随骨质疏松的发生已为许多流行病学研究所证实。绝经可引起糖代谢紊乱,产生胰岛素抵抗,而糖代谢紊乱是引起晚期糖化终末产物增加的主要原因。高水平的晚期糖化终末产物可导致成骨细胞数量减少,活性降低,骨形成降低,最终造成骨质疏松症。
目前,对绝经后骨质疏松的治疗主要采用激素替代疗法,虽然对骨质疏松有一定的疗效,但可引起乳腺癌和子宫内膜癌的发生。本发明采用卵巢切除方法制作大鼠骨质疏松模型,证明唑来磷酸对绝经后骨质疏松的防治作用。
大鼠(250-320g),雌雄各半,共50只。随机分为5组:假手术组,模型对照组,样品高、中、低三个剂量组。在无菌条件下,将大鼠腹腔注射1%戊巴比妥钠溶液,模型对照组和样品组麻醉后进行经背部切口,切除双侧卵巢。假手术组打开腹腔后切除少量脂防。手术后一周,将高、中、低三个剂量的唑来磷酸组样品稀释后供大鼠每日饮用。其它组饮用自来水,常规喂养3个月后,最后一次给药后次日处死并解剖大鼠,剥离左侧股骨,用游标卡尺测量股骨的长度,将股骨烤干至恒重,称量骨干重。
骨钙测定:依据国家标准GB12398-90进行测定。称取样品于小三角烧瓶中,加5mlHNO3;HCLO4(4∶1),加上漏斗,置于电热板上加热消化,如消化不完全,补加硝酸继续加热至无色透明为止,加2ml去离子水,加热以除去多余的硝酸。取下冷却,用2%氧化镧溶液定容至100ml容量瓶中。实验结果经统计学处理,作t检验判断显著性,结果见表3。
表3唑来磷酸对卵巢切除大鼠的股骨长度、重量和骨钙含量的影响(n=10,x±SD)
模型组与正常组比较:*P<0.05,**P<0.01
样品组与模型组比较:△P<0.05,△△P<0.01
由表3可知大鼠切除卵巢后三个月股骨长度、重量和骨钙含量均明显降低,与假手术组比较有显著性差异(P<0.01),经唑来磷酸治疗3个月,股骨长度、重量和骨钙含量明显增加,中、高剂量组与卵巢切除组比较有显著差异(P<0.01)。
实例4:唑来磷酸对卵巢切除大鼠的骨密度的影响
大鼠(250-320g),雌雄各半,共50只。随机分为5组:假手术组,模型对照组,样品高、中、低三个剂量组。在无菌条件下,将大鼠腹腔注射1%戊巴比妥钠溶液,模型对照组和样品组麻醉后进行经背部切口,切除双侧卵巢。假手术组打开腹腔后切除少量脂防。手术后一周,将高、中、低三个剂量的唑来磷酸组样品稀释后供大鼠每日饮用。其它组饮用自来水,常规喂养3个月后,最后一次给药后次日,以10%水合氯醛(350mg/kg,i.p.)麻醉大鼠,置于双能线骨密度测定仪探头下,仰位固定于检测台上,头与身体呈直线,线球管对准身体纵轴中点,选择大鼠骨质疏松敏感区域单侧(左侧)股骨中点的皮质骨和第三腰椎骨测定骨密度。实验结果经统计学处理,作t检验判断显著性,结果见表4。
表4唑来磷酸对卵巢切除大鼠骨密度的影响(n=10,x±SD)
模型组与正常组比较:*P<0.05,**P<0.01
样品组与模型组比较:△P<0.05,△△P<0.01
由表4可见,与假手术组相比模型组大鼠股骨密度和椎骨密度显著下降,唑来磷酸小、中、高剂量组均能提高卵巢切除大鼠股骨密度和椎骨密度。中、高剂量组与卵巢切除组比较有显著差异(P<0.01)。
Claims (5)
1、唑来磷酸用于制备预防及治疗骨质疏松症的药物,其特征在于唑来磷酸可以制备成临床上治疗骨质疏松症的药物制剂。
2、根据权利要求1所述的应用,其特征在于口服唑来磷酸的使用剂量范围为0.1mg~50mg。
3、根据权利要求1所述的应用,其特征在于包括含有唑来磷酸的用于治疗或预防骨质疏松的口服药物组合物。
4、根据权利要求1所述的唑来磷酸作为预防和治疗骨质疏松症药物的应用,其特征是唑来磷酸与临床上接受的药物载体或辅料配合制成治疗骨质疏松的片剂、胶囊剂、颗粒剂、混悬剂、干混悬剂、口服液等口服制剂形式。
5.唑来磷酸作为药物治疗骨质疏松的适应症。
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