CN1192685A - 用安仑络纳(alendronate)预防骨质疏松症 - Google Patents
用安仑络纳(alendronate)预防骨质疏松症 Download PDFInfo
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Abstract
安仑络纳,一种氨基双膦酸盐,能预防经绝后早期妇女的骨质疏松症。
Description
发明领域
本发明是关于使用安仑络纳，一种氨基双膦酸盐，以予防经绝后早期妇女的骨质疏松症。
发明背景
已经发现安仑络纳，4-氨基-1-羟基亚丁基-1，1-双膦酸及其药学上可接受的盐对治疗骨质疏松症有效。安仑络纳是骨吸收的特异性抑制剂，对骨矿物质有高度亲和力，在它抑制破骨细胞活力处被骨选择性地吸收。安仑络纳已显示出对恢复失去的骨质有效，但尚无迹象表明它能对其它方面健康的人预防骨的丢失。
妇女的骨质量高峰在30-35岁左右，此后一生中骨质呈进行性的丢失。在经绝后早期丢失加速，尤其是在骨小梁组成高的部位。
一般妇女一生中可能有40％以上的机会发生至少一次骨质疏松性骨折。这种骨折，尤其当发生在髋部时，会使生活质量明显下降并需要昂贵的治疗费用。虽然难以作出精确的估算，但所有骨质疏松性骨折的总开支和病情无疑会显著超过单纯的髋骨折。
目前预防骨质疏松症的唯一已获批准的疗法是雌激素替代疗法。在预防伴有内源性雌激素生成降低的骨丢失的同时，使用雌激素能有助于减轻经绝后症候群，如血管舒缩不稳定性和阴道萎缩，还能改善脂质分布型，因而有可能减少心血管疾病。然而在常用的预防骨丢失的剂量下，许多妇女虽经连续治疗仍丢失骨质。而且雌激素治疗还伴有某些严重的危险，包括子宫内膜癌、有症状的胆囊疾患，并有可能增加乳腺癌的发生率。在治疗方法中加用孕激素或每年进行子宫内膜活检可使某些危险降低，然而大部分妇女主要由于耐受性差及安全顾虑不愿接受长期的雌激素治疗。
理想的是能有一种制剂既能预防骨质疏松症而又不会带来雌激素那样的危险和可能发生的副作用。
发明概述
本发明是关于对具有正常骨矿物密度的妇女预防骨质疏松症的一种方法，包括在足够长的时间内使用预防有效剂量的安仑络纳或其药学可接受的盐。
本发明的另一方面是减少妇女骨折危险的一种方法，即在相当长时间里使用预防有效剂量的安仑络纳或其药学可接受的盐。
本发明的再一方面是籍使用预防有效剂量的安仑络纳或其药学可接受的盐为经绝后早期妇女预防骨质疏松症的一种方法。
在无预防措施的情况下骨微结构随骨丢失的发展而退变，导致单位骨质量的骨强度减低。已发现，按本发明预防使用安仑络纳能保持正常微结构及正常骨强度。因此本发明的又一方面是籍使用预防有效剂量的安仑络纳或其药学可接受的盐以保持正常骨微结构和骨强度的一种方法。
在说明书及权利要求中采用以下定义：
“预防有效剂量”对于当前无骨质疏松症的妇女是以预防骨质疏松症的妇女足以预防骨质疏松症的安仑络纳或其药学可接受的盐的量。这个量对于现患骨质疏松症的患者可以是也可以不是其药学可接受的量，即是以治疗骨质疏松症、恢复骨质量的量。
“相当长的时间”：一种持续的时间，即至少三年左右，最好更长。
“骨质疏松症”：人的骨矿物质密度低于骨矿物质峰值约2个标准差以上的状况。
“经绝后早期”：妇女闭经后少于五年左右的时间。
安仑络纳的制备可按美国专利5,019,651，4,992,007和1994年8月4日提交的美国申请系列号08/286,151中的任一方法进行，这些文件附于参考资料中。安仑络纳的药学可接受的盐包括碱金属(如钠、钾)盐，碱土金属(如钙)盐，无机酸盐如盐酸盐，有机酸盐如柠檬酸盐和氨基酸盐。优选钠盐形式，特别是单钠盐的三水合物。
本发明的化合物可采用口服剂型，如片剂、胶囊(每一种都包括持续释放或定时释放形式)，丸剂、粉剂、冲剂、酏剂，糊剂、酊剂、悬液剂、糖浆剂、乳剂和zydis等，而且这些化合物还可以静脉内(浓缩药团或输注液)、腹腔内、皮下或肌肉形式使用，包括以药剂学通常技术所熟知的一切形式来使用。所需化合物的有效无毒量能用作骨质疏松症的预防剂。
应用权利要求方法的剂量方案应根据多种因素来选择：包括患者的年龄、体重、性别和医学状况；用药途径；患者的肾肝功能；以及采用的化合物或盐的种类。一个普通熟练程度的医生能容易地决定并开出预防骨质疏松症所需药物的有效量。
本发明的口服剂量为每日每公斤体重0.05毫克(mg/kg/day)至1.0mg/kg/day。人的优选每日口服量在有效治疗期为2.5-20mg/天，优选的预防量为2.5，5或10mg/天。
安仑络纳可每日一次剂量或分次剂量投予。宜在无食物时用，最好是饭前30分钟至2小时，以便得到充分的吸收。
本发明方法中，有效成分通常与适当的药物稀释剂、赋形剂或载体(此处统称载体物质)混合使用。载体物质的选择根据药剂学常规及拟采用的投药形式，即口服片剂、胶囊、酏剂、糖浆剂等。例如，以片剂或胶囊口服时，活性成分可与口服无毒、药学可接受的惰性载体结合使用，如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、cros-carmellose钠硬脂酸镁，甘露糖醇，山梨糖醇等；液体口服时，药物成分可与任一种口服无毒、药学可接受的惰性载体联合使用，如酒精、甘油、水等。而且，在需要时，适当的粘合剂、滑润剂、崩解剂及着色剂也可加入到活性成分与惰性载体物质的混合物中。适宜的粘合剂可包括淀粉、明胶、天然糖如葡萄糖、无水乳糖、液态乳糖、β-乳糖、觳类甜味剂；天然和合成树胶如金合欢胶、黄蓍胶或藻酸钠；羧甲基纤维素，聚乙烯乙二醇，腊及其它这些剂型中使用的滑润剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠等。特别优选的片剂组方如美国专利5,358,941所示，见所附参考资料。
本方法所使用的化合物也可与作为目标药物载体的可溶性聚合物结合。此类聚合物可包括聚乙烯吡咯烷酮，吡喃共聚物，多羟基丙基-异丁烯酰胺等。
以下提供非限制性的例子以说明本发明。
例1
参加此研究的妇女一般健康状况良好，年龄为45-59岁，从居住于规定地区的受试者群体中随机选择。大多数为经绝后早期。参加者中经脊柱双能量x线密度测定发现有骨质疏松症者少于15％。
每一受试者随机分配为醚安慰剂，安仑络纳低剂量(每日ALN2.5mg)，安仑络纳高剂量(每日ALN 5mg)或公开标明的雌激素/孕激素(E/P)。雌激素/孕激素组(在美国)在整个日历中连续使用结合的雌激素PREMARIN(0.625mg/日)和醋酸甲羟孕酮PROVERA(5mg/日)。在美国以外地区，雌激素/孕激素组接受微粒化的17.6-雌二醇和醋酸炔诺酮(Trisequens)作为周期性治疗。所有受试者中每日钙摄取量低于500mg者则建议其增加钙摄入(通过食物或补给)达到此水平以上。分组情况见表1。每组的治疗期限见表2。
在头二年(对接受安仑络纳或安慰剂的妇女)采用双盲法，期末时作第一次分析。双盲持续到第四年末，此时对每个受试者个别地公开其措施。只通知受试者是否接受了安仑络纳的积极治疗，如果是，是治疗了两年还是四年。但不告知用药量。对于在第5和6年继续接受盲目法研究的受试者及研究人员，在此延长阶段中的治疗分配仍是保密的。
表I治疗分组
ALN＝安仑络纳E/P＝雌激素/孕激素
| 团组1 | 团组2 | |||
| 组别 | 处理 | 数量 | 数量 | 总计 |
| A | 安慰剂 | 150 | 300 | 450 |
| B | ALN 2.5mg | 150 | 300 | 450 |
| C | ALN 5mg | 150 | 300 | 450 |
| D | E/P | 150 | -- | 150 |
| 总计 | 600 | 900 | 1500 |
“A”组(见表2)的受试者按盲目法服用安慰剂四年。在四年末时通知她们在四年中服用了安慰剂。她们可以选择继续参加双盲的随机分配安慰剂和最佳剂量的安仑络纳或退出研究。
B1与C1组各接受2.5或5mg安仑络纳。
表2研究摘要表
| 研究年份 | ||||
| 组别 | 数量 | 1及2 | 3及4 | 5及6 |
| A | 450 | 安慰剂 | 安慰剂 | 最任剂量ALN或安慰剂* |
| B1 | 150 | ALN 2.5mg | ALN 2.5mg | ALN 2.5mg |
| B2 | 150 | ALN 2.5mg | ALN 2.5mg | 安慰剂 |
| B3 | 150 | ALN 2.5mg | 安慰剂 | |
| C1 | 150 | ALN 5mg | ALN 5mg | ALN 5mg |
| C2 | 150 | ALN 5mg | ALN 5mg | 安慰剂 |
| C3 | 150 | ALN 5mg | 安慰剂 | |
| D | 150 | E/P | E/P | |
ALN＝安仑络纳
最佳剂量为2.5或5mg
*安慰剂组在延长至5-6年时再随机分组
E/P＝雌激素/孕激素六年。B2及C2组各保持2.5及5mg的安仑络纳四年，然后在研究的最后两年换成安慰剂。继续参加5-6年研究的受试者双盲地分配为在5-6年服用活性药物或安慰剂。B3和C3组各服用2.5mg和5mg安仑络纳两年，然后在研究的第三和第四年换成安慰剂。四年后停止药物研究。
D组的受试者持续接受公开标志的雌激素/孕激素治疗四年，结束后停止药物研究。
四年后，接受安仑络纳的妇女经测量没有发生骨质疏松症的迹象，如骨矿物质密度的减少，而接受安慰剂的妇女却发现有骨矿物密度的减少。差异是统计学显著的。
Claims (7)
1.一种予防经绝后早期妇女骨质疏松症的方法，包括使用予防有效剂量的安仑络纳或其药学有效的盐。
2.权利要求1的方法，其中安仑络纳口服使用。
3.权利要求2的方法，其中安仑络纳每日一次使用。
4.权利要求3的方法，其中安仑络纳是单钠盐三水合物。
5.权利要求4的方法，其中剂量为2.5至20mg/日。
6.权利要求5的方法，其中剂量组可选择为2.5，5及10mg/日。
7.一种予防经绝后早期妇女骨质疏松症的方法，包括使用每日2.5至20mg的安仑络纳钠盐三水合物。
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| SE9901272D0 (sv) * | 1999-04-09 | 1999-04-09 | Astra Ab | New improved formulation |
| KR100317935B1 (ko) * | 1999-10-20 | 2001-12-22 | 유승필 | 대사성 골질환 치료용 약제조성물 및 이의 제조방법 |
| JP2010043119A (ja) * | 2009-10-16 | 2010-02-25 | Gador Sa | 骨の代謝病の予防および／または治療のための組成物、その組成物の調製方法およびその使用 |
| KR102472749B1 (ko) * | 2022-01-18 | 2022-12-02 | 주식회사 위엔씨 | 유해가스제거 및 항균탈취기능을 함유한 흡착소재 제조방법 |
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| WO1996038156A1 (en) | 1996-12-05 |
| TR199701482T1 (xx) | 1998-03-21 |
| BR9609020A (pt) | 1999-07-06 |
| AU709196B2 (en) | 1999-08-26 |
| EA199700449A1 (ru) | 1998-06-25 |
| CZ381197A3 (cs) | 1998-06-17 |
| NZ308935A (en) | 2000-07-28 |
| AU5882496A (en) | 1996-12-18 |
| HUP9900659A3 (en) | 2002-12-28 |
| EE03306B1 (et) | 2000-12-15 |
| BG102060A (en) | 1998-07-31 |
| NO975527D0 (no) | 1997-12-01 |
| KR19990022436A (ko) | 1999-03-25 |
| JPH10506648A (ja) | 1998-06-30 |
| ZA964465B (en) | 1996-12-11 |
| IS4617A (is) | 1997-11-19 |
| PL323669A1 (en) | 1998-04-14 |
| NO975527L (no) | 1997-12-01 |
| BG63103B1 (bg) | 2001-04-30 |
| HUP9900659A2 (hu) | 2001-04-28 |
| EP0828496A1 (en) | 1998-03-18 |
| CA2222318A1 (en) | 1996-12-05 |
| IL118422A0 (en) | 1996-09-12 |
| SK159597A3 (en) | 1998-06-03 |
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