CN1939314A - 用于治疗和预防骨质疏松症的二膦酸 - Google Patents
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Abstract
本发明涉及二膦酸或其药学上可接受的盐在制备用于预防或治疗特征在于病理性增加的骨吸收的疾病、特别是用于预防和治疗骨质疏松症的药物中的应用。
Description
本申请为2003年5月2日提交的申请号为PCT/EP2003/004629、发明名称为“用于治疗和预防骨质疏松症的二膦酸”的国际申请的分案申请,该申请于2004年9月29日进入中国国家阶段,申请号为03807565.2。
技术领域
本发明涉及二膦酸(盐)的应用,尤其是(1-羟基-3-(N-甲基-N-戊基)氨基亚丙基-1,1-二膦酸(伊班膦酸,ibandronic acid)或其药学上可接受的盐在制备用于预防或治疗特征在于病理性增加的骨吸收的疾病、特别是用于预防和治疗骨质疏松症的药物中的应用。
背景技术
骨主要起支撑作用,因而经常被认为是简单的构架物质。但是,骨是能够适合广泛的不同要求(它所暴露在的刺激物和伤害物(noxae))的复杂生物材料。内部假肢(endoprostheses)可以用作骨和关节的替代物。但是,内部假肢,即便经过了很高程度的人体工程学改良,对环境因子和负荷因子没有活性作用。
人和哺乳动物的许多疾病中涉及异常的骨吸收或与之相关。这些疾病包括但不限于骨质疏松症、佩吉特氏(Paget’s)病、假肢周围的骨流失或骨质溶解、恶性血钙过多和转移性骨病。这些疾病中最常见的是骨质疏松症,它最常见于绝经后的妇女。因为骨质疏松症和其它的与骨流失有关的疾病都是慢性病,所以认为适当的疗法通常也需要慢性治疗。
二膦酸(盐),即二膦酸或其药学上可接受的盐,是天然焦磷酸的合成类似物。由于它们对固相磷酸钙的显著亲合力,二膦酸(盐)能牢固地结合到骨矿物质上。具有药理学活性的二膦酸(盐)是本领域熟知的,并且是有效的骨吸收的抑制剂,因此可以用于治疗和预防涉及异常骨吸收的疾病,特别是骨质疏松症、佩吉特氏病、恶性血钙过多、转移性和代谢性骨病。
作为药物的二膦酸(盐)记载在例如EP-A-170,228、EP-A-197,478、EP-A-22,751、EP-A-252,504、EP-A-252,505、EP-A-258,618、EP-A-350,002、EP-A-273,190和WO-A-90/00798等中,它们在这里都引作参考。
现在已经上市的二膦酸(盐)的药物形式是口服制剂(片剂或胶囊)或静脉注射或输液用的溶液。它们在以治疗剂量施用时有较好的全身耐受性。但是,二膦酸(盐)类物质对皮肤和粘膜有刺激性,连续口服可能会产生消化道副作用,例如食道不良反应或肠胃紊乱。结果,同时也因为它们较低的口服生物利用率,迄今为止其口服给药途径仍然必须遵循对病人不便的使用方法。
二膦酸(盐)可以分成具有不同作用模式的两类。伊班膦酸(盐)属于比较有效的含氮二膦酸(盐)[Russell 1999 Russell RGG,Rogers MJ.二膦酸类:从实验室到临床再到实验室。Bone 25(1):97-106(1999);Rogers MJ,Gordon S,Benford HL,Coxon FP,Luckman SP,Monkkonen J,Frith JC.二膦酸类作用的细胞分子机制。Cancer 88(12)Suppl:2961-2978(2000)]。伊班膦酸(盐)是目前处于临床开发中的对骨质疏松症和转移性骨疾病最有效的二膦酸(盐)之一。在骨吸收的动物模型中,伊班膦酸(盐)的效力分别比利塞膦酸(盐)、阿仑膦酸(盐)、帕米膦酸(盐)和氯屈膦酸(盐)高出2、10、50和500倍[Mühlbauer R.C.,F.Bauss,R.Schenk,M.Janner,E.Bosies,K.Strein和H.Fleisch,BM 21.0955--一种有效的新的抑制骨吸收的二膦酸类化合物。J.Bone Miner.Res.6:1003-1011(1991)]。
伊班膦酸(盐)能够在不对矿化产生任何损害的情况下抑制骨吸收(Mühlbauer R.C.,F.Bauss,R.Schenk,M.Janner,E.Bosies,K.Strein和H.Fleisch,BM 21.0955--一种有效的新的抑制骨吸收的二膦酸类化合物。J.Bone Miner.Res.6:1003-1011(1991))。已经证明它能降低破骨细胞的活性从而抑制骨破坏。它在高剂量时也会减少破骨细胞的数量(MühlbauerR.C.,F.Bauss,R.Schenk,M.Janner,E.Bosies,K.Strein和H.Fleisch,BM 21.0955--一种有效的新的抑制骨吸收的二膦酸类化合物。J.BoneMiner.Res.6:1003-1011(1991))。
如上所述,二膦酸(盐)已经被接受在控制骨质疏松症方面具有较强的功效。但是,由于与口服生物利用率低有关的施用限制和肠胃作用的隐患,显然需要能够提供改进的方便性和适应性、产生更高的顺从性和较好的病人管理/满意程度的给药方案。本领域已经公开了间歇给药方案例如每周用药一次,但是这种间歇治疗不能产生理想的效果。
发明内容
现已发现,通过每月施用50至250mg的二膦酸或其药学上可接受的盐,特别是每月施用伊班膦酸(盐),即伊班膦酸或其药学上可接受的盐,可以改善对特征在于病理性增加的骨吸收的疾病(例如骨质疏松症)的预防或治疗。
因此,本发明涉及二膦酸或其药学上可接受的盐、特别是伊班膦酸或其药学上可接受的盐在制备用于预防或治疗特征在于病理性增加的骨吸收的疾病的药物中的应用,其中所述的药物
a)含有约50至250mg、优选约100至150mg的二膦酸或其药学上可接受的盐,且
b)每月在一天或连续的两天或三天口服用药。
每月口服施用至少120%、特别是120%至200%预期剂量的治疗,在方便性和顺从性方面会更加有利于病人,并具有较好的结果。“预期剂量”(100%)是指累积的有效日剂量。在完成伊班膦酸(盐)的临床开发计划之前,当停药间隔超过每日施用时,二膦酸(盐)都没能有前景地表现出减少骨折的功效。总之,按照单次或者多次片剂给药方案,按月口服二膦酸盐能产生减少骨折的好处是非常意外的。
因此,本发明涉及二膦酸或其药学上可接受的盐、特别是伊班膦酸或其药学上可接受的盐在制备用于预防或治疗特征在于病理性增加的骨吸收的疾病(例如骨质疏松症)的药物中的应用,其中所述的药物含有至少120%预期有效日剂量的二膦酸或其药学上可接受的盐,并且每月在一天或连续的两天或三天用药。
更优选地,本发明包括伊班膦酸或其药学上可接受的盐在制备用于预防或治疗特征在于病理性增加的骨吸收的疾病的药物中的应用,其中所述的药物
a)含有约100至约150mg的伊班膦酸或其药学上可接受的盐,且
b)每月在一天或连续的两天或三天口服用药。
具体实施方式
术语“二膦酸(盐)”是指特征在于两个膦酸基团通过膦醚键结合到一个中心(孪位的)碳原子上的化合物。这种P-C-P结构如下面的式I所示。应该指出的是,这里在提到本发明的治疗剂时所用的术语“二膦酸”也旨在包括二膦酸(盐)、二膦酸以及它们的盐和衍生物。除非特别说明,在提到二膦酸盐时所用的具体命名无意限制本发明的范围。
这里使用的术语“药学上可接受的”是指从毒性角度看该盐或螯合剂是可以接受的。
这里使用的术语“药学上可接受的盐”是指铵盐、碱金属盐如钾盐和钠(包括单钠、二钠和三钠)盐(这些是优选的)、碱土金属盐如钙盐和镁盐、有机碱的盐如二环己基胺盐、N-甲基-D-葡糖胺盐和氨基酸的盐如精氨酸盐、赖氨酸盐等。
术语“特征在于病理性增加的骨吸收的疾病”是指医学上定义的原因已知或未知的疾病(如绝经后的骨质疏松症、先天性的青少年骨质疏松症、伴有克莱恩费尔特综合征的骨质疏松症、男性骨质疏松症、营养因素导致的骨质疏松症、器官移植相关的骨质疏松症、与固定术有关的骨质疏松症、炎症和皮质类固醇引起的骨质疏松症)。
术语“每月在一天或连续的两天或三天”是指在一个月当中的一天或连续的两天或三天、优选每月在一天施用1至3次与剂量成比例(doseproportional)的或与剂量不成比例(non-dose proportional)的片剂。这里使用的术语“月”是根据普遍接受的时间度量含义即约4周、约30天或日历年的约1/12来使用的。
术语“药物”是指药物组合物。该术语包括单次或多次给药方案。
该药物优选每月施用一天。优选地,该药物以单次剂量施用,但是本发明的范围包括以亚剂量多次施用药物,例如每月在连续的两天或每月在连续的三天施用。
优选地,该药物含有至少100%、优选120%至200%、最优选120至150%有效剂量的二膦酸或其药学上可接受的盐、更优选伊班膦酸或其药学上可接受的盐。
术语“有效剂量”是指约50至约250mg、更优选约100至约150mg的二膦酸或其药学上可接受的盐,例如伊班膦酸或其药学上可接受的盐。如同指出的,有效剂量可以是单次剂量或多个亚剂量。例如,如果有效剂量是150mg,则剂量可以是一次150mg的剂量、在一天或者连续的两天施用的两次75mg的亚剂量、或在一天或连续的两天或三天施用的三次50mg的亚剂量;如果有效剂量是100mg,则剂量可以包括一次100mg的剂量、在一天或者连续的两天(优选在连续的两天)施用的两次50mg的亚剂量。
用作药物的“二膦酸及其药学上可接受的盐”记载在例如美国专利4,509,612、4,666,895、4,719,203、4,777,163、5,002,937、4,971,958和4,958,839以及欧洲专利申请252,504和252,505中,它们在这里引作参考。
制备二膦酸及其药学上可接受的盐的方法可以在例如美国专利3,962,432、4,054,598、4,267,108、4,327,039、4,407,761、4,621,077、4,624,947、4,746,654、4,922,077、4,970,335、5,019,651、4,761,406、4,876,248、J.Org.Chem.32,4111(1967)和欧洲专利申请252,504中找到,它们在这里引作参考。二膦酸的药学上可接受的盐也可以用于本发明。二膦酸的碱盐实例包括铵盐、碱金属盐如钾盐和钠(包括单钠、二钠和三钠)盐(这些是优选的)、碱土金属盐如钙盐和镁盐、有机碱的盐如二环己基胺盐、N-甲基-D-葡糖胺盐和氨基酸的盐如精氨酸盐、赖氨酸盐等。优选无毒的、生理上可接受的盐。这些盐可以用本领域熟知的方法制备,例如欧洲专利申请252,504和美国专利4,922,077中所描述的,它们在这里引作参考。
优选地,该药物含有100至150mg的伊班膦酸或其药学上可接受的盐。优选地,该药物以单次剂量施用。
在本发明的一个优选实施方案中,本发明的术语“二膦酸(盐)”对应于式I化合物
其中,A和X分别独立的选自氢、羟基、卤素、氨基、SH、苯基、烷基、单-或二烷基氨基、单-或二烷基氨基烷基、烷氧基、烷硫基、苯硫基和芳基或杂芳基,所述的芳基或杂芳基选自苯基、吡啶基、呋喃基、吡咯烷基、咪唑基和苯甲基,其中所述的芳基或杂芳基任选的被烷基取代。
在前面的化学式中,A可以包括X且X包括A,从而这两个基团可以形成同一个环结构的一部分。
前面的化学式也旨在包括A和/或X取代基是碳环、芳香和杂芳结构的情况,例如萘基、喹啉基、异喹啉基、金刚烷基和氯代苯硫基。
优选的结构是,其中的A选自氢、羟基和卤素,且X选自烷基、卤素、苯硫基、烷硫基和二烷基氨基烷基。
更优选的结构是,其中的A选自氢、羟基和Cl,且X选自烷基、Cl、氯代苯硫基和二烷基氨基烷基。
优选的二膦酸或其药学上可接受的盐选自阿仑膦酸、西马膦酸、氯屈膦酸、EB-1053、替鲁膦酸、依替膦酸、伊班膦酸、英卡膦酸、米诺膦酸(minodronate)、奈立膦酸、奥帕膦酸(olpadronate)、利塞膦酸、匹瑞膦酸(piridronate)、帕米膦酸、唑仑膦酸(zolendronate)或其可接受的盐,例如伊班膦酸单钠盐一水合物。
特别优选的是伊班膦酸(1-羟基-3-(N-甲基-N-戊基)氨基亚丙基-1,1-二膦酸)或其生理上可接受的盐,例如伊班膦酸单钠盐一水合物。
二膦酸盐和其药学上可接受的盐可以单独施用,或者与其它骨活性药物组合施用,它们可以是固定的组合,也可以在物理和时间上分离,所述的其它骨活性药物包括激素,例如甾类激素如雌激素;部分雌激素激动剂或雌激素-孕激素组合;降钙素、其类似物或其衍生物,例如鲑鱼、鳗鲡或人降钙素;甲状旁腺素或其类似物,如PTH(1-84)、PTH(1-34)、PTH(1-36)、PTH(1-38)、PTH(1-31)NH2或PPTS 893;SERM(选择性雌激素受体调节剂),例如雷洛昔芬、拉索昔芬(lasofoxifene)、TSE-434、FC1271、替勃龙、维生素D或其类似物。这些其它的骨活性药物可以比二膦酸(盐)更频繁地施用。
合适的药物组合物是本领域熟知的,并且已经记载在美国专利6,143,326和6,294,196中,在这里引作参考。
为了制备片剂、包衣片剂、糖衣丸或硬明胶胶囊,可将本发明的化合物与药学上惰性的无机或有机赋形剂一起混合。适合用于片剂、包衣片剂、糖衣丸或硬明胶胶囊的赋形剂实例包括乳糖、玉米淀粉或其衍生物、滑石粉或硬脂酸或其盐。
药物组合物还可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、香味剂、调节渗透压的盐、缓冲剂、包衣剂或抗氧剂。它们也可以含有其它有治疗价值的药物。优选地,药物组合物是膜包衣片剂,其中片芯含有50至200mg上面定义的二膦酸或其药学上可接受的盐以及一种或多种下述的药学上可接受的赋形剂:乳糖、聚乙烯吡咯烷酮、微晶纤维素、交联聚维酮、硬脂酸、二氧化硅,且其片衣含有一种或多种下述的药学上可接受的赋形剂:羟基丙基甲基纤维素、二氧化钛、滑石粉、聚乙二醇6000。这些成分是本领域熟知的,并且已经记载在美国专利6,143,326和6,294,196中。
本发明的另一方面是一种治疗、减轻或预防特征在于病理性增加的骨吸收的疾病的方法,包括给哺乳动物施用有效量的二膦酸或其药学上可接受的盐。本发明尤其涉及一种治疗、减轻或预防特征在于病理性增加的骨吸收的疾病的方法,包括口服有效量的二膦酸或其药学上可接受的盐,其中每月在一天或连续的两天或三天施用约50至250mg二膦酸或其药学上可接受的盐。如以上所指出的,有效量的二膦酸或其药学上可接受的盐可以以单个剂量或多个亚剂量施用。
优选地,该方法包括每月在一天或连续的两天或三天施用约50至250mg、优选约100至150mg二膦酸或其药学上可接受的盐。虽然该方法包括通过多次亚剂量给药来完成剂量,但优选的方法是单次给药。通过多次亚剂量给药的实例如下,如果有效剂量是150mg,则剂量可以是在一天或者连续的两天施用的两次75mg的亚剂量、或在一天或连续的两天或三天施用的三次50mg的亚剂量;如果有效剂量是100mg,则剂量可以是在一天或者连续的两天(优选在连续的两天)施用的两次50mg的亚剂量。优选的二膦酸(盐)是伊班膦酸或其药学上可接受的盐,例如伊班膦酸单钠盐一水合物。
优选地,在本发明的方法中,二膦酸选自阿仑膦酸、西马膦酸、氯屈膦酸、EB-1053、替鲁膦酸、依替膦酸、伊班膦酸、英卡膦酸、米诺膦酸、奈立膦酸、奥帕膦酸、利塞膦酸、匹瑞膦酸、帕米膦酸、唑仑膦酸或其药学上可接受的盐。更优选地,二膦酸是伊班膦酸或其药学上可接受的盐,例如伊班膦酸单钠盐一水合物。
下面的实施例将对本发明作进一步的解释。
实施例
实施例1药物组合物
本实施例公开了50mg片剂的组成。这些片剂的组成和制备都是本领域熟知的,并记载在例如美国专利6,143,326和6,294,196中。
通过根据二膦酸(盐)(例如伊班膦酸单钠盐一水合物)的量调整成分可以制备其它的组合物。
50mg膜包衣片剂 | |
组分 | mg/片 |
片芯: | |
伊班膦酸,单钠盐,一水合物 | 56.250 |
一水合乳糖 | 92.750 |
聚维酮K 25 | 5.000 |
微晶纤维素 | 30.000 |
交联聚维酮 | 10.000 |
纯化的硬脂酸 | 4.000 |
胶态二氧化硅 | 2.000 |
片衣: | |
羟基丙基甲基纤维素 | 5.1425 |
二氧化钛 | 2.4650 |
滑石粉 | 0.8925 |
聚乙二醇6,000 | 1.5000 |
总重: | 210.000 |
Claims (14)
1.二膦酸或其药学上可接受的盐在制备用于预防或治疗特征在于病理性增加的骨吸收的疾病的药物中的应用,其中所述的药物
a)含有至少120%预期有效日剂量的二膦酸或其药学上可接受的盐,及一种或多种药学上可接受的赋形剂;且
b)每月在一天或连续的两天或三天口服用药。
2.如权利要求1的应用,其中所述的疾病是骨质疏松症。
3.如权利要求1或2的应用,其中所述的有效剂量是约100mg至约150mg的二膦酸或其药学上可接受的盐。
4.如权利要求1至3中任意一项的应用,其中所述的二膦酸是伊班膦酸或其药学上可接受的盐。
5.如权利要求1至4中任意一项的应用,其中所述的有效剂量是约100mg的二膦酸或其药学上可接受的盐。
6.如权利要求1至4中任意一项的应用,其中所述的有效剂量是约150mg的二膦酸或其药学上可接受的盐。
7.如权利要求1至6中任意一项的应用,其中所述的二膦酸或其药学上可接受的盐是伊班膦酸单钠盐一水合物。
8.如权利要求1至7中任意一项的应用,其中所述的药物是膜包衣片剂,其片芯含有50至250mg权利要求1至7中定义的二膦酸或其药学上可接受的盐以及一种或多种下述的药学上可接受的赋形剂:乳糖、聚乙烯吡咯烷酮、微晶纤维素、交联聚维酮、硬脂酸、二氧化硅,且其片衣含有一种或多种下述的药学上可接受的赋形剂:羟基丙基甲基纤维素、二氧化钛、滑石粉、聚乙二醇6000。
9.如权利要求1至8中任意一项的应用,其中所述的药物是以单次剂量施用。
10.如权利要求1至8中任意一项的应用,其中所述的药物是以多次亚剂量施用。
11.一种预防或治疗特征在于病理性增加的骨吸收的疾病的方法,包括口服有效量的二膦酸或其药学上可接受的盐,其中每月在一天或连续的两天施用50至250mg二膦酸或其药学上可接受的盐。
12.如权利要求11的方法,其中所述的二膦酸是伊班膦酸或其药学上可接受的盐。
13.如权利要求11或12的方法,其中所述的二膦酸或其药学上可接受的盐按照权利要求1至10中任意一项的定义施用。
14.如上所述的本发明。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107011380A (zh) * | 2016-01-28 | 2017-08-04 | 臧伟 | 一种二膦酸衍生物及含二膦酸衍生物的组合物治疗骨折的应用 |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8119159B2 (en) * | 1999-02-22 | 2012-02-21 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
US7658938B2 (en) | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
US20070148228A1 (en) * | 1999-02-22 | 2007-06-28 | Merrion Research I Limited | Solid oral dosage form containing an enhancer |
US20050070504A1 (en) * | 2001-12-21 | 2005-03-31 | The Procter & Gamble Co. | Risedronate compositions and their methods of use |
AU2002360619B2 (en) * | 2001-12-21 | 2006-10-05 | Allergan Pharmaceuticals International Limited | Method for the treatment of bone disorders |
EP1494683A1 (en) * | 2002-04-05 | 2005-01-12 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
RU2329809C2 (ru) * | 2002-05-10 | 2008-07-27 | Ф.Хоффманн-Ля Рош Аг | Применения бисфосфоновых кислот для лечения и профилактики остеопороза |
MXPA04010866A (es) | 2002-12-20 | 2005-01-25 | Hoffmann La Roche | Formulacion de ibandronato de dosis elevada. |
US20050261250A1 (en) * | 2004-05-19 | 2005-11-24 | Merck & Co., Inc., | Compositions and methods for inhibiting bone resorption |
KR20070043043A (ko) * | 2004-08-23 | 2007-04-24 | 테바 파마슈티컬 인더스트리즈 리미티드 | 고체 및 결정 이반드로네이트 나트륨 및 이들의 제조 방법 |
JP5828608B2 (ja) * | 2005-02-01 | 2015-12-09 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | イバンドロネート多形a |
EP1848727B1 (en) * | 2005-02-01 | 2015-06-17 | F.Hoffmann-La Roche Ag | Ibandronate polymorph b |
US20070049557A1 (en) * | 2005-08-24 | 2007-03-01 | Hashim Ahmed | Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers |
CN105232482A (zh) * | 2006-04-07 | 2016-01-13 | 默里昂研究Iii有限公司 | 包含增强剂的固体口服剂型 |
CA2649636A1 (en) | 2006-04-20 | 2007-11-01 | F. Hoffmann-La Roche Ag | Diazepan derivatives modulators of chemokine receptors |
JP5290198B2 (ja) * | 2006-12-20 | 2013-09-18 | ミラン ファーマシューティカルズ ユーエルシー | ホットメルト顆粒化潤滑剤を含んでなる医薬組成物 |
AU2009244797B2 (en) * | 2008-05-07 | 2015-01-22 | Merrion Research Iii Limited | Compositions of peptides and processes of preparation thereof |
EP2210596A1 (en) | 2009-01-22 | 2010-07-28 | Laboratorios Liconsa, S.A. | Pharmaceutical composition of ibandronate sodium salt or a hydrate thereof |
EP2400851A4 (en) * | 2009-02-25 | 2012-09-05 | Merrion Res Iii Ltd | COMPOSITION AND ACTIVE COMPOSITION OF BISPHOSPHONATES |
CN102573809B (zh) | 2009-07-31 | 2017-07-21 | 格兰泰股份有限公司 | 结晶方法和生物利用度 |
US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US20160016982A1 (en) | 2009-07-31 | 2016-01-21 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US20110182985A1 (en) * | 2010-01-28 | 2011-07-28 | Coughlan David C | Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof |
US9089484B2 (en) * | 2010-03-26 | 2015-07-28 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor Xa inhibitors for oral administration |
WO2012071517A2 (en) | 2010-11-24 | 2012-05-31 | Thar Pharmaceuticals, Inc. | Novel crystalline forms |
JP2014501784A (ja) | 2011-01-07 | 2014-01-23 | メリオン・リサーチ・Iii・リミテッド | 経口投与用の鉄の医薬組成物 |
JP5874545B2 (ja) * | 2011-06-20 | 2016-03-02 | アステラス製薬株式会社 | 経口投与用医薬組成物 |
WO2016120378A1 (en) | 2015-01-29 | 2016-08-04 | Novo Nordisk A/S | Tablets comprising glp-1 agonist and enteric coating |
US10195218B2 (en) | 2016-05-31 | 2019-02-05 | Grunenthal Gmbh | Crystallization method and bioavailability |
Family Cites Families (130)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US500937A (en) * | 1893-07-04 | Conduit railway insulator | ||
US124314A (en) * | 1872-03-05 | Improvement in preparing paper for buildings | ||
DE2405254C2 (de) | 1974-02-04 | 1982-05-27 | Henkel KGaA, 4000 Düsseldorf | Verwendung von 3-Amino-1-Hydroxypropan-1, 1-diphosphonsäure oder ihrer wasserlöslichen Salze bei der Beeinflußung von Calciumstoffwechselstörungen im menschlichen oder tierischen Körper |
DE2534391C2 (de) | 1975-08-01 | 1983-01-13 | Henkel KGaA, 4000 Düsseldorf | 1-Hydroxy-3-aminoalkan-1,1-diphosphonsäuren |
DE2745083C2 (de) | 1977-10-07 | 1985-05-02 | Henkel KGaA, 4000 Düsseldorf | Hydroxydiphosphonsäuren und Verfahren zu deren Herstellung |
US4252742A (en) | 1979-07-13 | 1981-02-24 | Ciba-Geigy Corporation | Chemical process for the preparation of 2,6-dialkylcyclohexylamines from 2,6-dialkylphenols |
DE2943498C2 (de) | 1979-10-27 | 1983-01-27 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur Herstellung von 3-Amino-1-hydroxypropan-1,1-diphosphonsäure |
DE3016289A1 (de) | 1980-04-28 | 1981-10-29 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur herstellung von omega -amino-1-hydroxyalkyliden-1,1-bis-phosphonsaeuren |
IT1201087B (it) | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | Bifosfonati farmacologicamente attivi,procedimento per la loro preparazione e relative composizioni farmaceutiche |
FR2531088B1 (fr) | 1982-07-29 | 1987-08-28 | Sanofi Sa | Produits anti-inflammatoires derives de l'acide methylenediphosphonique et leur procede de preparation |
US4509612A (en) | 1982-09-28 | 1985-04-09 | Applied Power Inc. | Latch mechanism for a tilt-cab truck |
JPS59145179A (ja) | 1983-01-11 | 1984-08-20 | Ricoh Co Ltd | 補充交換用部品を検知可能にした事務機器 |
IT1195993B (it) | 1984-01-12 | 1988-11-03 | Gentili Ist Spa | Forme farmaceutiche a base di difosfonati |
DE3428524A1 (de) | 1984-08-02 | 1986-02-13 | Boehringer Mannheim Gmbh, 6800 Mannheim | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
DE3434667A1 (de) | 1984-09-21 | 1986-04-03 | Henkel KGaA, 4000 Düsseldorf | 4-dimethylamino-1-hydroxybutan-1,1-diphosphonsaeure, deren wasserloesliche salze, verfahren zu ihrer herstellung sowie ihre verwendung |
IT1196315B (it) | 1984-10-29 | 1988-11-16 | Gentili Ist Spa | Procedimento per la preparazione di acidi difosfonici |
US4812311A (en) | 1984-12-21 | 1989-03-14 | The Procter & Gamble Company | Kit for use in the treatment of osteoporosis |
DE3512536A1 (de) | 1985-04-06 | 1986-10-16 | Boehringer Mannheim Gmbh, 6800 Mannheim | Neue diphosphonsaeure-derivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US4761406A (en) | 1985-06-06 | 1988-08-02 | The Procter & Gamble Company | Regimen for treating osteoporosis |
DE3540150A1 (de) | 1985-11-13 | 1987-05-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
DE3623397A1 (de) | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
DE3626058A1 (de) | 1986-08-01 | 1988-02-11 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
DE3640938A1 (de) | 1986-11-29 | 1988-06-01 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindung enthaltende arzneimittel |
US4973576A (en) | 1987-03-10 | 1990-11-27 | Yamanouchi Pharmaceutical Co., Ltd. | Bisphophonic acid derivatives and pharmaceutical compositions containing the same |
CA1339805C (en) | 1988-01-20 | 1998-04-07 | Yasuo Isomura | (cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active |
DE3822650A1 (de) | 1988-07-05 | 1990-02-01 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US4958839A (en) | 1988-07-12 | 1990-09-25 | Guzik Technical Enterprises, Inc. | Disc clamp employing resilient cone for spreading balls |
DE3825654A1 (de) * | 1988-07-28 | 1990-02-01 | Bosch Gmbh Robert | Sicherheitseinrichtung an einer handwerkzeugmaschine |
JP2691914B2 (ja) | 1988-09-09 | 1997-12-17 | 株式会社リコー | 画像形成装置 |
US5018651A (en) | 1988-12-27 | 1991-05-28 | Hull Harold L | Side or end dump article carrier |
US4922077A (en) | 1989-01-31 | 1990-05-01 | Raytheon Company | Method of laser marking metal packages |
DE3917153A1 (de) * | 1989-05-26 | 1990-11-29 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US4922007A (en) | 1989-06-09 | 1990-05-01 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
JP2985205B2 (ja) | 1990-01-25 | 1999-11-29 | ミノルタ株式会社 | 画像形成装置 |
US5335048A (en) | 1990-01-30 | 1994-08-02 | Minolta Camera Kabushiki Kaisha | Efficient control system of image forming apparatus |
JPH03226767A (ja) | 1990-01-31 | 1991-10-07 | Minolta Camera Co Ltd | 画像形成装置管理システム |
US5356887A (en) | 1990-01-31 | 1994-10-18 | Merck & Co., Inc. | Pharmaceutical compositions containing insoluble calcium salts of amino-hydroxybutylidene bisphoshonic acids |
US5019651A (en) | 1990-06-20 | 1991-05-28 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof |
JPH04151765A (ja) | 1990-10-16 | 1992-05-25 | Fujitsu Ltd | ファクシミリ装置の消耗品自動発注方式 |
KR100274734B1 (ko) * | 1991-11-22 | 2000-12-15 | 제이코버스 코넬리스 레이서 | 리제드로네이트 지연-방출성 조성물 |
WO1993011786A1 (en) | 1991-12-17 | 1993-06-24 | Procter & Gamble Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
JPH05224479A (ja) | 1992-02-10 | 1993-09-03 | Toshiba Corp | 画像形成装置 |
TW237386B (zh) | 1992-04-15 | 1995-01-01 | Ciba Geigy | |
DE69316013T2 (de) | 1992-06-30 | 1998-07-09 | Procter & Gamble Pharma | Verwendung von phosphinate zur behandlung der osteoporose |
JPH06111039A (ja) | 1992-09-25 | 1994-04-22 | Toray Ind Inc | 光学読み取り識別マークの記録方法 |
US5358941A (en) * | 1992-12-02 | 1994-10-25 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids with lactose |
JPH06250802A (ja) | 1993-02-22 | 1994-09-09 | Ricoh Co Ltd | プリンタ |
FR2703590B1 (fr) | 1993-04-05 | 1995-06-30 | Sanofi Elf | Utilisation de derives d'acide bisphosphonique pour la preparation de medicaments destines a favoriser la reparation osseuse . |
US5510517A (en) * | 1993-08-25 | 1996-04-23 | Merck & Co., Inc. | Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids |
US5431920A (en) * | 1993-09-21 | 1995-07-11 | Merck Frosst, Canada, Inc. | Enteric coated oral compositions containing bisphosphonic acid antihypercalcemic agents |
JPH07239825A (ja) | 1994-02-28 | 1995-09-12 | Canon Inc | 状態通報方法およびそれを用いたネットワークシステム |
TW390813B (en) | 1994-04-29 | 2000-05-21 | Merck & Co Inc | Wet granulation formulation for bisphosphonic acids |
US20010007863A1 (en) | 1998-06-18 | 2001-07-12 | Merck & Co., Inc. | Wet granulation formulation for bisphosphonic acids |
GB9408775D0 (en) | 1994-05-04 | 1994-06-22 | Ciba Geigy Ag | Use of certain methanebisphosphonic acid derivatives to prevent prothesis loosening and prothesis migration |
US5462932A (en) | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
JPH07325514A (ja) | 1994-05-30 | 1995-12-12 | Ricoh Co Ltd | サプライ発注システム |
JPH08152814A (ja) | 1994-11-30 | 1996-06-11 | Mita Ind Co Ltd | 画像形成装置の管理システム |
JPH08152825A (ja) | 1994-11-30 | 1996-06-11 | Mita Ind Co Ltd | 画像形成装置の管理システム |
FR2727629A1 (fr) | 1994-12-06 | 1996-06-07 | Sanofi Sa | Trousse pour cycle de traitement de l'osteoporose |
JP3261900B2 (ja) | 1994-12-13 | 2002-03-04 | 村田機械株式会社 | ファクシミリ装置 |
CA2208714C (en) | 1994-12-28 | 2003-10-21 | Gador S.A. | Bone mass anabolic composition comprising olpadronate |
JPH08211792A (ja) | 1995-02-03 | 1996-08-20 | Mita Ind Co Ltd | 画像形成装置の管理システム |
EP0809502A4 (en) * | 1995-02-17 | 2001-12-05 | Merck & Co Inc | PROCESS FOR REDUCING THE RISK OF BONE FRACTURES OTHER THAN VERTEBRAL FRACTURES |
US20010051616A1 (en) | 1995-02-17 | 2001-12-13 | David B. Karpf | Method of lessening the risk of vertebral fractures |
JPH08315052A (ja) | 1995-05-18 | 1996-11-29 | Ricoh Co Ltd | 自動発注システム |
JPH08310007A (ja) | 1995-05-19 | 1996-11-26 | Oki Data:Kk | シリアルプリンタ |
JPH09120238A (ja) | 1995-10-25 | 1997-05-06 | Canon Inc | 出力装置 |
JPH09156123A (ja) | 1995-12-04 | 1997-06-17 | Brother Ind Ltd | プリンタ |
JPH09185474A (ja) | 1995-12-27 | 1997-07-15 | Fuji Xerox Co Ltd | 印刷管理装置 |
JP3363680B2 (ja) | 1995-12-28 | 2003-01-08 | ブラザー工業株式会社 | カートリッジの真偽判別方法及びそれを利用した出力装置 |
JPH09259355A (ja) | 1996-03-21 | 1997-10-03 | Oki Electric Ind Co Ltd | 梱包された商品の確認処理システム |
DE19615812A1 (de) | 1996-04-20 | 1997-10-23 | Boehringer Mannheim Gmbh | Pharmazeutische Zubereitung enthaltend Diphosphonsäuren zur oralen Applikation |
US5930553A (en) | 1997-04-25 | 1999-07-27 | Hewlett-Packard Company | Image forming and office automation device consumable with memory |
US5730715A (en) | 1996-06-14 | 1998-03-24 | Becton Dickinson And Company | Method for the iontophoretic administration of bisphosphonates |
US5781405A (en) * | 1996-09-30 | 1998-07-14 | Gateway 2000, Inc. | Electronic device having rotatably mounted infrared device with a pair of pegs fitting into a pair of holes |
US6905701B2 (en) | 1997-06-11 | 2005-06-14 | Umd, Inc. | Formulations for transmucosal vaginal delivery of bisphosphonates |
US6572874B1 (en) | 1998-05-15 | 2003-06-03 | Umd, Inc. | Vaginal delivery of bisphosphonates |
US5994329A (en) * | 1997-07-22 | 1999-11-30 | Merck & Co., Inc. | Method for inhibiting bone resorption |
EP0998292B1 (en) | 1997-07-22 | 2001-11-21 | Merck & Co., Inc. (a New Jersey corp.) | Method for inhibiting bone resorption |
US6015801A (en) | 1997-07-22 | 2000-01-18 | Merck & Co., Inc. | Method for inhibiting bone resorption |
US6432932B1 (en) | 1997-07-22 | 2002-08-13 | Merck & Co., Inc. | Method for inhibiting bone resorption |
US6124314A (en) | 1997-10-10 | 2000-09-26 | Pfizer Inc. | Osteoporosis compounds |
SE9703691D0 (sv) | 1997-10-10 | 1997-10-10 | Astra Ab | Pharmaceutical compositions |
JP3065053B2 (ja) | 1998-01-06 | 2000-07-12 | セイコーエプソン株式会社 | 機器監視システム、ローカル監視装置、統合監視装置、機器監視方法、及び、プログラムを格納したコンピュータ可読媒体 |
CA2336201A1 (en) | 1998-06-24 | 1999-12-29 | Merck & Co., Inc. | Compositions and methods for inhibiting bone resorption |
US6816968B1 (en) | 1998-07-10 | 2004-11-09 | Silverbrook Research Pty Ltd | Consumable authentication protocol and system |
IT1303672B1 (it) | 1998-07-28 | 2001-02-23 | Nicox Sa | Sali nitrati di farmaci attivi nei disordini ossei |
US6494562B1 (en) | 1998-09-03 | 2002-12-17 | Hewlett-Packard Company | Method and apparatus for identifying a sales channel |
FR2784031B1 (fr) * | 1998-10-02 | 2002-02-01 | Sanofi Elf | Utilisation de derives de l'acide bisphosphonique pour la preparation d'un medicament destine au traitement des boiteries |
EP0998933A1 (de) | 1998-10-09 | 2000-05-10 | Boehringer Mannheim Gmbh | Verfahren zur Herstellung von bisphosphonathaltigen pharmazeutischen Zusammensetzungen zur oralen Applikation |
EP0998932A1 (de) * | 1998-10-09 | 2000-05-10 | Boehringer Mannheim Gmbh | Feste pharmazeutische Darreichungsform enthaltend Diphosphonsäure oder deren Salze und Verfahren zu ihrer Herstellung |
US6331533B1 (en) | 1998-11-16 | 2001-12-18 | Merck & Co., Inc. | Method for inhibiting dental resorptive lesions |
KR100453779B1 (ko) | 1998-12-04 | 2004-10-20 | 로쉐 디아그노스틱스 게엠베하 | 내인공삽입물의 골형성을 개선시키기 위한 이밴드론산염의용도 |
US6229655B1 (en) * | 1998-12-22 | 2001-05-08 | Minolta Co., Ltd. | Zoom lens system |
WO2000042665A1 (de) * | 1999-01-11 | 2000-07-20 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Mos-leistungsbauelement und verfahren zum herstellen desselben |
SE9901272D0 (sv) | 1999-04-09 | 1999-04-09 | Astra Ab | New improved formulation |
CA2368648A1 (en) | 1999-04-09 | 2000-10-19 | Karo Bio Ab | Estrogen receptors and bone |
CA2308532C (en) | 1999-05-12 | 2005-11-29 | Gador S.A. | Use of bisphosphonates for the treatment of osteogenesis imperfecta |
CN1202828C (zh) | 1999-05-21 | 2005-05-25 | 诺瓦提斯公司 | 二膦酸在制备抑制或逆转血管发生的药物中的用途 |
US6965411B1 (en) | 1999-06-24 | 2005-11-15 | Jones Richard A | Remote camera positioner |
AR024462A1 (es) | 1999-07-01 | 2002-10-02 | Merck & Co Inc | Tabletas farmaceuticas |
US6903836B2 (en) | 1999-09-10 | 2005-06-07 | Hewlett-Packard Development Company, L.P. | Hard copy cost recovery systems, an apparatus for tracking usage information for a hard copy device, hard copy devices, and a usage accounting method |
US6793934B1 (en) * | 1999-12-08 | 2004-09-21 | Shire Laboratories, Inc. | Solid oral dosage form |
US6285060B1 (en) * | 1999-12-30 | 2001-09-04 | Siliconix Incorporated | Barrier accumulation-mode MOSFET |
JP2001253827A (ja) | 2000-02-15 | 2001-09-18 | Pfizer Prod Inc | 骨粗鬆症を治療するための組成物および方法 |
US20020004218A1 (en) * | 2000-03-31 | 2002-01-10 | Rodan Gideon A. | Methods for identifying compounds useful for inhibiting geranylgeranyl diphosphate synthase |
US7271187B2 (en) | 2000-04-06 | 2007-09-18 | Tim Neuberger | Compositions and methods for promoting tissue regeneration |
US6468559B1 (en) * | 2000-04-28 | 2002-10-22 | Lipocine, Inc. | Enteric coated formulation of bishosphonic acid compounds and associated therapeutic methods |
GB0012209D0 (en) | 2000-05-19 | 2000-07-12 | Novartis Ag | Organic compounds |
AU7410901A (en) | 2000-06-20 | 2002-01-02 | Novartis Ag | Method of administering bisphosphonates |
US6476006B2 (en) | 2000-06-23 | 2002-11-05 | Teva Pharmaceutical Industries, Ltd. | Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates |
AU2001271055B2 (en) | 2000-07-17 | 2005-07-07 | Astellas Pharma Inc. | Pharmaceutical composition improved in peroral absorbability |
US6638920B2 (en) * | 2000-07-21 | 2003-10-28 | Merck & Co., Inc. | Compositions and methods of preventing or reducing the risk or incidence of skeletal injuries in horses |
US6750213B2 (en) | 2000-10-19 | 2004-06-15 | Merck & Co., Inc. | Estrogen receptor modulators |
WO2002058708A1 (en) | 2001-01-23 | 2002-08-01 | Gador S.A. | Composition comprising bisphosphonates for prevention and/or treatment of metabolic diseases of bones, process for preparing such composition and use thereof |
AR034199A1 (es) | 2001-02-01 | 2004-02-04 | Riderway Corp | Composicion farmacologica liquida para el tratamiento de enfermedades oseas y procedimientos para su elaboracion |
BR0116862A (pt) | 2001-02-06 | 2004-01-13 | Royal Alexandra Hosp Children | Medicamento, métodos para tratar um paciente com osteonecrose e/ou osteocondrite dissecans, para prevenir a osteonecrose e/ou osteocondrite dissecans em um paciente em risco de cada uma das ditas doenças, uso de um medicamento, e, método para prevenir a destruição da cartilagem ou condrólise associadas com osteonecrose e/ou osteocondrite dissecans |
CA2438848C (en) | 2001-03-01 | 2011-05-03 | Emisphere Technologies, Inc. | Compositions for delivering bisphosphonates |
AU2002305359B2 (en) | 2001-05-10 | 2005-05-26 | Merck & Co., Inc. | Estrogen receptor modulators |
US6998678B2 (en) * | 2001-05-17 | 2006-02-14 | Infineon Technologies Ag | Semiconductor arrangement with a MOS-transistor and a parallel Schottky-diode |
JP2005516928A (ja) | 2001-12-13 | 2005-06-09 | メルク エンド カムパニー インコーポレーテッド | 骨異常のためのビスホスホネート液体製剤 |
US20050070504A1 (en) | 2001-12-21 | 2005-03-31 | The Procter & Gamble Co. | Risedronate compositions and their methods of use |
AU2002360619B2 (en) * | 2001-12-21 | 2006-10-05 | Allergan Pharmaceuticals International Limited | Method for the treatment of bone disorders |
DE10262418B3 (de) * | 2002-02-21 | 2015-10-08 | Infineon Technologies Ag | MOS-Transistoreinrichtung |
US7488496B2 (en) * | 2002-03-06 | 2009-02-10 | Christer Rosen | Effervescent compositions comprising bisphosphonates and methods related thereto |
PL372920A1 (en) * | 2002-03-13 | 2005-08-08 | Merck & Co,Inc. | Fluorinated 4-azasteroid derivatives as androgen receptor modulators |
EP1494683A1 (en) | 2002-04-05 | 2005-01-12 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
RU2329809C2 (ru) | 2002-05-10 | 2008-07-27 | Ф.Хоффманн-Ля Рош Аг | Применения бисфосфоновых кислот для лечения и профилактики остеопороза |
MXPA04010866A (es) * | 2002-12-20 | 2005-01-25 | Hoffmann La Roche | Formulacion de ibandronato de dosis elevada. |
GB0424543D0 (en) * | 2004-11-05 | 2004-12-08 | Varintelligent Bvi Ltd | Driving method for high frame rate display system |
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Cited By (1)
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CN107011380A (zh) * | 2016-01-28 | 2017-08-04 | 臧伟 | 一种二膦酸衍生物及含二膦酸衍生物的组合物治疗骨折的应用 |
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