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CN1079672C - 口服阿来屈酯液体制剂 - Google Patents

口服阿来屈酯液体制剂 Download PDF

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CN1079672C
CN1079672C CN95193086A CN95193086A CN1079672C CN 1079672 C CN1079672 C CN 1079672C CN 95193086 A CN95193086 A CN 95193086A CN 95193086 A CN95193086 A CN 95193086A CN 1079672 C CN1079672 C CN 1079672C
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alendronate
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sodium citrate
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CN1148341A (zh
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G·S·布伦纳
A·V·凯德尔
D·普雷泽
D·T·怀特福德
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Abstract

通过服用容易吞服的阿来屈酯液体制剂来治疗的预防难于吞咽的病人的骨损失症。还叙述了糖浆、水溶液、由用前冲调粉末得到的水溶液等阿来屈酯的药物剂型，用它们来进行治疗。

Description

口服阿来屈酯液体制剂
发明领域
本发明一般涉及阿来屈酯的口服液体制剂，即4-氨基-1-羟基亚丁基-1，1-二膦酸一钠三水合物，用它来抑制吞咽困难病人的骨吸收。
发明背景
正常的骨骼是永恒地进行钙吸收及钙再沉积的活组织，其净效果保持着恒定的矿物质平衡。这种双向过程一般称之为“骨的滚动”。对于正常生长的骨骼，矿物质的沉积处于与矿物质吸收的平衡之中，而在某些病理条件下，骨吸收超过了骨沉积，比如由于恶性肿瘤或原发性甲状旁腺机能亢进或者骨质疏松症。在另一些病理条件下，可能出现不希望数量的钙沉积，因此会导致如异位钙化、骨关节炎、肾或膀胱结石、动脉粥样硬化和变形性骨炎，这是一种异常高的骨吸收及随后的异常钙沉积共同作用的结果。
阿来屈酯，4-氨基-1-羟基亚丁基-1，1-二膦酸一钠三水合物，是一种治疗骨病，包括骨质疏松症克服骨吸收的药剂，在属于默克(Merck)的美国专利4,922,007和5,019,651中叙述了它作为组合物、用法以及合成方法，同时叙述了其它药物可接受的盐。
有一些情况，比如老年妇女正在服用阿来屈酯治疗骨质疏松症(即骨稀疏)，或者认为有演变为骨质疏松的危险，而且同时经历着吞咽困难。
然而，阿来屈酯目前已以片剂的形式给所有的病人口服。而对于不能很容易吞咽药片的一些病人，唯一可获得的是固体口服剂形是个缺点。再有，这些病人可能在阿来屈酯病人群体中占有很大百分比，因为这种药也打算用给老年病人群体。
在这些场合下，所希望的是用一种改善的口服制剂来有效地治疗使这些老年妇女得到最好的治疗，克服吞咽困难的问题。
发明概述
本发明提出一种方法，通过给吞咽困难的病人施用药物有效量的阿来屈酯口服液体制剂，来治疗和/或预防所述病人骨损失。此液体制剂可以呈糖浆状、水溶液状或水可溶化的阿来屈酯粉末状，它含有缓冲剂来调节溶液的pH值，含有络合剂防止形成不溶的阿来屈酯络合物。
本发明的液体口服药物组合物在一种液体药学上可接受的载体比如纯水中含有有药效数量的阿来屈酯；还含有缓冲剂如柠檬酸盐，以保持pH值在2-8，优选在4-6；还含有络合剂如柠檬酸盐或EDTA，以抑制阿来屈酯在水相介质中沉淀。也提供一种含有高浓度蔗糖的上述水溶液，成为一种糖浆，为了市场需要也可以加入矫味剂。
也可提供一种含有粉末供用时溶化的药物组合物，它在药学上可接受的干赋形剂中含有有药效数量的阿来屈酯，同时也有缓冲剂如柠檬酸盐和络合剂存在，所述粉末可溶于水。
本发明的详细说明和优选实施例
呈糖浆、水溶液或用时冲配的粉末水溶液状的阿来屈酯口服溶液有易于服用的优点，对于那些难以吞咽固体口服剂型的病人增加了配合性。用时冲配的粉末还有另一个优点，就是最大限度地减小了占用护士室、药房、医院及库房的空间。这些制剂具有可进行剂量滴定的好处，这将是人们所希望的。
这种方法可以用有骨生成效果量的阿来屈酯来治疗人，特别是绝经后的妇女，需要用这种治疗来抑制骨吸收。在骨折、骨不连合、缺损等情况下，这种需要就局部增加。在系统性骨疾病，如在骨质疏松症、骨关节炎、变形性骨炎、骨软化、骨髓瘤和其它类型的癌、类固醇疗法和与年龄有关的骨本质损失时，这种需要都增大。
在本文中使用的“抑制骨吸收”一词表示治疗和预防骨损失，特别是抑制由于直接或间接的破骨细胞形成或者活性的改变，而使现有的骨骼无论从无机相和/或从有机基质相向外迁移。因此，本文使用的“骨吸收抑制剂”指的是通过直接或间接改变破骨细胞的形成能力或者说活性来防止骨损失的药物，它可以增加病人治疗群体的骨质量。
本文中使用的“成骨效果”指的是能影响成熟骨骼“滚动”的数量，正如在本文中所用的，有成骨效果的剂量也称为“有药效的”。
本文中使用的“治疗”一词，表示(1)给病人提供一定量的阿来屈酯，足能有预防作用地防止虚弱和/或不健康状态发展；和/或(2)给病人提供足够量的阿来屈酯，使得减轻或消除了疾病状态和/或病态的征兆，以及虚弱和/或不健康的状态。
包括了供施用阿来屈酯的本发明药物制剂一般将包括有成骨效果量的阿来屈酯，以促进骨骼生长，此外还有药物可接受的赋形剂。最好用干燥的惰性载体，比如粉末状的糖，包括蔗糖和乳糖、淀粉及其衍生物、纤维素及其衍生物、树胶、脂肪酸及其盐一起制备成组合物。
对于液态制剂，适合的液体赋形剂/载体是纯水和盐溶液。
其它适用的赋形剂和其它的辅助添加剂如下：
溶剂
乙醇
甘油
丙二醇
稳定剂
EDTA(乙二胺四乙酸)
防腐剂
苯甲酸钠
山梨酸
对羟基苯甲酸甲酯
对羟基苯甲酸丙酯
缓冲剂
柠檬酸/柠檬酸钠
酒石酸氢钾
酒石酸氢钠
邻苯二甲酸氢钾
邻苯二甲酸氢钠
磷酸二氢钾
磷酸氢二钠
矫味剂
糖精
乳糖
蔗糖
果糖
山梨糖醇
天冬酰苯丙氨酸甲酯
粘度剂
纤维素衍生物，包括：
羟甲基纤维素
羟丙基纤维素
着色剂
FD&C兰2
FD&C红33
此外，为了将该水液pH值维持在2-8范围，优选在4-6，存在缓冲剂是必须的。
缓冲系统一般是弱酸及其可溶盐的混合物，比如柠檬酸钠/柠檬酸；或者是二价酸的单阳离子或双阳离子盐，比如酒石酸氢钾、酒石酸氢钠、邻苯二甲酸氢钾、邻苯二甲酸氢钠、磷酸二氢钾和磷酸氢二钠。
使用的缓冲剂系统的量取决于：
(1)希望的pH值，以及
(2)阿来屈酯的量
一般说来，使用的缓冲剂的量为缓冲剂与制剂中阿来屈酯的摩尔比为0.5-50∶1，以保持pH值为2-9，一般缓冲剂与阿来屈酯的摩尔比为1-10。
一种有用的缓冲剂是柠檬酸钠/柠檬酸，一般含量为5-50mg/ml的柠檬酸钠至1-15mg/ml的柠檬酸。
还存在有络合剂为的是防止阿来屈酯与可溶的金属离子如Ca、Mg、Fe、Al和Ba形成金属络合物而发生沉淀，它们可能由玻璃容器或橡胶塞子浸出，也可能存在于一般的自来水中。络合剂的作用是与阿来屈酯进行竞争络合的药剂，产生可溶性金属络合物，而阿来屈酯一般形成不溶的金属络合物。络合剂包括作用为缓冲剂/络合剂的柠檬酸缓冲剂或EDTA。当使用EDTA时，其用量为组合物重量的0.005-0.1％，和0.005-2份重量EDTA比1份重阿来屈酯，优选大约为组合物重的0.01％。优选只使用柠檬的盐缓冲剂。
三种阿来屈酯的口服剂形的实施例是：
口服水溶液
将阿来屈酯散药溶于水或适当的助溶剂中达到所需浓度。按需要加入矫味剂、着色剂、粘度剂、防腐剂、稳定剂和缓冲剂。将此溶液装到多剂量或单剂量包装中。
由瓶中直接使用此水溶液。
一般配方
阿来屈酯                      0.5-10.0mg
柠檬酸钠                          5-50mg
柠檬酸                            1-15mg
纯水                           适量至1ml
在此制剂中也可按下面专门加入添加剂、助溶剂、矫味剂、着色剂、防腐剂、稳定剂和缓冲剂：
专门配方
阿来屈酯                      0.5-10.0mg
柠檬酸钠                          5-50mg
柠檬酸                            1-15mg
野樱桃(粉)a                    10-200mg
FDC红No.33b                   0.1-1.0mg
山梨酸                        0.05-0.2％
糖精c                           1-100mg
丙二醇                            5-20％
纯水                           适量至1ml
a也可使用野樱桃以外的矫味剂
b也可选择FDC No33以外的着色剂以配合其它矫味剂
c也可改用蔗糖或天冬氨苯丙氨酸甲酯作为甜味剂
口服糖浆
将阿来屈酯散药加到10-85％的蔗糖溶液中达到所需的浓度。如果需要加入添加剂如甘油、山梨糖醇、矫味剂、着色剂、粘度剂、防腐剂、稳定剂和缓冲剂。将最终的溶液装入多剂量或单剂量包装中。
可直接由瓶中取用糖浆，或加到少量饮用水中以易于吞服。
一般配方
阿来屈酯                            0.5-10.0mg
柠檬酸                                  1-15mg
柠檬酸钠                                5-50mg
蔗糖                                   10-85％
纯水                                 适量至1ml
也可以专门在制剂中再加入如下的添加剂，比如甘油、山梨糖醇、矫味剂、着色剂、防腐剂、稳定剂和缓冲剂：
专门制剂
阿来屈酯                            0.5-10.0mg
柠檬酸                                  1-15mg
柠檬酸钠                                5-50mg
甘油                                    5-25％
蔗糖                                   10-40％
山梨糖醇                               10-40％
野樱桃(粉)a                          10-200mg
FDC红No.33b                          0.1-10mg
山梨酸                              0.05-0.2％
纯水                                 适量至1ml
a也可用野樱桃以外的矫味剂
b也可选用FDC No.33以外的着色剂以与其它矫味剂相匹配
用前冲调的粉末
用一种或多种如下的添加剂与阿来屈酯散药掺和至均匀：矫味剂、着色剂、防腐剂、稳定剂，特别是用缓冲剂。然后把粉状掺和物装入多剂量容器或单剂量包装中。
可将此粉末溶于普通的饮用水中，冲调成阿来屈酯的水溶液。
用于用前冲调的粉末配方
             每个单位剂量容器的量d：
阿来屈酯                             2-50mg
蔗糖                             100-1000mg
柠檬酸钠                           25-500mg
柠檬酸                              5-500mg
d容器可以是瓶(可向其中加入水)或药囊袋。另外，可以在多剂量
容器中提供散装药物。
所需的精确剂量将随病人的年龄、身材、性别和状态；要治疾病的种类和严重程度等而变化。因此不能预先就规定精确的剂量，这将由护理医生决定。然而，如下所述，通过动物模型的常规实验可确定适当的用量。一般说来，对于任何口服液体制剂中的阿来屈酯的有效剂量大约为1.5-3000μg/kg体重，优选为约10μg/kg-200μg/kg体重。
本发明的方法和组合物可用来治疗骨折、缺损和由骨质疏松的病理状态导致的疾病、骨关节炎、变形性骨炎、骨质缺乏、骨软化、癌以外的多发骨髓瘤导致的骨损失、其它治疗(如类固醇)的副作用导致的骨损失和与年龄有关的骨体损失等。

Claims (20)

1、在药学上可接受的载体中含有有药效数量的阿来屈酯；还含有效量能维持组合物的pH值为2-8范围的缓冲剂；还含有防止阿来屈酯在水溶液中产生沉淀的络合剂的药物组合物。
2、权利要求2的药物组合物是液体。
3、权利要求3的药物组合物，其中所述液体是糖浆。
4、权利要求2的药物组合物，其中所述液体是水溶液。
5、权利要求1的药物组合物，它是一种用前冲调的粉末。
6、权利要求5的可溶于水的药物组合物。
7、权利要求1的药物组合物，其中阿来屈酯的用量为每g组合物0.0005-0.5g。
8、权利要求1的药物组合物，其中所述药学上可接受的赋形剂是纯水。
9、权利要求1的药物组合物，其中所述缓冲剂是柠檬酸钠/柠檬酸、酒石酸氢钾、酒石酸氢钠、磷酸二氢钾和磷酸氢二钠。
10、权利要求1的药物组合物，其中所述缓冲剂的量为缓冲剂与阿来屈酯的摩尔比为0.5-50比1。
11、权利要求1的药物组合物，其中所述络合剂为EDTA。
12、权利要求11的药物组合物，其中所述EDTA的用量为每重量份阿来屈酯0.005-2重量份。
13、权利要求1的药物组合物，其中所述pH值在4-6的范围内。
14、权利要求1的药物组合物，它是有如下制剂的糖浆：
阿来屈酯                      0.5-10.0mg
柠檬酸                            1-15mg
柠檬酸钠                          5-50mg
蔗糖                             10-85％
纯水                           适量至1ml
15、权利要求14的药物组合物，它是有如下制剂的糖浆：
阿来屈酯                      0.5-10.0mg
柠檬酸                            1-15mg
柠檬酸钠                          5-50mg
甘油                              5-25％
蔗糖                              10-40％
山梨糖醇                          10-40％
野樱桃(粉)或其它矫味剂           10-200mg
FDC红No.33或其它着色剂          0.1-1.0mg
山梨酸                         0.05-0.2％
纯水                            适量至1ml
16、权利要求1的药物组合物，它是具有如下制剂的水溶液：
阿来屈酯                       0.5-10.0mg
柠檬酸钠                           5-50mg
柠檬酸                             1-15mg
纯水                            适量至1ml
17、权利要求16的组合物，它具有如下的制剂
阿来屈酯                       0.5-10.0mg
柠檬酸钠                           5-50mg
柠檬酸                             1-15mg
野樱桃(粉)或其它矫味剂           10-200mg
FDC红No.33或其它着色剂          0.1-1.0mg
山梨酸                         0.05-0.2％
糖精或蔗糖或天冬氨苯丙氨酸甲酯    1-100mg
丙二醇                             5-20％
纯水                            适量至1ml
18、权利要求1的药物组合物，它是具有如下制剂的用前冲调粉末：
阿来屈酯                           2-50mg
蔗糖                           100-1000mg
柠檬酸钠                         25-500mg
柠檬酸                            5-500mg
19、权利要求1所定义的药物组合物用于制备治疗和/或预防难于吞服的对象骨损失的药物的用途。
20、权利要求19的用途，其中的骨损失与废用导致的骨质疏松症、与年龄、与类固醇治疗、与类风湿病、与变形性骨炎或与癌症有关。
CN95193086A 1994-05-17 1995-05-12 口服阿来屈酯液体制剂 Expired - Fee Related CN1079672C (zh)

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