CN106458915B - 新的伊伐布雷定盐及其制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title description 5
- 229960003825 ivabradine Drugs 0.000 claims abstract description 21
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 229950005627 embonate Drugs 0.000 claims description 12
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 10
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
- C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
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Abstract
本发明涉及式(I)的伊伐布雷定半双羟萘酸盐及其水合物。本发明还涉及药物。
Description
本发明涉及伊伐布雷定的新盐、其制备方法以及包含其的药物组合物。
伊伐布雷定或3-{3-[{[(7S)-3,4-二甲氧基二环[4.2.0]辛-1,3,5-三烯-7-基]甲基}(甲基)氨基]丙基}-7,8-二甲氧基-1,3,4,5-四氢-2H-3-苯并氮杂-2-酮,以及其可药用酸加成盐,更特别是其盐酸盐,具有非常有价值的药理学和治疗特性,尤其是减缓心率的特性,这使得这些化合物可用于治疗或预防心肌缺血的多种临床表现,例如心绞痛、心肌梗塞和相关的节律紊乱,以及涉及节律紊乱的多种疾病,尤其是室上性心律失常,并可用于收缩性心力衰竭和舒张性心力衰竭。
伊伐布雷定及其可药用酸加成盐、更特别是其盐酸盐的制备和治疗用途已经在欧洲专利EP 0 534 859中描述。
本发明涉及式(I)的伊伐布雷定的半双羟萘酸盐:
及其水合物,涉及制备所述盐的方法,以及包含其的药物组合物,特别是那些允许该活性成分随时间控制释放的组合物。
双羟萘酸也称为4,4'-甲烷二基二(3-羟基萘-2-甲酸)。
式(I)的化合物的伊伐布雷定/双羟萘酸比例为1/0.5。
式(I)的化合物通过将伊伐布雷定盐酸盐用双羟萘酸的二钠盐或双羟萘酸钠在水性介质中处理而获得。
将伊伐布雷定盐酸盐和双羟萘酸钠以1/0.5到1/0.6的比例混合。
接着,将由此制备的式(I)的化合物用有机溶剂如二氯甲烷从水性介质中萃取。
在式(I)的化合物形成后,可将其有利地溶于甲醇中,以除去残余的有机溶剂。
本发明还涉及药物组合物,其包含作为活性成分的伊伐布雷定半双羟萘酸盐以及一种或多种惰性的无毒的可药用赋形剂或载体。
对于本发明的药物组合物,可被特别提及的是那些适合于口服、胃肠外(静脉内、肌内或皮下)、经皮或透皮、鼻内、直肠、经舌、眼部或呼吸道给药的组合物,尤其是片剂、糖锭剂、舌下片剂、明胶胶囊、胶囊剂、栓剂、乳膏剂、软膏剂、表皮凝胶、可注射或可饮用的制剂、气雾剂、滴眼剂或滴鼻剂。
除了伊伐布雷定的半双羟萘酸盐,本发明的药物组合物还包含一种或多种赋形剂或载体,例如稀释剂、润滑剂、粘合剂、崩解剂、吸附剂、着色剂、甜味剂。
可被提及的赋形剂或载体的例子包括:
◆对于稀释剂:乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素、甘油;
◆对于润滑剂:二氧化硅、滑石粉、硬脂酸及其镁盐和钙盐、聚乙二醇;
◆对于粘合剂:硅酸铝和硅酸镁、淀粉、麦芽糖糊精、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮;
◆对于崩解剂:琼脂、海藻酸及其钠盐、泡腾合剂。
在药物组合物中的伊伐布雷定半双羟萘酸盐的百分比优选为5%-50%重量。
所用剂量根据患者的性别、年龄和体重、给药途径、疾病性质和任何联合治疗的性质而变化,范围为每24小时2.5-30mg伊伐布雷定,更优选每天5-15mg,还更优选每天10-15mg。
药物组合物中稀释剂的百分比优选为40%-80%重量。
药物组合物中润滑剂的百分比优选为0.2%-10%重量。
药物组合物中粘合剂的百分比优选为5%-50%重量。
申请人已经发现,使用伊伐布雷定的半双羟萘酸盐能够制备具有活性成分控制释放的药物组合物,同时克服了常规方法产生的问题。
已经推荐和制备了多种用于药物活性成分的控制释放的药物组合物,用于其经口服、含服、舌下、眼部、直肠、阴道内和/或胃肠外途径给药。这些新的药物组合物的目标基本上是为了:
-减少药物的给药频率,
-在介质中或在预期的生物学位点获得相对恒定的活性成分水平,
-获得与药物的药理学活性相关的释放曲线。
最普遍用于控制释放的原理是将活性成分与赋形剂在基质中掺合,所述赋形剂大多数具有聚合物性质。
不论所面对的基质组成怎样,要获得它都会遇到具体的生产问题,例如:
-有很多步骤的复杂生产方法,
-活性成分在生产过程中的稳定性以及所用赋形剂的稳定性,
-调节活性成分释放速度很困难,通常随时间而变化,并且依赖于例如使用压制方法的聚合物批次的粒径,
-导致获得基本上仅适合一种给药途径的药物形式的生产方法,
-由于步骤的多次重复导致的批次间的重现性。
使用伊伐布雷定的半双羟萘酸盐能够获得活性成分的控制释放特性,不需要使用现有技术所描述的复杂的盖伦制剂技术。
因此,申请人已经显示,在本发明的药物组合物中使用伊伐布雷定的半双羟萘酸盐能够允许伊伐布雷定的控制释放,甚至当所用的盖伦制剂对应于使用伊伐布雷定盐酸盐来实现活性成分的立即释放的制剂时也是如此。
尽管全部的伊伐布雷定盐酸盐在体外在15分钟内释放,但本申请所述的体外溶出实验显示,在约6小时后仅有80%的伊伐布雷定半双羟萘酸盐被释放。
以下实施例举例说明本发明。
实施例1:制备伊伐布雷定的半双羟萘酸盐
元素分析在Carlo Erba 1108装置上进行。
结果用产品的水分含量校正,所述水分含量为1.82%(用库仑法测定)。
将4.1g的伊伐布雷定盐酸盐(8.12mmol)溶于200mL水中,将2.0g的双羟萘酸钠(4.63mmol)溶于200mL水中。
在剧烈搅拌下,将双羟萘酸钠溶液加入伊伐布雷定盐酸盐溶液中。立即沉淀形成半双羟萘酸盐。维持搅拌约30分钟,然后用200mL二氯甲烷第一次萃取伊伐布雷定的半双羟萘酸盐,接着用100mL二氯甲烷萃取第二次。合并有机部分,用100mL水清洗。有机相用硫酸镁干燥,得到澄清的黄色溶液。
将有机相在旋转蒸发仪中于40℃真空蒸发至干。得到黄色粉末。
将黄色粉末在40℃在真空中(10毫巴)干燥16小时,接着溶于200mL甲醇。
将溶液在旋转蒸发仪中于40℃真空蒸发至干。再次得到黄色粉末。
将黄色粉末在40℃在真空中(10毫巴)干燥20小时。
1H NMR谱显示残留甲醇含量为0.8%。
随后将粉末在80℃在真空中(10毫巴)再干燥24小时,得到3.53g产品,其具有的残留甲醇含量小于0.1%。
产率=66.5%
元素分析:
元素 | %理论值 | %校正的平均值 |
C | 69.77 | 69.40 |
H | 6.69 | 6.60 |
N | 4.23 | 4.25 |
O | 19.31 |
校正结果的方法:
对于C的例子:69.14*100/(100-1.82)=69.40%
对于H的例子:6.68*100/(100-1.82)–2*1.82/18=6.60%(因为水的氢原子必须被考虑在内(2/18))
实施例2:药物组合物
包含剂量为5mg伊伐布雷定的100mg片剂的制剂配方
实施例3:溶出实验
溶出的操作条件
欧洲药典(2.9.3)描述的桨式溶出装置
溶出介质:0.01N盐酸(pH~2.1),已脱气
介质温度:37℃±0.5℃
介质体积:500mL±5mL
桨叶旋转速度:50rpm±2rpm
标准取样时间:0、15、30和45min。
增加的取样时间:1、2、4、6、8、12和16h
移出体积:1mL
移出体积的替代:无
测试的单位数目:6
每瓶的单位数目:1
表1–溶出度结果
图1是上表所示数据的图解说明。
Claims (4)
1.式(I)的伊伐布雷定的半双羟萘酸盐:
2.制备伊伐布雷定半双羟萘酸盐的方法,其特征在于:在水性介质中将伊伐布雷定盐酸盐和双羟萘酸钠混合,伊伐布雷定盐酸盐和双羟萘酸钠的比例为1/0.5到1/0.6,随后用有机溶剂从水性介质中萃取伊伐布雷定半双羟萘酸盐。
3.药物组合物,其包含作为活性成分的伊伐布雷定半双羟萘酸盐以及一种或多种惰性的无毒的可药用赋形剂或载体。
4.根据权利要求3的药物组合物,其用于治疗或预防心绞痛、心肌梗塞和相关的节律紊乱、室上性心律失常以及收缩性心力衰竭或舒张性心力衰竭。
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CN101386594A (zh) * | 2007-09-11 | 2009-03-18 | 瑟维尔实验室 | 1,2,4,5-四氢-3h-苯并氮杂䓬化合物、其制备方法与包含它们的药物组合物 |
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