CN101677943B - 使用苯甲醇的多剂量浓缩艾司洛尔 - Google Patents

使用苯甲醇的多剂量浓缩艾司洛尔 Download PDF

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CN101677943B
CN101677943B CN2008800170791A CN200880017079A CN101677943B CN 101677943 B CN101677943 B CN 101677943B CN 2008800170791 A CN2008800170791 A CN 2008800170791A CN 200880017079 A CN200880017079 A CN 200880017079A CN 101677943 B CN101677943 B CN 101677943B
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迪帕克·蒂瓦里
乔治·奥沃
列哈·纳亚克
肯尼斯·E·布尔霍普
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Abstract

本发明公开了基本上不含其它有关的艾司洛尔酯的浓缩的艾司洛尔注射剂和稀释的艾司洛尔组合物。浓缩艾司洛尔制剂包含约25-1000mg/ml的艾司洛尔和约1-25％w/v的苯甲醇及其组合。组合物还可用作多剂量组合物。本发明还公开了通过稀释本发明的浓缩品而制备的稀释的即用艾司洛尔组合物。本发明还公开了制备和使用本发明即用组合物的方法。

Description

使用苯甲醇的多剂量浓缩艾司洛尔
发明背景
本发明涉及稳定性增强的浓缩艾司洛尔制剂。更具体地说，本发明涉及用苯甲醇稳定的浓缩艾司洛尔制剂。本发明的组合物还适合作为多剂量组合物。另外，本发明涉及通过稀释本发明的浓缩艾司洛尔组合物制备的即用(ready-to-use)稀释组合物。
艾司洛尔(及其药学可接受的盐，例如盐酸盐)和有关化合物具有β-肾上腺素能阻断活性。β-阻断剂当以适当剂量给药时，是用于治疗和预防心脏病的治疗有效药剂。艾司洛尔是短效β-阻断剂，通常在紧急救护背景下被使用，以控制患者的心率。艾司洛尔的短效性质是由于它的不稳定的脂族甲酯基在血液中快速水解所致。
艾司洛尔的即用等渗浓缩制剂公开在美国专利Nos.5,017,609、6,310,094和6,528,540中，所述文献作为参考并入本文。制备艾司洛尔的方法和使用这样的化合物治疗或预防心脏病的方法公开在美国专利4,387,103和4,593,119中，所述文献作为参考并入本文。目前市售的艾司洛尔浓缩制剂受美国专利5,017,609的保护，其包含约250mg/ml的艾司洛尔盐酸盐、25体积％的乙醇、25体积％的丙二醇、17mg/ml的三水乙酸钠和0.715体积％的冰醋酸。该组合物不计划用于直接注射，而是用适当的稀释剂进行后续稀释。
艾司洛尔盐酸盐{3-[4-[2-羟基-3-(异丙基氨基)丙氧基]苯基]丙酸甲酯盐酸盐}在水中的稳定性由不稳定的脂族甲酯基团的酸/碱催化水解速率来介导，并且其降解成为ASL-8123{甲基-3-[4-[2-羟基-3-(异丙基氨基)丙氧基]苯基]丙酸}。即用等渗制剂在真正的含水制剂中解决了一些稳定性问题并且只具有一种降解物ASL-8123。目前市售的浓缩制剂采用赋形剂(乙醇和丙二醇)来稳定水解反应，但是这些赋形剂导致形成其它有关的酯降解物。因此，目前市售的艾司洛尔浓缩制剂在长期储存条件下导致除了ASL-8123之外还形成艾司洛尔的乙酯和丙酯。另外，用来稳定目前市售的艾司洛尔浓缩制剂的赋形剂(乙醇和丙二醇)已经与潜在的注射部位疼痛或刺激有关。
因此，希望提供稳定的浓缩艾司洛尔组合物，其消除了有关酯降解物的形成，不包含可能具有刺激性的丙二醇和乙醇赋形剂，比现有技术的浓缩组合物的制造更简单，并且任选可被保存使得能够用于多剂量应用。
发明概述
在本发明的一个方面，提供了浓缩艾司洛尔制剂。浓缩艾司洛尔制剂包含约25-1000mg/ml的艾司洛尔(或其药学可接受的盐)、约1到25体积％的苯甲醇和任选的约0.005到约2摩尔(M)的缓冲剂。该组合物的pH调节为约3.5到约7.0之间。苯甲醇，一般被用作防腐剂，已经出人意料地被发现可稳定本发明的浓缩艾司洛尔组合物。
在本发明的另一个方面，提供了即用组合物和该组合物的给药方法。该方法包括以下步骤：提供约25-1000mg/ml的艾司洛尔(或其药学可接受的盐)和1-25％重量/体积的苯甲醇的浓缩艾司洛尔制剂，从该液体选择一定体积用适当的稀释剂进一步稀释，然后将稀释的产品给患者注射。
本发明的优点是，与现有技术的浓缩艾司洛尔组合物不同，本发明的制剂不形成其它有关的艾司洛尔酯的降解物。
本发明的另一个优点是其提供了制剂的多剂量应用的灵活性，而没有微生物交叉污染。
本发明的另一个优点是其减少了由丙二醇和乙醇赋形剂引起的注射部位疼痛/刺激的可能性。
本发明的另一个优点是其提供了无菌的浓缩艾司洛尔组合物，其包含较少的赋形剂并且比现有技术的浓缩品的制备更简单。
附图说明
图1是描述艾司洛尔在乙醇和丙二醇存在下发生酯交换产生相应 的酯的化学路线。
发明详述
本发明的组合物包含艾司洛尔或其药学可接受的盐例如盐酸盐，和苯甲醇。本文使用的“艾司洛尔”是指艾司洛尔游离碱及其药学可接受的盐。浓缩品中艾司洛尔的浓度约25-1000mg/ml，优选约250mg/ml。
如上所述，艾司洛尔的主要降解途径是其脂族羧甲酯部分水解产生ASL-8123。这一降解取决于pH、缓冲剂浓度和艾司洛尔浓度。目前市售的艾司洛尔浓缩制剂由于乙醇和丙二醇的存在得以稳定。然而，过去的稳定性数据表明艾司洛尔在这些溶剂存在下经历酯交换反应，产生艾司洛尔的乙酯和丙二醇酯(参见图1)。
本发明的组合物包含一定量的苯甲醇以稳定艾司洛尔浓缩组合物。尽管苯甲醇一般被用作防腐剂，但是出乎意料地发现其稳定本发明的浓缩艾司洛尔组合物。通常，苯甲醇的存在量取决于存在的艾司洛尔浓度。苯甲醇在组合物中的典型范围为约1到25％重量/体积(w/v)。对于250mg/ml的艾司洛尔浓度而言，苯甲醇优选以约10％w/v的浓度存在。
本发明的浓缩品还可包含药学可接受的缓冲剂以帮助保持pH在约3.5到约7.0的范围。pH优选保持在约4.5到约5.5之间，更优选保持在4.9到5.1之间。当pH在4.0到6.0范围以外时，艾司洛尔的降解发生最快，并且在约5.0的pH周围最稳定。适当的缓冲剂是在所需pH范围提供充分缓冲能力并且对注射给患者是药学可接受的那些缓冲剂。可用于本发明的缓冲剂的实例包括但不限于乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸及其共轭酸。缓冲剂的浓度为约0.005到约2M。在优选的实施方案中，缓冲剂包含乙酸钠和冰醋酸的组合。缓冲剂的优选组合包括约0.005到约0.3M的乙酸钠和约0.05到约0.3M的冰醋酸。
用于容纳艾司洛尔浓缩品的适当容器是本领域已知的。它们包括小瓶、注射器和安瓿形式。容器可由聚合物材料或玻璃制成。优选的聚合物容器不含聚氯乙烯(PVC)。容器优选具有优异的屏障性质。优选的容器保留有水分屏障，诸如包括屏障层或二级包装的玻璃容器或聚合物容器。铝套袋是优选的水分屏障，用作自身缺乏水分屏障的聚合物容器的二级包装。优选的容器应能经得起最终灭菌，诸如压热。
本发明的组合物是无菌的。该组合物优选被制备然后在其最终容器中通过压热进行灭菌。或者，浓缩品可被无菌制备或单独通过压热最终灭菌，然后使用无菌程序置于无菌容器中。在制药工业中被用来实现成品最终灭菌的典型压热周期是121℃历时15分钟。本发明的艾司洛尔浓缩品可以在115到130℃压热约5到40分钟的时段，稳定性合格。压热灭优选在约119到122℃的温度范围内进行约10到36分钟的时间段。
在一个实施方案中，将浓缩品置于透明玻璃或塑料注射器中并进行最终灭菌。这些预灌装注射器可以提供成各种体积，从而允许通过将预灌装注射器的内容物分配到标准或定制的预灌装静脉流体袋中，而快速和容易地制备小体积或大体积的非肠道剂量。
在另一个实施方案中，本发明的浓缩艾司洛尔组合物被包装在密封小瓶中，优选I型处理玻璃的小瓶。
本发明还涉及使用本发明的艾司洛尔浓缩品制备的稀释的艾司洛尔组合物。执业医师可以使用用于给患者输注的优选稀释剂制得稀释浓度的艾司洛尔。适当的稀释剂包括本领域有技术的执业医师使用的稀释剂。典型实例包括但不限于氯化钠溶液，林格液或葡萄糖溶液。当需要时，艾司洛尔的稀释浓度根据需要而变，典型的浓度范围为约5至约25mg/ml的艾司洛尔，优选10mg/ml。
本发明稀释组合物的适当给药途径包括静脉内、皮下、皮内、肌肉内、关节内和鞘内。稀释组合物优选通过静脉内输注给药。
以下实施例的组合物和制备方法进一步说明了本发明，但不应解释成限制其范围。
实施例1
以下描述了包含250mg/ml的艾司洛尔盐酸盐和苯甲醇的艾司洛尔浓缩品的制备。该组合物各成分的浓度如下所示：
  成分   浓度
  艾司洛尔   250mg/mL
  三水乙酸钠   17mg/mL
  冰醋酸   0.00715mL/mL
  苯甲醇，USP   10％w/v
  注射用水，USP   适量
用于混合、过滤和灌装的设备和玻璃器皿经过彻底洗涤和除热原。将过滤器组件、灌装管组件和其它部件和设备进行灭菌。将冷注射用水的最终容积的百分之八十(80％)集中在混合槽中。然后将冰醋酸和乙酸钠加入到该槽中。将艾司洛尔盐酸盐称重并加入到该槽中。称重需要量的苯甲醇并加入到该槽中。将溶液搅拌直到所有的赋形剂溶解为止。然后使用氢氧化钠或盐酸将溶液调节到pH 5.0。将溶液用注射用水补足到最终体积并混合。将溶液灌装在10毫升I型处理的燧石安瓿中并密封。将产品在122℃灭菌20分钟。
实施例2
艾司洛尔盐酸盐在55℃下在水中或水-苯甲醇溶液中的稳定性分别被概括在表1和表2中。实施例1的制剂在55℃的水中的稳定性概括在表3中。如数据所显示的，苯甲醇的存在大大降低了艾司洛尔的降解(表2)。并且当苯甲醇与保持pH在5.0的缓冲剂一起使用时，艾司洛尔的降解被进一步降低(表3)。丙酯降解物峰(根据HPLC图谱，在0.55和0.60的近似相对滞留时间处)和乙酯降解物峰(在2.10的近似相对滞留时间处)的缺乏，表明本发明不包含在现有技术的目前市售的艾司洛尔浓缩制剂中所发现的任何降解物。用苯甲醇代替乙醇和丙二醇消除了艾司洛尔的酯交换反应以及乙酯和丙二醇酯降解物的形成，从而改善了现有技术浓缩制剂的稳定性和安全性模式。
表1.250mg/ml艾司洛尔盐酸盐在55℃的水中的稳定性
Figure G2008800170791D00061
*在RRT＝0.55，0.60和2.10处
表2.带有10％苯甲醇的250mg/ml艾司洛尔盐酸盐在55℃水中的稳定性
Figure G2008800170791D00071
*在RRT＝0.55，0.60和2.10处
表3.带有10％苯甲醇的250mg/ml艾司洛尔盐酸盐在55℃的经缓冲的水中的稳定性
Figure G2008800170791D00072
*在RRT＝0.55，0.60和2.10处
尽管已经参考某些优选的实施方案对本发明进行了描述，但应理解的是优选的实施方案仅仅说明本发明的原理。因此，本领域技术人员可进行改变和/或变化而不脱离所附权利要求所限定的本发明的真实精神和范围。

Claims (17)

1.浓缩的艾司洛尔组合物，其包含：
a)25-1000mg/ml的艾司洛尔；和
b)1-25%w/v的苯甲醇；
其中组合物的pH为3到7。
2.权利要求1的组合物，还包含缓冲剂。
3.权利要求2的组合物，其中缓冲剂包括乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸中的至少一种及其共轭酸。
4.权利要求3的组合物，其中缓冲剂包含乙酸钠和乙酸。
5.权利要求2的组合物，其中缓冲剂的存在量为0.005到2M。
6.权利要求1的组合物，其包含：
a)250mg/ml的艾司洛尔；
b)10%w/v的苯甲醇；和
c)0.1M的乙酸盐。
7.权利要求1的组合物，其包含：
a)50mg/ml的艾司洛尔；
b)2%w/v的苯甲醇；
c)0.1M的乙酸盐。
8.包含艾司洛尔的即用组合物，其通过以下方法制备：
a)提供一定体积的第一组合物，所述第一组合物包含25-1000mg/ml的艾司洛尔和1-25%w/v的苯甲醇，其中第一组合物的pH为3到7；和
b)将一定体积的第一组合物用一定体积的第二组合物稀释，所述第二组合物包含用于非肠道给药的药学可接受的稀释剂。
9.权利要求8的组合物，其中第一组合物还包含缓冲剂。
10.权利要求9的组合物，其中缓冲剂包括乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸中的至少一种及其共轭酸。
11.权利要求10的组合物，其中缓冲剂包含乙酸钠和乙酸。
12.权利要求9的组合物，其中缓冲剂的存在量为0.005到2M。
13.权利要求8的组合物，其中第二组合物选自：磷酸盐缓冲盐水和林格液。
14.权利要求9的组合物，其中第一组合物包含：
a)250mg/ml的艾司洛尔；
b)10%w/的苯甲醇；和
c)0.1M的乙酸盐。
15.权利要求9的组合物，其中第一组合物包含0.1M的乙酸盐；
a)50mg/ml的艾司洛尔；和
b)2%w/v的苯甲醇。
16.浓缩的艾司洛尔组合物，其组成如下：
a)25-1000mg/ml的艾司洛尔；
b)1-25%w/v的苯甲醇；
c)0.005-2M的缓冲剂，
其中组合物的pH为3到7。
17.权利要求8的组合物，其中第二组合物选自：盐水和葡萄糖溶液。
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