CN1390129A - 含依匹那丁的溶液 - Google Patents

含依匹那丁的溶液 Download PDF

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CN1390129A
CN1390129A CN00815547A CN00815547A CN1390129A CN 1390129 A CN1390129 A CN 1390129A CN 00815547 A CN00815547 A CN 00815547A CN 00815547 A CN00815547 A CN 00815547A CN 1390129 A CN1390129 A CN 1390129A
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沃尔克·特雷克
杰罗尔德·杜施勒
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Abstract

本发明是关于一种局部使用的包含依匹那丁的水性溶液,其可以是消旋体或对映体形式,也可以是药理上可接受的酸加成盐形式。

Description

含依匹那丁的溶液
本发明是关于一种局部使用的包含依匹那丁(Epinastin)的水性溶液，其可以是以消旋体，对映体形式，以及也可以是以药理上可接受的酸加成盐形式存在。
发明背景
眼睛的过敏反应(本文以下以眼部过敏反应表示)表明一系列不同定义的症状。作为眼部过敏反应的实例有：季节性过敏结膜炎，经常性过敏结膜炎，巨细胞过敏结膜炎，春天发生的角膜结膜炎或是异位性角膜结膜炎。鼻子过敏反应的实例(本文以下以鼻腔过敏反应表示)包括季节性过敏鼻炎及经常性过敏鼻炎。
眼部及鼻腔过敏反应的免疫机理基于包括因组胺所引起的发炎过程。由于组胺释放所引起的过敏反应会发生在上述的眼部及鼻腔过敏反应的初期。
而且，眼部及鼻腔的过敏反应是由于其他肥大细胞介质以及具有毒性的嗜酸性细胞颗粒蛋白质及酶的释放所引起。中性白细胞及嗜酸性细胞流入眼结膜及鼻腔粘膜组织将引起后期的反应，(下文称为LPR)。LPR通常在因组胺引起的过敏反应发生后3-6小时之内出现。LPR的特点是产生血管扩张及球结膜水肿，以及产生结膜及鼻腔粘膜肿胀的现象。
虽然因组胺产生的过敏反应可以使用给药抗组胺药来消除，但是，使用纯抗组胺药对于中性白细胞及嗜酸性细胞流入眼结膜及鼻腔粘膜组织是没有影响的。
发明目的
本发明的目的是提供局部使用的溶液，其可抑制中性白细胞及嗜酸性细胞流入眼结膜及鼻腔粘膜组织，因此降低或是防止LPR的发生，而且其特性是较长持续的活性。
发明详述
意想不到的是，我们发现局部使用含有依匹那丁的水性溶液，可任选地以消旋体，对映体形式，并也可以是药理上可接受的酸加成盐形式使用，其可用于解决本发明的目的，因为其可抑制中性白细胞及嗜酸性细胞流入眼结膜组织及鼻腔粘膜，因此降低或是阻止LPR的发生，而且其特性是较长且有持续的活性。
化合物依匹那丁(3-氨基-9，13b-二氢-1H-二苯并[c，f]咪唑[1，5-a]氮杂_(azepine))及其酸加成盐是第一次在德国专利申请P 30 08 944.2中提出。
以包含依匹那丁的局部使用溶液作为抑制嗜酸性细胞及中性白细胞流入的效果，是以所谓老鼠的“被动性眼部过敏反应”模型来证明。实验描述：
于实验动物，老鼠的眼睑注射抗血清使产生过敏反应后72小时，以静脉注射卵清蛋白再重新激发。有些实验动物在注射卵清蛋白之前15分钟，已事先在结膜囊上使用含有本发明的依匹那丁的溶液。在给予卵清蛋白之后2小时，将实验动物杀死，并且检查结膜以测定其中嗜酸性细胞，中性白细胞以及肥大细胞粒化的量。结果：
已事先使用含有本发明的依匹那丁溶液(0.05～0.5％)进行前处理的动物，其结膜中具有明显的较低的嗜酸性细胞含量。事先已使用含有本发明的依匹那丁溶液进行前处理的动物，其结膜中具有明显较低的淋巴细胞含量(p＜0.01)。事先已使用含有本发明的依匹那丁溶液进行前处理的动物，经测定约有35％肥大细胞去粒化的抑制性(p＜0.01)。
因此，本发明是关于一种局部使用的含有依匹那丁的水性溶液，其或者可以消旋体，对映体形式，以及或者以其药理上可接受的酸加成盐形式存在，其浓度是0.005至0.5，优选是0.02至0.1，更优选的是0.03至0.07毫克/毫升溶液。
根据本发明是优选使用所述含有依匹那丁盐酸盐的水性溶液作局部应用。
适当的水性溶剂是于生理上可接受的水性溶剂，特别优选的是生理上可接受的生理食盐水溶液。
根据本发明，优选的，局部使用溶液的制备通常含有0.005至0.5，优选是0.02至0.1，更优选是0.03至0.07毫克/毫升的依匹那丁，或其以消旋体，其对映体的形式，以及也可以是其药理上可接受的酸加成盐形式，以及使用生理食盐水溶液作为主要的载体。根据本发明的溶液的pH值，优选的是以适当的缓冲液系统保持在6.5-7.2的范围内。该制备中还可包括传统的，药剂上可接受的赋形剂、防腐剂、稳定剂和/或穿透促进剂。
可在本发明溶液中使用的优选载体是纯水，尤其是生理食盐水。
本发明可以使用的赋形剂包括粘度剂，如聚乙烯醇，聚乙烯吡咯烷酮(povidone)，羟基丙基甲基纤维素，泊洛沙姆(poloxamers)，羧基甲基纤维素，卡波姆(carbomers)及羟基乙基纤维素。但本发明并不限制在所述范围。
本发明溶液中使用的优选防腐剂包括，氯苄烷铵，氯代丁醇，硫柳汞，苯基乙酸汞及苯基硝酸汞，但本发明并不限制在所述范围。
穿透促进剂可以是，例如，表面活性剂，特定的有机溶剂，如二甲基亚砜及其他的亚砜，二甲基乙酰胺及吡咯烷酮，杂环胺的特定酰胺类，二元醇，如丙二醇，亚丙基碳酸盐，油酸，烷基胺及其衍生物，各种阳离子，阴离子，非离子性及两性的表面活性剂及其类似物。
为调节溶液的张力，必要时或按需要可加入物质。上述物质包括盐，特别是氯化钠，氯化钾，甘露糖醇及甘油或是其他适当的，生理上可接受的用于调整张力的试剂，但本发明将不限于上述这些。
可以使用多种缓冲液及物质来调整pH值，只要所得的制备物是生理上可接受的。所述的缓冲液包括乙酸缓冲液，柠檬酸缓冲液，磷酸缓冲液及硼酸缓冲液。
同样的，本发明可使用的生理上可接受的抗氧化剂包括，焦亚硫酸氢钠，硫代硫酸钠，乙酰基半胱胺酸，丁基化羟基茴香醚及丁基化羟基甲苯，但本发明将不限于此。
其他可加入本发明溶液中的载体成份是螯合剂。优选的螯合剂是乙二胺四乙酸二钠(Na-EDTA)，虽然也可以采用其他的螯合剂，或是与乙二胺四乙酸二钠组合使用。
根据本发明所述局部使用水性溶液，它可用于结膜或是鼻腔粘膜。对于本发明目的来说，关于眼部使用的溶液与鼻部应用的溶液一样重要。
本发明不仅是关于前述的本发明溶液，而且关于使用前述局部应用的水性溶液以抑制中性白细胞及嗜酸性细胞流入眼结膜组织及鼻腔粘膜。
本发明也关于依匹那丁的用途，或以其消旋体，其对映体形式，或者以其药理上可接受的酸加成盐形式使用，以生产本发明的局部应用的水性溶液来治疗眼结膜或是鼻腔粘膜的失调，其中的治疗有用的包括抑制中性白细胞及嗜酸性细胞流入眼结膜及鼻腔粘膜的组织的过敏反应。
优选的是，上述用于抑制LPR，特别是治疗所列疾病的开始。
示于下表1的实施例可阐明本发明，但不以此为限。
表1   溶液10.005％[克/100毫升]   溶液20.01％[克/100毫升]   溶液30.05％[克/100毫升]   溶液40.10％[克/100毫升]   溶液50.01％[克/100毫升]   溶液60.05％[克/100毫升]   溶液70.10％[克/100毫升]
依匹那丁盐酸盐     0.0500     0.0100     0.0500     0.1000     0.0100     0.0500     0.1000
 Na-EDTA     0.0500     0.0500     0.0500     0.0500       -       -       -
氯化钠     0.5000     0.5000     0.5000     0.5000     0.5000     0.5000     0.5000
磷酸二氢钠二水合物     0.7800     0.7800     0.7800     0.7800     0.4100     0.4100     0.4100
氯苄烷铵     0.0101     0.0101     0.0101     0.0101     0.0101     0.0101     0.0101
氢氧化钠     0.0001     0.0001     0.0001     0.0001       -       -       -
磷酸二氢钠二水合物      -       -       -       -     0.6500     0.6500     0.6500
羟基乙基纤维素      -       -       -       -     0.1000     0.1000     0.1000
水    99.4198    99.4598    99.4198     99.3698     99.0749     99.0349     99.9849
   100.8100    100.8100    100.8100    100.8100    100.7550     100.7550     100.7550

Claims (5)

1.一种含有依匹那丁的局部使用的水性溶液，其任选地以消旋体，对映体形式，或者以其药理上可接受的酸加成盐的形式存在，该溶液浓度是0.005至0.5毫克/毫升。
2.根据权利要求1的溶液，其含有依匹那丁盐酸盐。
3.根据权利要求1或2的溶液，其特征是，以生理上可接受的缓冲液调整其pH至6.5至7.2之间。
4.根据权利要求3的溶液，其特征是，其还包括防腐剂。
5.根据权利要求1至4中之一溶液的用途，它用于抑制中性白细胞及嗜酸性细胞流入眼结膜或鼻腔粘膜的组织。
CNB00815547XA 1999-11-12 2000-10-14 含依匹那丁的溶液 Expired - Lifetime CN1292752C (zh)

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DE19954516A DE19954516A1 (de) 1999-11-12 1999-11-12 Epinastin-haltige Lösungen

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TWI750248B (zh) * 2016-10-28 2021-12-21 日商參天製藥股份有限公司 含依匹斯汀之點眼液
CN115448927A (zh) * 2022-10-20 2022-12-09 重庆瑞泊莱医药科技有限公司 一种氢溴酸依匹斯汀晶型ii及其制备方法

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