CN104491876A - 含玻璃酸钠的依匹斯汀滴眼液及其制备方法 - Google Patents
含玻璃酸钠的依匹斯汀滴眼液及其制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 14
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Abstract
本发明涉及一种含玻璃酸钠的盐酸依匹斯汀滴眼液及其制备方法。该滴眼液中，盐酸依匹斯汀的含量为0.05-0.5％，玻璃酸钠的含量为0.01-0.5％，pH值控制在4.0-7.5。本发明选用玻璃酸钠可延长药物在眼部的滞留时间，并提高生物利用度。
Description
技术领域
本发明涉及一种含玻璃酸钠的盐酸依匹斯汀滴眼液及其制备方法
背景技术
过敏性结膜炎是一类常见的眼表过敏性疾病，其主要是由I型及IV型变态反应引起。该病最主要的症状是眼痒，常伴有结膜充血、水肿和乳头、滤泡增生等体征。根据临床表现、病程及预后差异，过敏性结膜炎可分为5种类型：季节性过敏性结膜炎、常年性过敏性结膜炎、春季角结膜炎、巨乳头性结膜炎和特应性角结膜炎。其患病率约为总人口的20％，我国过敏性结膜炎好发于中青年，以常年性过敏性结膜炎和季节性过敏性结膜炎为主要类型。临床上用于过敏性结膜炎的常用药物有：(1)抗组胺类；(2)肥大细胞稳定剂；(3)双效药物；(4)非甾体抗炎药；(5)糖皮质激素类；(6)免疫抑制剂。
盐酸依匹斯汀(Epinastine hydrochloride)为第二代抗组胺药，具有选择性抑制外周H1受体的作用，无中枢镇静作用和抗胆碱作用。临床多用于治疗过敏性鼻炎、湿疹、荨麻疹、皮炎、皮肤瘙痒症、银屑病、过敏性支气管哮喘等。其临床疗效和副作用方面要优于苯海拉明、非那根、扑尔敏、西替利嗪等其他抗过敏药物。盐酸依匹斯汀用于过敏性结膜炎，在改善眼痒和结膜充血方面疗效甚好，且不会增加眼表损害和干眼症的危险。
盐酸依匹斯汀滴眼液(商品名：Elestat)由美国Allergan公司研制开发，于2004年在国外上市，用于治疗过敏性结膜炎。但是该滴眼液用药后由于受泪液稀释、鼻泪管排泄等导致药液外溢流失，眼部的生物利用度较低，作用的时间也极为短暂。为了延长滴眼液的作用时间，提高生物利用度，改善治疗效果，可在普通的滴眼液制剂处方中加入增粘剂，增加滴眼液的黏度，延长药物在眼部的滞留时间，从而提高药物的生物利用度。制剂中常用的增粘剂有例如卡波姆、泊洛沙姆、羟丙甲纤维等。但是在这些辅料中：卡波姆凝胶遇盐类电解质黏度会下降，且卡波姆可造成视力模糊；泊洛沙姆对温度敏感而不稳定；羟丙甲纤维素等合成高分子聚合物，其溶液属于牛顿流体，眨眼时有疼痛感。因此，以上这些增粘剂大多不适于配制滴眼液。
综上所述，本领域迫切需要开发一种可以延缓药液外溢流失，延长药物滞留时间的盐酸依匹斯汀滴眼液。
发明内容
针对上述问题，申请人做了大量的研究，最终发现在盐酸依匹斯汀滴眼液中加入玻璃酸钠可解决上述问题。玻璃酸又称透明质酸，是一种广泛存在于机体各组织中的粘多糖，具有良好的生物相容性、增粘作用、生物粘附以及铺展润湿能力。此外，玻璃酸钠与盐酸依匹斯汀带有相反电荷，可形成离子对从而促进药物在眼部的滞留。
本发明的目的是提供一种含有玻璃酸钠的盐酸依匹斯汀滴眼液，它能增加滴眼液的黏度，延长药物在眼部的滞留时间，从而提高药物在眼部的生物利用度。
本发明所述滴眼液由药物活性成分、增粘剂、抗氧剂、等渗调节剂、pH调节剂、缓冲盐、防腐剂及注射用水组成。
本发明所述滴眼液中各组分重量百分含量为：
本发明所述玻璃酸钠的相对分子质量Mr＝10万-400万。
本发明所述缓冲盐为醋酸-醋酸钠缓冲液或柠檬酸-柠檬酸钠缓冲液。
本发明所述等渗调节剂为氯化钠和葡萄糖中的一种或几种。
本发明所述适量的pH调节剂使滴眼液pH至4.0-7.5。
本发明所述防腐剂选自苯扎氯铵、苯扎溴铵、羟苯甲酯、羟苯乙酯或羟苯丙酯中的一种或几种。
本发明所述pH调节剂选自氢氧化钠和盐酸中的一种或几种。
本发明所述滴眼液的制备方法，步骤包括：在注射用水中加入盐酸依匹斯汀、缓冲盐、等渗调节剂、EDTA-2Na溶解后，再加入溶胀完全的玻璃酸钠溶液，搅拌均匀后加入pH调节剂，过滤灌装。
本发明所述滴眼液的用法用量：每侧一次1滴，一日2次。
本发明所述滴眼液的特点在于：黏度增加可防止药液外溢流失，使药物长时间滞留病灶区，从而提高药物的生物利用度。
具体实施方式
下文将结合实例对本发明做详细说明，但这些具体例并不用于限定本发明。
实施例1盐酸依匹斯汀滴眼液的制备
100mL注射用水中包含：
制备方法：在注射用水中加入盐酸依匹斯汀、磷酸二氢钠、氯化钠、乙二胺四乙酸二钠、苯扎氯铵溶解后，再加入溶胀完全的玻璃酸钠溶液，搅拌均匀后加入酸或碱调节pH至7.0，过滤灌装。
实施例2盐酸依匹斯汀滴眼液的制备
100mL注射用水中包含：
制备方法：同实施例1的制备方法
实施例3盐酸依匹斯汀滴眼液的制备
100mL注射用水中包含：
制备方法：同实施例1的制备方法
实施例4盐酸依匹斯汀滴眼液黏度的测定
分别测定实施例1、实施例2和实施例3滴眼液的黏度。结果如表1所示：
表1盐酸依匹斯汀滴眼液的黏度
实施例5兔眼泪液药物动力学实验
样品：
1)对照组：盐酸依匹斯汀滴眼液上市制剂(商品名：Elestat)；试验组：实施例1、实施例2、实施例3
2)实验方法：健康新西兰白兔，雌性，体重1.5-2.0kg，随机分为4组，每组3只。分别在兔眼结膜囊内滴加滴眼液50μL。滴眼后于15、30、60、90、120、180、240、360min将毛细管置于眼睑内，吸取泪液10μL，置于塑料离心管中，加入90μL甲醇涡旋2min，10000rpm离心10min，取上清液20μ1进样HPLC分析，计算盐酸依匹斯汀的泪液浓度。统计矩法计算的药动学参数药时曲线下面积(AUC)以及平均滞留时间(MRT)，数据如表2所示：
表2盐酸依匹斯汀滴眼液在兔泪液中的药动学参数
结果显示，所有试验组与对照组相比AUC及MRT均有显著性差异(P＜0.05)，且试验组中实施例1、实施例2、实施例3的AUC分别为对照组AUC的3.2倍、6.1倍、6.4倍。这表明玻璃酸钠的加入可延长药物在泪液中的滞留时间，从而提高药物在眼部的生物利用度。
Claims (8)
1.一种滴眼液，包括如下组分及含量：
所有百分数均为重量百分数。
2.如权利要求1所述的滴眼液，其特征在于所述玻璃酸钠的相对分子质量Mr＝10万-400万。
3.如权利要求1所述的滴眼液，其特征在于所述缓冲盐为磷酸盐缓冲液或柠檬酸盐缓冲液。
4.如权利要求1所述的滴眼液，其特征在于所述等渗调节剂为氯化钠和葡萄糖中的一种或几种。
5.如权利要求1所述的滴眼液，其特征在于所述适量的pH调节剂使滴眼液pH至4.0-7.5。
6.如权利要求1所述的滴眼液，其特征在于所述防腐剂选自苯扎氯铵、苯扎溴铵、羟苯甲酯、羟苯乙酯或羟苯丙酯中的一种或几种。
7.如权利要求1所述的滴眼液，其特征在于所述pH调节剂选自氢氧化钠和盐酸中的一种或几种。
8.如权利要求1-5所述滴眼液的制备方法，步骤包括：在注射用水中加入盐酸依匹斯汀、缓冲盐、等渗调节剂、乙二胺四乙酸二钠、防腐剂溶解后，再加入溶胀完全的玻璃酸钠溶液，搅拌均匀后加入pH调节剂调节pH至4.0-7.5，过滤灌装。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292752C (zh) * | 1999-11-12 | 2007-01-03 | 贝林格尔·英格海姆国际有限公司 | 含依匹那丁的溶液 |
| CN100998863A (zh) * | 2006-01-12 | 2007-07-18 | 上海新药研究开发中心 | 防治白内障的n－乙酰肌肽滴眼液及制备方法 |
| CN102670493A (zh) * | 2012-05-22 | 2012-09-19 | 宁夏康亚药业有限公司 | 盐酸洛美沙星滴眼液及其制备方法与应用 |
-
2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292752C (zh) * | 1999-11-12 | 2007-01-03 | 贝林格尔·英格海姆国际有限公司 | 含依匹那丁的溶液 |
| CN100998863A (zh) * | 2006-01-12 | 2007-07-18 | 上海新药研究开发中心 | 防治白内障的n－乙酰肌肽滴眼液及制备方法 |
| CN102670493A (zh) * | 2012-05-22 | 2012-09-19 | 宁夏康亚药业有限公司 | 盐酸洛美沙星滴眼液及其制备方法与应用 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020125318A (ja) * | 2017-05-01 | 2020-08-20 | 参天製薬株式会社 | 点眼剤 |
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