CN102008470B - 复方制剂及其预防和治疗噪声性听力损伤的用途 - Google Patents
复方制剂及其预防和治疗噪声性听力损伤的用途 Download PDFInfo
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Abstract
本发明公开了一种复方制剂，包含α-硫辛酸和尼莫地平，所述α-硫辛酸与尼莫地平的含量比为5∶1～40∶1。本发明还公开了上述复方制剂用于预防和治疗噪声性听力损伤的用途。本发明复方制剂，不仅提高了药效，而且减小了尼莫地平的用量，降低了副作用，改善了患者的顺应性。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种复方制剂及其预防和治疗噪声性听力损伤的用途。
背景技术
α-硫辛酸(α-lipoic acid，ALA)，是一种天然的二硫化合物，其化学名称是1，2-二硫戊环-3-戊酸，首次从猪肝中分离出来，属于一种B族维生素。α-硫辛酸是一种高效亲脂的自由基清除剂，在水相和脂质相中溶解性较好，易穿过细胞膜，对血脑屏障有好的穿透性。它在预防及治疗与自由基有关的疾病，如：癌症、衰老、糖尿病、动脉粥样硬化、脑和神经组织的退化性等疾病中发挥着重要的作用。
尼莫地平(nimodipine，NIM)是一种Ca2+通道阻滞剂，通过有效阻止Ca2+进入细胞内，从而抑制平滑肌收缩达到解除血管痉挛的目的。临床上多用于治疗脑血管痉挛、脑梗塞、脑动脉硬化、老年性脑功能障碍等。
噪声是一种常见的危害人类身心健康的环境因素，持续的噪声刺激会影响耳蜗毛细胞，使其ATP需要量增加，毛细胞和支持细胞的耗氧量、耗葡萄糖量增加，出现局部相对缺血，造成毛细胞及螺旋器的退行性病变。另有研究发现，噪声暴露后在耳蜗螺旋血管纹内出现超氧阴离子自由基，耳蜗体液内羟自由基水平显著升高，自由基产生过多是引起噪声性听力损伤的一个重要原因。自由基含量增加及胞内钙离子的超载引起细胞结构、静纤毛、DNA及蛋白质的异常，最终导致细胞的坏死和凋亡。
噪声对听觉功能的影响主要表现在听觉敏感度下降、听力阈值升高、语言接受和信号辨别力变差，严重时可造成耳聋。噪声引起的听力阈移分为暂时性和永久性两种。首先出现听觉适应、暂时性听力阈移，属于可恢复的生理性改变。继续接触高强度噪声即发生永久性听力阈移，时间延长可致全频受损，甚至噪声性耳聋，属于不可恢复的改变。噪声除引起听觉损伤外还会诱发多种不良反应，如头痛、头晕、耳鸣、失眠、全身乏力等症状。
目前常用预防和治疗噪声性听力损伤的药物种类主要有：改善微循环药物，包括卡波金(含95％氧气和5％二氧化碳的混合气体)、钙离子拮抗剂类、皮质类固醇类、ATP、硝普钠、低分子右旋糖酐、银杏叶制剂、川芎、丹参和葛根素等药物；促进神经营养代谢药物，包括神经营养因子、维生素B1、维生素B12等；清除氧自由基药物，包括氧自由基清除剂、抗氧化剂SOD、维生素C、维生素E等。然而，对于逐年增加的噪声性听力损伤，至今尚无有效且针对性强的治疗药物。
发明内容
本发明要解决的技术问题是提供一种包含α-硫辛酸和尼莫地平的复方制剂，该复方制剂能有效治疗因自由基和钙离子增加引起的疾病。
此外，还需要提供一种上述复方制剂用于预防和治疗噪声性听力损伤的用途。
为了解决上述技术问题，本发明通过如下技术方案实现：
在本发明的一个方面，提供了一种复方制剂，包含α-硫辛酸和尼莫地平，所述α-硫辛酸与尼莫地平的含量比为5∶1～40∶1。
所述α-硫辛酸包括其左旋体和/或右旋体。
优选的，在每200mg～1000mg制剂单位，含α-硫辛酸40mg～400mg，尼莫地平1mg～80mg。更优选的，在每200mg～1000mg制剂单位，含α-硫辛酸80mg～200mg，尼莫地2mg～40mg。
所述复方制剂的剂型包括片剂、口崩剂、颗粒剂、或胶囊剂。
在本发明的另一方面，还提供了一种复方制剂的用途，用于制备预防噪声性听力损伤的药物。所述复方制剂用于预防噪声性听力损伤时，α-硫辛酸与尼莫地平的最佳含量比为20∶1。
在本发明的另一方面，还提供了一种复方制剂的用途，用于制备治疗噪声性听力损伤的药物。所述复方制剂用于治疗噪声性听力损伤时，α-硫辛酸与尼莫地平的最佳含量比为10∶1。
本发明复方制剂，充分利用了氧自由基清除剂α-硫辛酸和钙离子拮抗剂尼莫地平之间的协同作用，不仅提高了药效，而且减小了尼莫地平的用量，降低了副作用，改善了患者的顺应性。动物实验表明，本发明复方制剂具有很好的药效学协同作用，可用于制备预防和治疗噪声性听力损伤的复方药物。
具体实施方式
本发明复方制剂包含α-硫辛酸与尼莫地平，该α-硫辛酸与尼莫地平的含量比为5∶1～40∶1。本发明复方制剂充分利用氧自由基清除剂α-硫辛酸和钙离子拮抗剂尼莫地平之间的协同作用，在合适的剂量范围内，从引起病因的两个方面入手，达到协同治疗的效果。
优选的，本发明复方制剂，每200mg～1000mg制剂单位，含α-硫辛酸40mg～400mg，尼莫地平1mg～80mg。更优选的，在每200mg～1000mg制剂单位，含α-硫辛酸80mg～200mg，尼莫地平2mg～40mg。
实施例1 复方制剂对噪声性听力损伤的预防作用
听觉偏移实验
64只正常体重纯白色豚鼠，随机分为对照组、硫辛酸组、尼莫地平组、联合用药组，各组动物暴露倍频程噪声(4kHz中心频率)115dB SPL 4h。实验组动物暴露前2d连续给予各药物，对照组动物相应时间给予等量的生理盐水。各组动物暴露后不同时间测定豚鼠的听觉偏移，观察α-硫辛酸和尼莫地平对噪声暴露后豚鼠听觉偏移调节的协同作用。二药的协同作用采用q检验。实验结果见下表1和表2。
表1 α-硫辛酸和尼莫地平单用和合用时，对噪声暴露后豚鼠听觉偏移的影响。
在表1中，LA指α-硫辛酸、NIM指尼莫地平；平均听觉偏移变化指测定时与噪声暴露前比较；数据为平均数；*P＜0.05，**P＜0.01与对照组相比。
表2 α-硫辛酸和尼莫地平协同作用的判定。
表2是噪声暴露后，测得7日内平均听觉偏移值，以＜20dB为有效，再对二药的协同作用采用q检验。Pla＝2/8指硫辛酸组共有8只豚鼠，其中有2只显效，另外6只为无效，其余类推。
实验结果表明，当α-硫辛酸和尼莫地平以5∶1～40∶1的比例联用时，对噪声暴露后豚鼠的听觉偏移调节作用具有协同预防效果，当α-硫辛酸和尼莫地平比例为20∶1时，协同预防作用最明显。
实施例2 复方制剂对噪声性听力损伤的治疗作用
听觉偏移实验
80只正常体重纯白色豚鼠，随机分为对照组、硫辛酸组、尼莫地平组、联合用药组，各组动物暴露倍频程噪声(4kHz中心频率)115dB SPL 4h。实验组动物暴露当天至暴露后7d连续给予各药物，对照组动物相应时间腹腔注射等量的生理盐水。各组动物暴露后不同时间测定豚鼠的听觉偏移，观察α-硫辛酸和尼莫地平对噪声暴露后豚鼠听觉偏移调节的协同作用。二药的协同作用采用q检验。实验结果见下表3和表4。
表3 α-硫辛酸和尼莫地平单用和合用时，对噪声暴露后豚鼠听觉偏移的影响。
在表3中，LA指α-硫辛酸、NIM指尼莫地平；平均听觉偏移变化指测定时与噪声暴露前比较；数据为平均数；*P＜0.05，**P＜0.01各组与对照组相比。
表4 α-硫辛酸和尼莫地平协同作用的判定。
表4是噪声暴露后，测得7日内平均听觉偏移值，以＜20dB为有效，再对二药的协同作用采用q检验。Pla＝4/10指硫辛酸组共有10只豚鼠，其中有4只显效，另外6只为无效，其余类推。
实验结果表明，当α-硫辛酸和尼莫地平以5∶1～40∶1的比例联用时，对噪声暴露后豚鼠的听觉偏移调节作用具有协同治疗效果，当α-硫辛酸和尼莫地平比例为10∶1时，协同治疗作用最明显。
实施例3
每200mg～1000mg剂量单位：
α-硫辛酸∶尼莫地平 5∶1
辅料(包括崩解剂、填充剂、粘合剂、助流剂、润滑剂等) 适量
制成口崩剂或颗粒剂
制备方法：将上述处方量的尼莫地平、辅料置40摄氏度烘箱中干燥2小时，α-硫辛酸常温真空干燥2小时。然后各主要成分分别过80目筛，精密称量，等量递加混合30分钟，确定每片重量后制成口崩剂或颗粒剂。
实施例4
每200mg～1000mg剂量单位：
α-硫辛酸∶尼莫地平 10∶1
辅料(包括崩解剂、填充剂、粘合剂、助流剂、润滑剂等) 适量
胶囊
制备方法：将上述处方量的尼莫地平、辅料置40摄氏度烘箱中干燥2小时，α-硫辛酸常温真空干燥2小时。然后各主要成分分别过80目筛，精密称量，等量递加混合30分钟，确定每片重量后制成胶囊。
实施例5
每200mg～1000mg剂量单位：
α-硫辛酸∶尼莫地平 20∶1
辅料(包括崩解剂、填充剂、粘合剂、助流剂、润滑剂等) 适量
制成口崩剂或颗粒剂
制备方法：将上述处方量的尼莫地平、辅料置40摄氏度烘箱中干燥2小时，α-硫辛酸常温真空干燥2小时。然后各主要成分分别过80目筛，精密称量，等量递加混合30分钟，确定每片重量后制成口崩剂或颗粒剂。
实施例6
每200mg～1000mg剂量单位：
α-硫辛酸∶尼莫地平 40∶1
辅料(包括崩解剂、填充剂、粘合剂、助流剂、润滑剂等) 适量
制成片剂
制备方法：将上述处方量的尼莫地平、辅料置40摄氏度烘箱中干燥2小时，α-硫辛酸常温真空干燥2小时。然后各主要成分分别过80目筛，精密称量，等量递加混合30分钟，确定每片重量后直接粉末压片。
以上所述实施例仅表达了本发明的实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (9)
1.一种复方制剂，其特征在于，包含α-硫辛酸和尼莫地平，所述α-硫辛酸与尼莫地平的含量比为5∶1～20∶1。
2.根据权利要求1所述的复方制剂，其特征在于，所述α-硫辛酸选自其左旋体和/或右旋体。
3.根据权利要求1所述的复方制剂，其特征在于，在每200mg～1000mg制剂单位，含α-硫辛酸40mg～400mg，尼莫地平1mg～80mg。
4.根据权利要求3所述的复方制剂，其特征在于，在每200mg～1000mg制剂单位，含α-硫辛酸80mg～200mg，尼莫地平2mg～40mg。
5.根据权利要求1所述的复方制剂，其特征在于，所述复方制剂的剂型为片剂、颗粒剂、或胶囊剂。
6.权利要求1所述复方制剂的用途，其特征在于，用于制备预防噪声性听力损伤的药物。
7.根据权利要求6所述的用途，其特征在于，所述复方制剂中α-硫辛酸与尼莫地平的含量比为20∶1。
8.权利要求1所述复方制剂的用途，其特征在于，用于制备治疗噪声性听力损伤的药物。
9.根据权利要求8所述的用途，其特征在于，所述复方制剂中α-硫辛酸与尼莫地平的含量比为10∶1。
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| 刁明芳等.α_硫辛酸对噪声性听力损伤的保护作用观察.《中国眼耳鼻喉科杂志》.2002,第2卷(第5期),第274-277页. * |
| 刁明芳等.噪声刺激后豚鼠耳蜗抗氧化能力的变化和α_硫辛酸对声损伤的保护作用.《生理学报》.2003,第55卷(第6期),第672-676页. * |
| 尹时华等.氯丙嗪、尼莫地平在豚鼠噪声性听力损失中的保护作用.《咸宁学院学报(医学版)》.2003,第17卷(第3期),第167-170页. * |
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