CN116509993A - 一种用于防治视网膜病的药物及其制备方法 - Google Patents
一种用于防治视网膜病的药物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于防治视网膜病的药物及其制备方法,所述药物以神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐作为活性成分。本发明的药物不仅可以在保证治疗效果的同时降低药物的成本。特别是,药物活性成分以特定的比例进行给药,还可以进一步的提高治疗效果。显示了本发明的药物对于防治视网膜病具有良好的治疗作用。
Description
技术领域
本发明属于医药技术领域,具体涉及一种用于防治视网膜病的药物及其制备方法。
背景技术
视网膜是位于眼睛内部组织的光感层,其通过视神经将视觉信息传递到大脑。视网膜的中心就是所谓的黄斑,是能够区分精细详细视觉的仅有的部分。由于某些原因,例如白内障手术、玻璃体后部脱离、糖尿病增殖性视网膜病变或者创伤,视网膜可能与其下层的支持组织分离。当视网膜脱离时,视网膜被抬起或者牵拉离开其正常位置,并且离开了其血液供应及营养源。
起始的脱离可能是局部的,但是如果不接受治疗,整个视网膜可能脱离。如果其保持脱离,视网膜将会退化和失去其发挥功能的能力。如果黄斑保持脱离,中央视觉将会损失。如果未接受正确的治疗,视网膜脱离可能因此引起永久的视觉损失,并且导致失明。
另外,许多类型的视网膜病是增殖性的,最经常由新生血管化(neovascularization)或血管过度生长引起。血管生成是可能导致失明或严重视力丧失的视网膜病的前兆。糖尿病性视网膜病(DR)是糖尿病的并发症,并且是发达国家中工作年龄成人失明的主要原因。2012年全世界有超过3.71亿糖尿病患者,并且这一数字正在迅速增加。该疾病由高葡萄糖诱导的血管功能障碍和重塑引发。随后因为VEGF和其他生长因子的产生增加引起组织缺血/缺氧和后续的血管生成(新生血管化),导致增生性糖尿病性视网膜病(PDR)。此外,在糖尿病性视网膜病的病理条件下,ROS增加和Src激活是VEGF介导的内皮细胞增殖和血管渗漏的关键,VEGF介导的内皮细胞增殖和血管渗漏是糖尿病新生血管化的病理基础。由于组织纤维化,DR可进一步发展为视网膜表面上的纤维血管增生,引起视网膜脱离。
针对视网膜病,本申请的在先授权专利CN108101883B公开了一种新的化合物,其对于醛糖还原酶具有十分显著的抑制作用,甚至优于现有的醛糖还原酶抑制剂,因此对糖尿病综合症如糖尿病心脑血管病变、糖尿病肾病、糖尿病神经病变、糖尿病视网膜病变,特别是糖尿病视网膜病变具有很好的预防和治疗作用。
此外,中国授权专利CN103948581B还公开了含有左卡尼汀和L-精氨酸的药物组合物,用于联合制备治疗糖尿病视网膜病变神经损伤药物中的应用,尤其是制备治疗糖尿病视网膜病变的视网膜神经损伤和Müller细胞损伤药物中的应用。本发明通过细胞和动物实验证明,与单独使用左卡尼汀相比,联合L-精氨酸可以更加有效地保护糖尿病视网膜病变神经损伤,尤其是糖尿病视网膜病变的视网膜神经损伤和Müller细胞损伤,达到了协同增效的技术效果。
作为对视网膜病的研究,本申请的发明人之一曾探讨了神经生长因子(NGF)对大鼠视网膜缺血-再灌注损伤的保护作用。方法:将4O只SPF级Wistar大鼠随机分为4组,正常组、模型组和治疗组(NGF500BU组和NGF1000BU组),建立大鼠视网膜缺血一再灌注模型,以NGF或生理盐水干预,通过免疫组织化学法检测各组实验大鼠视网膜萎缩和视神经节细胞缺血坏死情况。结果模型组大鼠右眼在发生缺血-再灌注损伤后5d时,可见明显视网膜萎缩变化,具体表现为视网膜厚度比减少,内核层变薄。经过NGF治疗后,各治疗组大鼠右眼损伤情况得到明显修复,修复损伤的程度与NGF剂量呈正相关;治疗组大鼠右眼视网膜厚度比增加,内核层厚度也明显增加,与模型组大鼠比较差异均有统计学意义(P<O.O1)。NGF500BU组大鼠视网膜神经节变性和坏死得到明显修复,坏死神经节细胞数与模型组比较差异有统计学意义(P<0.01);NGF1000BU组大鼠视网膜坏死和变性神经节细胞数与模型组比较差异有统计学意义(P<0.01)。研究结论显示NGF球旁注射可扩散到视网膜,对视网膜缺血-再灌注损伤产生保护作用。相关的研究成果发表在中国老年学杂志2018年3月第38期。
然而,使用神经生长因子(NGF)治疗视网膜缺血-再灌注损伤,其存在成本较高的缺陷,而且其治疗效果还有待进一步提高。本发明是在该在先研究的基础上进一步研究并得以完成。
发明内容
基于上述原因,本发明提出一种用于防治视网膜病的药物及其制备方法。具体而言,为了实现本发明的目的,本发明拟采用如下的技术方案:
本发明一方面涉及一种用于防治视网膜病的药物,所述药物以神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐作为活性成分。
在本发明的一个优选实施方式中,所述神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐的用量比为500BU:5-50μg;优选地,所述用量比为500BU:10-30μg;特别优选地,所述用量比为500BU:18-22μg。
在本发明的一个优选实施方式中,所述药物组合物中还包括药学上可接受的辅料,所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
本发明中,所述活性成分在药物中的含量无特殊限制,可在很宽的范围内进行选择,通常可为质量百分比的1~20%,较佳的为质量百分比2~10%,最佳的为质量百分比5~8%。
在本发明的一个优选实施方式中,所述药物为注射制剂,其包括药学上可接受的辅料。
对于本发明的注射制剂而言,也没有特别的限定,包括但不限于注射液、冻干粉针剂等。
为了制备注射制剂形式的药物组合物,可将溶液或悬浮液消毒后(最好加入适量的氯化钠,葡萄糖或甘油等),制成与血液等渗压的针剂。在制备针剂时,也可使用本领域内任何常用的载体。例如,水,乙醇,丙二醇,乙氧基化的异硬脂醇,聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外,还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明另一方面还涉及上述药物的制备方法,其特征在于将所述神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐与药学上可接受的载体制成血液等渗压的针剂。
本发明另一方面还涉及上述药物的用途,所述药物组合物用于制备预防和/或治疗视网膜病的药物。
在本发明的一个优选实施方式中,所述视网膜病是视网膜缺血-再灌注损伤。
有益效果
实验结果表明,本发明的药物不仅可以在保证治疗效果的同时降低药物的成本。特别是,药物活性成分以特定的比例进行给药,还可以进一步的提高治疗效果。显示了本发明的药物对于防治视网膜病具有良好的治疗作用。
具体实施方式
为了进一步理解本发明,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
如无特殊说明,本发明实施例中所涉及的试剂均为市售产品,均可以通过商业渠道购买获得。
实施例1:
1材料与方法
1.1实验动物
实验用健康无眼疾的SPF级Wistar大鼠60只,雌雄各半,体重200-250g,购自哈尔滨医科大学实验动物学部;实验前在佳木斯大学实验动物中心进行适应性饲养。正常饲养,正常光照。
1.2实验试剂
水合氯醛购自天根生化科技有限公司;NGF、酒精、甲醛溶液、磷酸盐缓冲液(PBS)购自北京赛驰生物科技有限公司;SABC免疫组化试剂盒、c-fos和c-jun多克隆抗体均购自武汉博士德生物技术有限公司;其他实验所用试剂均为分析纯。
化合物1,如下式所示,按中国授权专利CN108101883B实施例所记载的合成方法制备得到。
1.3实验方法
1.3.1实验动物分组及给药
将60只SPF级健康成年Wistar大鼠随机分为6组,分别为正常组、模型组、阳性对照组(即NGF1000BU组)、实验组1(NGF 500BU+10μg化合物1)、实验组2(NGF 500BU+20μg化合物1)和实验组3(NGF 500BU+30μg化合物1),每组l0只,雌雄各半。腹腔内注射戊巴比妥钠0.04g/kg(20g/L)麻醉,眼内滴入2滴1%盐酸丁卡因角膜表面麻醉,阳性对照组和实验组1-3大鼠的右眼分别注射指定量的药物;正常组和模型组大鼠左右眼、阳性对照组和实验组1-3大鼠左眼注射同体积生理盐水;每天1次,连续4d,第2~4次给药前用***轻麻。于首次给药30min后模型组和治疗组大鼠进行视网膜缺血一再灌注造模。
1.3.2视网膜缺血-再灌注模型制备
选用一次性4号针头自角膜缘刺人大鼠右眼前房,避开血管丛,针头连接生理盐水进行灌注,升高眼压至16kPa,灌流60min后抽出针头,轻压角膜缘放出房水,眼压恢复正常,出现血流再灌注;同时随着眼压下降,眼球***,视网膜充血,瞳孔出现红光反射;滴加抗生素眼药后放回饲养笼。术后第2天观察大鼠的反应,无术眼感染,角膜浑浊,晶状体混浊,瞳孔对光反射存在,则实验动物建模成功。
1.3.3取材及组织固定
于实验第5天时将各实验组大鼠断头处死,摘取眼球后置于生理盐水中冲洗,后置于1%戊二醛和10%甲醛混合溶液中固定,后将眼球自上而下纵切至瞳孔中央,再向内、外各成120。夹角切成三等分,然后在鼻侧、颞侧、下侧各纵行切取一条组织,制成蜡块,留存备用。
1.3.4相关指标计算
通过显微镜观察记录视网膜神经部九层总厚度(简称视网膜厚度)、视网膜厚度比(损伤眼/正常眼)、内核层厚度、内核层厚度比(损伤眼/正常眼)。以正常对照眼(左眼)的神经节细胞计数为100%,计算损伤眼(右眼)正常神经节细胞、变性神经节细胞与坏死神经节细胞所占的百分率。
1.4统计学方法
采用SPSS 22.0软件进行单因素方差分析及t检验。
2结果
2.1药物对缺血大鼠视网膜萎缩的影响
模型组大鼠右眼在发生缺血-再灌注损伤后5d时,可见明显的视网膜萎缩变化,具体表现为视网膜厚度比减少(P<0.01),内核层变薄(P<O.05)。然而,经过药物治疗后,大鼠右眼缺血-再灌注损伤得到明显修复(P<0.O1)。阳性对照组大鼠右眼视网膜厚度比和内核层厚度比与正常组比较接近,但仍明显低于正常组,实验组1-3的大鼠右眼视网膜厚度比和内核层厚度比与正常组更接近,其中实验组2的大鼠右眼视网膜厚度比和内核层厚度比与正常组最接近,实验结果见表1。
表1药物对缺血大鼠视网膜萎缩的影响(x±s,n=10)
实验分组 | 视网膜厚度比 | 内核层厚度比 |
正常对照组 | 116.32±17.85 | 113.85±19.22 |
模型组 | 90.38±13.66 | 90.56±18.34 |
阳性对照组 | 111.57±12.89 | 105.36±18.74 |
实验组1 | 113.31±15.45 | 108.97±18.45 |
实验组2 | 114.48±14.37 | 111.38±17.62 |
实验组3 | 113.38±13.91 | 109.47±18.93 |
2.2药物对大鼠视网膜神经节细胞缺血坏死的保护作用
模型组大鼠右眼在发生缺血-再灌注损伤后5d时,神经节细胞发生明显变性坏死,正常神经节细胞计数显著减少(P<0.05)。与模型组比较,经过药物治疗后,大鼠视网膜神经节变性和坏死的情况得到明显修复(P<0.01)。其中,实验组2的大鼠视网膜神经节变性和坏死的情况得到更为明显的修复,实验结果见表2。
表2药物对缺血大鼠视网膜神经节细胞的影响及其病变分布(x±s,n=10)
上述结果表明,采用化合物1代替部分NGF,不仅可以在保证治疗效果的同时降低药物的成本。特别是,以实验组2的比例进行给药,还可以进一步的提高治疗效果。显示了本发明的药物对于防治视网膜病具有良好的治疗作用。
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (10)
1.一种用于防治视网膜病的药物,所述药物以神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐作为活性成分;
2.根据权利要求1所述的药物,所述神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐的用量比为500BU:5-50μg。
3.根据权利要求1所述的药物,所述神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐的用量比为500BU:10-30μg。
4.根据权利要求1所述的药物,所述神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐的用量比为500BU:18-22μg。
5.根据权利要求1所述的药物,所述药物组合物中还包括药学上可接受的辅料,所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
6.根据权利要求1-5任意一项所述的药物,所述药物为注射制剂,其包括药学上可接受的辅料。
7.根据权利要求6所述的药物,所述注射制剂选自注射液或冻干粉针剂。
8.权利要求1-7任意一项所述药物的制备方法,其特征在于将所述神经生长因子(NGF)以及式(1)所示的化合物或其药学上可接受的盐与药学上可接受的载体制成血液等渗压的针剂。
9.权利要求1-7任意一项所述药物的用途,所述药物组合物用于制备预防和/或治疗视网膜病的药物。
10.根据权利要求9所述的用途,所述视网膜病是视网膜缺血-再灌注损伤。
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