CN110496215A - 一种治疗老视的水性滴眼液及其制备方法 - Google Patents
一种治疗老视的水性滴眼液及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种治疗老视的水性滴眼液及其制备方法,以重量组分计,包括0.5‑1份的卡巴胆碱或其药学上可接受的盐、2~4份的α‑硫辛酸、0.05~0.2份重组人表皮生长因子、100份载体液、0.001~0.003份的抑菌剂、调节组合物pH介于7~7.5的pH调节剂、调节组合物渗透压介于200m~660mOsm/kg的渗透压调节剂、调节组合物粘度介于4.0~5.0cPa·s的粘度调节剂,通过滴用本发明的滴眼液,可以在短时间内降低老光度数以对抗老视,改善近视力,在一定程度上摆脱对老花镜的依赖,还可以通过α‑硫辛酸的抗氧化作用,软化晶状体,逐渐改善眼部调节功能,消除部分老花眼。
Description
技术领域
本发明涉及眼科药物技术领域,具体涉及一种治疗老视的水性滴眼液及其制备方法。
背景技术
随着年龄的增长,人体的眼调节能力逐渐下降从而引起患者视近困难,必须在其静态屈光矫正之外另加凸透镜才能有清晰的近视力,这种现象称为老视,本质是一种身体机能逐渐退化的现象。老视眼的发生和发展与年龄直接相关大多出现在45岁以后,其发生迟早和严重程度还与其他因素有关,如原先的屈光不正状况、身高阅读习惯、照明以及全身健康状况等。
据统计,全球约有11亿老视患者,在35岁及以上人群中的发病率高达35.6%,40岁及以上人群中的发病率高达40.3%,主要的临床表现有以下几种:(1)感觉自己手臂太短了,伸长手臂也看不清手中的物体或书籍;(2)日照或灯光很好时没有阅读问题,黄昏或灯光昏暗时,突然看不清除书上的字;(3)视疲劳症状:看书一会儿,就出现字迹模糊,或者头疼、眼酸或嗜睡等,之后就出现明显近距阅读不清、或无法阅读的感觉了;(4)原先近视者阅读时喜欢把原来的近视眼睛摘掉,但是由于度数有高低,有双眼屈光参差,有散光等,靠单纯摘掉眼睛来阅读时,还会伴有许多不适;(5)原先有远视者往往比一般人更早出现老视。
临床上一般采用验光配镜的方法矫正老视花眼,也就是常说的阅读眼镜,适合阅读时临时性佩戴,不能看中等距离的物体;如果要看中等距离的物体,需要验光时调节并降低花镜的度数。在日常生活和工作中,近视或远视者必须有两副眼镜在更替使用,非常不方便,而且该矫正方案无法对老视进行病理性的根治或缓解。目前还没有商品化的治疗老视的滴眼液,所以提供一种使用方便、能够调节进步调节能力的老视专用滴眼液是临床上亟待解决的问题。
发明内容
本发明的目的在于克服上述现有技术的缺点,提供一种治疗老视的水性滴眼液及其制备方法,通过滴用本滴眼液,不仅可以对抗老视,降低老光度数,改善近视力,在一定程度上摆脱对老花镜的依赖。还可以通过α-硫辛酸的抗氧化作用,软化晶状体,逐渐改善眼部调节功能,消除部分老花眼,提高近视力。
为实现上述目的,本发明提供如下技术方案:
一种治疗老视的水性滴眼液,以重量组分计,包括0.5-1份的卡巴胆碱或其药学上可接受的盐、2~4份的α-硫辛酸、0.05~0.2份重组人表皮生长因子、100份载体液、0.001~0.003份的抑菌剂、调节组合物pH介于7~7.5的pH调节剂、调节组合物渗透压介于200m~660mOsm/kg的渗透压调节剂,调节组合物粘度介于4.0~5.0cPa·s的粘度调节剂;
本发明的突出创新点是联用了卡巴胆碱、α-硫辛酸、重组人表皮生长因子三种有效成分,卡巴胆碱是人工合成的拟胆碱药,能直接作用于瞳孔括约肌产生即刻的缩瞳效果,同时具有抗胆碱酯酶作用,能维持较长的缩瞳时间,产生“小孔成像效应”,可以有效的降低老视状态,减少老视度数,改善近视力;α-硫辛酸是一种存在于线粒体的辅酶,能消除导致加速老化与致病的自由基,硫辛酸是国际公认的“万能抗氧化剂”,兼具脂溶性与水溶性的特性,因此可以在全身通行无阻,到达任何一个细胞部位,提供人体全面效能,它带有8个碳的链和含有两个相邻硫原子的杂环,极易提供一个或两个氢原子,它被细胞快速吸收且转化成二氢硫辛酸盐DHLA,能够俘获自由基,螯合金属,重新生成维生素E和C,增加细胞中的谷胱甘肽,抑制基因表达,抑制黄嘌呤氧化酶,所以α-硫辛酸是治疗和预防人浅层眼病特别有利的活性组分;重组表皮生长因子本质是一种在分子水平上调节细胞代谢的小分子多肽,具有激活表皮细胞、内皮细胞、成纤维细胞、促进角膜修复的作用,针对老年人,重组表皮生长因子通过激活细胞膜上的受体,主动对受损的角膜、晶状体进行修复,提高整体眼睛的调节能力,有效改善老视。
优选地,以重量组分计,还包括0.6~1.2份天然冰片、0.05~0.2份透明质酸钠、0.8~1.3份牛磺酸、0.4~0.8份维生素B6、0.8~1.3份维生素B12,其中天然冰片,又名右旋龙脑,可以清凉醒神、缓解眼部疲劳,用在滴眼液里还具有增强产品的杀菌力、防霉防腐的作用;透明质酸钠是一种眼部良好的润滑成分,可以保护角膜内皮、虹膜、晶状体和视网膜,防止老年人眼膜黏连或过度干涩;牛磺酸是一种含硫氨基酸,是视网膜的主要构成氨基酸,可以在房水和玻璃体中防止蛋白质的糖化和氧化,对于老年人的眼部具有很好的疏解作用;维生素B6、维生素B12皆是营养补充剂,是针对老年人群的添加成分。
优选地,所述pH调节剂采用硼酸缓冲液、磷酸缓冲液、硼酸盐缓冲液的一种,其中效果最好的为磷酸盐缓冲液,为了避免对眼部的刺激以及使活性成分处于能够发挥最大药效的环境中,所以利用pH调整剂将整体滴眼液的pH调整至中性范围,其中磷酸盐缓冲液的效果最好。
优选地,所述渗透压调节剂采用氯化钠、硼酸、硼砂的一种,其中效果最好的是氯化钠,当滴眼液的整体渗透压和眼球差距过大时,不易吸收,同时由于眼球对渗透压有一定的耐受范围,所以调整可以不必非常精准,其中采用氯化钠进行调整效果最好。
优选地,所述粘度调节剂为采用MC、PEG、PVA、PVP的一种,其中最好的PEG,可利用粘度调节剂将滴眼液的整体粘度调整至合适区间,方便患者滴入眼睛。
优选地,所述抑菌剂为以下的一种或多种:醋酸苯汞、硫柳汞、苯扎溴铵、三叔丁醇,其中效果最好的是苯扎溴铵,由于滴眼液并非一次性使用,所以需要加入抑菌剂,适合本发明滴眼液pH以及不与活性成分产生配伍禁忌的抑菌剂具有多种,其中效果最好的是苯扎溴铵。
优选地,以重量组分计,还包括1.2~2份的复合氨基酸,所述复合氨基酸具体为赖氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸、缬氨酸的等比例混合物,所述复合氨基酸主要用于补充老年人的眼部营养,特别选择的是人体必需氨基酸的复合剂。
一种制备上述眼元素滴眼液的制备方法:
(a)称取0.5-1份的卡巴胆碱或其药学上可接受的盐、2~4份的α-硫辛酸充分溶解于10份的载体液中,为制备液A;
(b)称取0.6~1.2份天然冰片碾磨至粒径≤5mm,充分溶解于10份的载体液中,为制备液B;
(c)称取0.05~0.2份透明质酸钠、0.8~1.3份牛磺酸、0.4~0.8份维生素B6、0.8~1.3份维生素B12、1.2~2份的复合氨基酸充分溶解于10份的载体液中,为制备液C;
(d)将制备液A、制备液B、制备液C充分混合,并加入0.05~0.2份重组人表皮生长因子、能使组合物pH介于7~7.5的pH调节剂、能使组合物渗透压介于200m~660mOsm/kg的渗透压调节剂、能使组合物粘度介于4.0~5.0cPa·s的粘度调节剂、0.001~0.003份的抑菌剂,最后加入70份载体液。
与现有技术相比,本发明的有益效果是:(1)添加“万能抗氧化剂”硫辛酸,它带有8个碳的链和含有两个相邻硫原子的杂环,极易提供一个或两个氢原子,它被细胞快速吸收且转化成二氢硫辛酸盐DHLA,能够俘获自由基,螯合金属,重新生成维生素E和C,是治疗和预防人浅层眼病特别有利的活性组分;
(2)添加具有缩瞳效果的卡巴胆碱,能直接作用于瞳孔括约肌产生即刻的缩瞳效果,同时具有抗胆碱酯酶作用,能维持较长的缩瞳时间,可以有效的降低老视状态,减少老视度数,改善近视力;
(3)添加重组表皮生长因子,生长因子通过与细胞膜上的受体结合,促进细胞的分化、增殖、分泌、移行与细胞间质有机整合完成组织修复,完成分子细胞学水平上的主动修复;
(4)通过维生素、牛磺酸、复合氨基酸的添加,增加眼部的营养元素,能够修复角膜、调节晶状体,给老年人群的眼部提供足够的营养;
(5)整体滴眼液的粘度、渗透压接近天然泪液,并添加天然冰片、透明质酸钠等醒神、润滑的成分,可以缓解眼部疲劳,增加湿润度,缓解老年人的眼部干涩问题。
附图说明
图1为α-硫辛酸结构示意图;
图2为卡巴胆碱结构示意图。
具体实施方式
下面将结合本发明实施例中的附图,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。
本发明的突出创新点是联用了卡巴胆碱、α-硫辛酸、重组人表皮生长因子三种有效成分,卡巴胆碱是人工合成的拟胆碱药,能直接作用于瞳孔括约肌产生即刻的缩瞳效果,同时具有抗胆碱酯酶作用,能维持较长的缩瞳时间,产生“小孔成像效应”,可以有效的降低老视状态,减少老视度数,改善近视力;α-硫辛酸是一种存在于线粒体的辅酶,能消除导致加速老化与致病的自由基,硫辛酸是国际公认的“万能抗氧化剂”,兼具脂溶性与水溶性的特性,因此可以在全身通行无阻,到达任何一个细胞部位,提供人体全面效能,它带有8个碳的链和含有两个相邻硫原子的杂环,极易提供一个或两个氢原子,它被细胞快速吸收且转化成二氢硫辛酸盐DHLA,能够俘获自由基,螯合金属,重新生成维生素E和C,增加细胞中的谷胱甘肽,抑制基因表达,抑制黄嘌呤氧化酶,所以α-硫辛酸是治疗和预防人浅层眼病特别有利的活性组分;重组表皮生长因子本质是一种在分子水平上调节细胞代谢的小分子多肽,具有激活表皮细胞、内皮细胞、成纤维细胞、促进角膜修复的作用,针对老年人,重组表皮生长因子通过激活细胞膜上的受体,主动对受损的角膜、晶状体进行修复,提高整体眼睛的调节能力,有效改善老视。
一种治疗老视的水性滴眼液,以重量组分计,包括0.5-1份的卡巴胆碱或其药学尚可接受的盐、2~4份的α-硫辛酸、0.05~0.2份重组人表皮生长因子、100份载体液、所述载体液为无菌注射用水;还包括0.6~1.2份天然冰片、0.05~0.2份透明质酸钠、0.8~1.3份牛磺酸、0.4~0.8份维生素B6、0.8~1.3份维生素B12,其中天然冰片,又名右旋龙脑,从樟科植物的新鲜枝、叶经提取加工制成,气味芬芳,可以清凉醒神、缓解眼部疲劳,用在滴眼液里还具有增强产品的杀菌力、防霉防腐的作用;透明质酸钠是一种眼部良好的润滑成分,可以保护角膜内皮、虹膜、晶状体和视网膜,防止老年人眼膜黏连或过度干涩;牛磺酸是一种含硫氨基酸,是视网膜的主要构成氨基酸,可以在房水和玻璃体中防止蛋白质的糖化和氧化,对于老年人的眼部具有很好的疏解作用;维生素B6、维生素B12皆是营养补充剂,是针对老年人群的添加成分。
本滴眼液还包括0.001~0.003份的抑菌剂,所述抑菌剂为以下的一种或多种:醋酸苯汞、硫柳汞、苯扎溴铵、三叔丁醇,其中效果最好的是苯扎溴铵,由于滴眼液并非一次性使用,所以需要加入抑菌剂,适合本发明滴眼液pH以及不与活性成分产生配伍禁忌的抑菌剂具有多种,其中效果最好的是苯扎溴铵。
本滴眼液还包括调节组合物pH介于7~7.5的pH调节剂,所述pH调节剂采用硼酸缓冲液、磷酸缓冲液、硼酸盐缓冲液的一种,其中效果最好的为磷酸盐缓冲液,为了避免对眼部的刺激以及使活性成分处于能够发挥最大药效的环境中,所以利用pH调整剂将整体滴眼液的pH调整至中性范围,其中磷酸盐缓冲液的效果最好,原液以无水磷酸二氢钠8g配成1000ml溶液,无水磷酸氢二钠9.437g配成1000ml溶液,可调整pH的范围是5.9-8.0。
本滴眼液还包括调节组合物渗透压介于200m~660mOsm/kg的渗透压调节剂,所述渗透压调节剂采用氯化钠、硼酸、硼砂的一种,其中效果最好的是氯化钠,当滴眼液的整体渗透压和眼球差距过大时,不易吸收,同时由于眼球对渗透压有一定的耐受范围,所以调整可以不必非常精准,其中采用氯化钠进行调整效果最好。
本滴眼液还包括调节组合物粘度介于4.0~5.0cPa·s的粘度调节剂,所述粘度调节剂为采用MC、PEG、PVA、PVP的一种,其中最好的PEG,可利用粘度调节剂将滴眼液的整体粘度调整至合适区间,方便患者滴入眼睛
本滴眼液还包括1.2~2份的复合氨基酸,所述复合氨基酸具体为赖氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸、缬氨酸的等比例混合物,所述复合氨基酸主要用于补充老年人的眼部营养,特别选择的是人体必需氨基酸的复合剂。
一种制备上述眼元素滴眼液的制备方法:
(a)称取0.5-1份的卡巴胆碱或其药学尚可接受的盐、2~4份的α-硫辛酸充分溶解于10份的灭菌注射用水中,为制备液A;
(b)称取0.6~1.2份天然冰片碾磨至粒径≤5mm,充分溶解于10份的灭菌注射用水中,为制备液B;
(c)称取0.05~0.2份透明质酸钠、0.8~1.3份牛磺酸、0.4~0.8份维生素B6、0.8~1.3份维生素B12、1.2~2份的复合氨基酸充分溶解于10份的灭菌注射用水中,为制备液C;
(d)将制备液A、制备液B、制备液C充分混合,并加入0.05~0.2份重组人表皮生长因子、能使组合物pH介于7~7.5的pH调节剂、能使组合物渗透压介于200m~660mOsm/kg的渗透压调节剂、能使组合物粘度介于4.0~5.0cPa·s的粘度调节剂、0.001~0.003份的抑菌剂,最后加入70份灭菌注射用水。
该品禁用于有心血管疾患包括心律不齐、心搏徐缓、低血压的病人以及迷走神经兴奋、癫痫、甲亢、帕金森病、支气管哮喘、消化道溃疡和尿路梗塞的病人。
1.禁忌症(1)对本药过敏。(2)缩瞳功能不良,如急性虹膜炎。(3)甲状腺功能亢进。(4)低血压。(5)消化性溃疡。(6)支气管哮喘。(7)心律失常等心脏病。(8)癫痫。(9)震颤麻痹。(10)闭角型青光眼。(11)机械性肠梗阻。(12)尿路梗阻、痉挛等。
2.慎用(1)有视网膜剥离史者。(2)角膜擦伤者(本药可能被大量吸收)。(3)近期发生过心肌梗死者。(4)原发性高血压患者。(5)胃肠道痉挛。
3.药物对妊娠的影响尚不清楚本药是否对胎儿有害,妊娠期间使用应权衡利弊。
4.药物对哺乳的影响尚不清楚本药是否分泌入乳汁,哺乳期妇女慎用。
实施例:
按上述制备三种不同的滴眼剂,其成分和主要活性成分如表1所示;
表1 三种滴眼剂的生产成分、活性成分表
表2 三种滴眼剂的一般性状表
动物刺激性试验:
以健康家兔作为研究对象进行动物实验,随机等分为3组:空白对照、对照组和实验组1#、实验组2#、实验组3#,对于实验组1#、实验组2#、实验组3#,采用单剂量给药方式,每次给药50μl;空白对照组不进行给药,实验组以相同剂量的生理盐水进行给药;分别在单次给药后的2小时进行裂隙灯检查,并按照Draize刺激性实验评分标准对角膜浑浊程度、结膜的充血、水肿及分泌物、虹膜充血或初学进行评分,并进行刺激性评级,整体结果表明:1#、2#、3#型滴眼剂对动物眼部刺激性评分小于3,可认为无明显刺激性,动物实验具有很好的耐受性。
人体实验:
选取50-70周岁,老视度数在2.0D以上的患者共60人随机分为3组,进行充分告知并签署实验知情同意书后,利用1#、2#、3#型滴眼液进行滴眼,并在25分钟后再次测试视力;
对于施用1#型滴眼液的A组,施用前患者的平均老视度数为3.2D,施用25分钟后老视度数减轻0.60±0.8D;
对于施用2#型滴眼液的B组,施用前患者的平均老视度数为3.5D,施用25分钟后老视度数减轻0.55±1.2D;
对于施用1#型滴眼液的A组,施用前患者的平均老视度数为3.3D,施用25分钟后老视度数减轻0.70±1.5D;
证明该滴眼液可以在短时间内提高老视患者的视力,且以3#型配方的效果最好,经测试三组滴眼液给药后药物作用长达6-8个小时,基本满足白天的视力需要。
Claims (8)
1.一种治疗老视的水性滴眼液,其特征在于:以重量组分计,包括0.5-1份的卡巴胆碱或其药学上可接受的盐、2~4份的α-硫辛酸、0.05~0.2份重组人表皮生长因子、100份载体液、0.001~0.003份的抑菌剂、调节组合物pH介于7~7.5的pH调节剂、调节组合物渗透压介于200m~660mOsm/kg的渗透压调节剂、调节组合物粘度介于4.0~5.0cPa·s的粘度调节剂。
2.根据权利要求1所述的一种治疗老视的水性滴眼液,其特征在于:所述pH调节剂采用硼酸缓冲液、磷酸缓冲液、硼酸盐缓冲液中的任意一种,其中效果最好的为磷酸盐缓冲液。
3.根据权利要求1所述的一种治疗老视的水性滴眼液,其特征在于:所述渗透压调节剂采用氯化钠、硼酸、硼砂中的任意一种,其中效果最好的是氯化钠。
4.根据权利要求1所述的一种治疗老视的水性滴眼液,其特征在于:所述粘度调节剂为采用MC、PEG、PVA、PVP中的任意一种,其中效果最好的PEG。
5.根据权利要求1所述的一种治疗老视的水性滴眼液,其特征在于:所述抑菌剂为以下的一种或多种:醋酸苯汞、硫柳汞、苯扎溴铵、三叔丁醇,其中效果最好的是苯扎溴铵。
6.根据权利要求1-5任一所述的一种治疗老视的水性滴眼液,其特征在于:以重量组分计,还包括1.2~2份的复合氨基酸,所述复合氨基酸具体为赖氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸、缬氨酸的一种或多种。
7.根据权利要求1-5任一所述的一种治疗老视的水性滴眼液,其特征在于:以重量组分计,还包括1.2~2份的复合氨基酸,所述复合氨基酸具体为赖氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸、缬氨酸的等重量比例的混合物。
8.一种权利要求7所述的治疗老视的水性滴眼液的制备方法:
(a)称取0.5-1份的卡巴胆碱或其药学尚可接受的盐、2~4份的α-硫辛酸充分溶解于10份的载体液中,为制备液A;
(b)称取0.6~1.2份天然冰片碾磨至粒径≤5mm,充分溶解于10份的载体液中,为制备液B;
(c)称取0.05~0.2份透明质酸钠、0.8~1.3份牛磺酸、0.4~0.8份维生素B6、0.8~1.3份维生素B12、1.2~2份的复合氨基酸充分溶解于10份的载体液中,为制备液C;
(d)将制备液A、制备液B、制备液C充分混合,并加入0.05~0.2份重组人表皮生长因子、能使组合物pH介于7~7.5的pH调节剂、能使组合物渗透压介于200m~660mOsm/kg的渗透压调节剂、能使组合物粘度介于4.0~5.0cPa·s的粘度调节剂、0.001~0.003份的抑菌剂,最后加入70份载体液。
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