CN116139067B - 透明质酸锌形成凝胶的方法及含有透明质酸锌的滴眼凝胶及其制备 - Google Patents
透明质酸锌形成凝胶的方法及含有透明质酸锌的滴眼凝胶及其制备 Download PDFInfo
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- CN116139067B CN116139067B CN202111386148.XA CN202111386148A CN116139067B CN 116139067 B CN116139067 B CN 116139067B CN 202111386148 A CN202111386148 A CN 202111386148A CN 116139067 B CN116139067 B CN 116139067B
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Abstract
本发明公开了一种使低浓度、小分子量透明质酸锌形成凝胶的方法、含透明质酸锌的抑菌滴眼凝胶及其制备,在低浓度小分子量透明质酸锌溶液中加入麦角硫因和依克多因,促进透明质酸锌形成凝胶,同时提供了含有小分子量透明质酸锌、麦角硫因和依克多因的抑菌滴眼凝胶。本发明能够使低浓度、低分子量的透明质酸锌形成凝胶剂型,所得凝胶有更好的延展性和透明性,粘度更低,提高了患者的舒适度,使用依从性好;此外,低粘度的凝胶还提高了药物成分在角膜上的渗透性,提高了药物的吸收和利用率。
Description
技术领域
本发明涉及一种使低浓度、小分子量透明质酸锌形成凝胶的方法,还涉及一种含低浓度、小分子量透明质酸锌的抑菌滴眼凝胶及其制备方法,属于眼部用品技术领域。
背景技术
角膜炎、结膜炎、眼睑炎等常见的眼部疾病大多数情况下为眼部感染引起的,眼部的感染性炎症是由于一些外源致炎因素感染引起的疾病,病原微生物包括细菌、病毒、真菌等,通常采用抗菌或抗病毒类的滴眼剂进行治疗。眼部炎症的一般临床表现为疼痛、畏明、流泪、眼睑痉挛、虹膜充血等,甚至会引起视觉减退。
滴眼液主要是通过角膜和结膜进行吸收,当药物滴入眼部,首先会渗透进入角膜内,角膜是药物渗透的主要屏障,通常所用滴眼液在眼部滞留时间短和药物利用率低。滴眼液中的药物会经鼻泪管进入鼻腔或消化道,从而被全身吸收,这增加了诱发副作用和毒性的风险。眼用凝胶剂型能够延长药物在眼部的滞留时间,防止药物进入鼻腔或消化道,但是为了满足形成凝胶的要求,成胶的高分子成分含量较高,形成的凝胶粘度较大、透明性较差,一是容易增加使用的不舒适感,降低患者的依从性,二是凝胶粘度大虽然能防止药物流失,但会降低角膜的渗透性,也不利于活性成分的有效吸收和利用。
在眼部组织中锌元素的含量很高,眼组织中锌含量与眼健康密切相关,当眼部缺乏锌元素时也会出现眼表疾病。研究表明,锌可以调整内皮细胞与血管生成相关的功能。溶液中的锌离子可以刺激内皮细胞增殖,促进受伤的单层细胞修复。锌是70多种酶的辅因子,其中一些酶参与了伤口愈合的生物过程。伤口愈合时肉芽形成以及上皮再形成过程中锌的消耗量增加。透明质酸锌中含有锌元素,具有抗微生物的作用,且小分子量的透明质酸锌会在炎症部位聚集,这说明小分子量的透明质酸锌具有更好的抗炎、抗菌作用。但是小分子量的透明质酸锌在较低浓度时不能形成凝胶,因此对炎症部位的集中作用差,利用率低。
发明内容
针对现有技术存在的不足,本发明提供了一种使低浓度、小分子量透明质酸锌形成凝胶的方法,该方法采用透明质酸锌、麦角硫因和依克多因共同作用,能够使低分子量、低浓度的透明质酸锌形成凝胶剂型,该凝胶跟高浓度大分子量的透明质酸锌凝胶相比有更好的延展性和透明性,粘度更低,也便于透明质酸锌在炎症部位的集中作用,提高了药物利用率。
本发明具体技术方案如下:
一种使低浓度、小分子量透明质酸锌形成凝胶的方法,该方法是:在低浓度小分子量透明质酸锌溶液中加入麦角硫因和依克多因,促进透明质酸锌形成凝胶。
进一步的,所述小分子量透明质酸锌的分子量为1kDa-80kDa,优选为10kDa-60kDa。
进一步的,在体系中,小分子量透明质酸锌的含量为0.5-3wt%,优选为0.5-1.5wt%。麦角硫因的含量为0.5-2wt%,优选为0.6-1wt%。依克多因的含量为0.5-2wt%,优选为1-1.5wt%。在此含量范围内,体系能形成凝胶。
本发明还提供了一种抑菌滴眼凝胶,该凝胶包括小分子量透明质酸锌、麦角硫因和依克多因;其中,透明质酸锌在抑菌滴眼凝胶中的含量为0.5-3wt%,麦角硫因在抑菌滴眼凝胶中的含量为0.5-2wt%,依克多因在抑菌滴眼凝胶中的含量为0.5-2wt%。
在实验过程中惊奇的发现,虽然小分子量、低浓度的透明质酸锌不能形成凝胶,但是当小分子量透明质酸锌与麦角硫因和依克多因复配时,低浓度的小分子量透明质酸锌能够形成凝胶,所形成的凝胶具有很好的延展性和透明性、较低的粘度和较低的降解速度,有效的避免了眼用药物随眨眼和进入鼻泪管等的流失,提高了药物在角膜的渗透性和利用率,还能降低患者在使用凝胶剂时的异物感、不适感,不会引起视线模糊,增加了患者的依从性。另外,小分子量透明质酸锌作为增稠剂、保湿剂,可以保持眼睛的湿润,同时作为抑菌剂其抑菌作用更强,麦角硫因和依克多因的加入更增强了其抑菌、杀菌的作用,并且还能够清除自由基,预防和治疗轻度白内障。
进一步的,所述小分子量透明质酸锌的分子量为1kDa-80kDa,优选为10kDa-80kDa,更优选为10kDa-60kDa。小分子透明质酸锌在抑菌滴眼凝胶中的含量优选为0.5-1.5wt%。
麦角硫因(巯基组氨酸三甲基内盐,ergothioneine,EGT)是一种晶态含硫化合物,是唯一可以在螯合金属离子的同时使组织红细胞避免遭受活性氧化物破坏的天然抗氧化剂,在组织中达到mmol/L浓度即可以激发细胞的天然抗氧化防御体系。很多的眼部疾病都是由于氧化作用引起的,例如白内障的形成原因是由于紫外线对眼球晶状体的累积辐射造成的,同时随着年龄的增长,活性氧化物使眼球中的抗氧化剂减少也会引起白内障的形成。麦角硫因既能吸收紫外线辐射,又能保护眼球中的其他抗氧化剂,并且同时具备水溶性和稳定性,因此可以将其作为眼药水原料添加入眼药水中,预防和治疗白内障。麦角硫因具有抗氧化及抗炎活性,特别是由于麦角硫因转运体的存在,使麦角硫因在某些方面比谷胱甘肽拥有更加优越的生理性能。眼病疾病中很大的一个因素是由于氧化作用,作为天然抗氧化剂的麦角硫因在治疗眼部疾病时能起到重要的作用。
进一步的,麦角硫因在抑菌滴眼凝胶中的含量优选为0.6-1wt%。
依克多因(ectoine)又名四氢甲基嘧啶羧酸,是一种小分子的环状氨基酸衍生物,与细胞内的新陈代谢相容,对细胞环境无毒,即使浓度高达100mM,并不影响细胞的生物大分子功能或生理功能,是一种重要的渗透压补偿溶质。依克多因为两性分子(-COOH、-NH2),兼具两性离子的特点,分子表面电荷分布密集且形成特殊的静电势,使其可通过与水分子之间的静电作用,进一步强化水分子之间的氢键作用,降低水活性,促进较稳定“水复合物”形成,达到保湿及长效保湿效果。依克多因能有效提高蛋白质的稳定性并保护磷脂双分子层(细胞膜)和DNA,对生物大分子的保护降低了不利环境对细胞的损伤。依克多因可降低促炎因子及炎症因子的表达,阻断炎症反应。依克多因还能够稳定泪膜,在眼表面形成一层保护膜,降低泪液的蒸发率,对眼损伤具有修护作用;维持角膜的湿润性以及防止角膜脱水,在眨眼及眼球转动时起到润滑的作用,减少眨眼的频率,减轻眼睛干燥的症状,促进角膜上皮细胞迁移,减少眼部炎症,改善滴眼液中防腐剂的毒性作用。
进一步的,依克多因在抑菌滴眼凝胶中的含量优选为1-1.5wt%。
进一步的,上述抑菌滴眼凝胶除了抑菌成分外,还包括防腐剂、渗透压调节剂、缓冲盐、pH调节剂、水等成分中的一种或多种。这些成分可以根据现有滴眼液以及眼部护理产品中公开的配方中进行选择。
进一步的,所述防腐剂为羟苯乙酯钠,其水溶性好,抑菌效果明显。羟苯乙酯钠的添加量优选为0.005-0.01wt%,低于一般滴眼液的使用量,从而降低了防腐剂对眼部的刺激以及毒性。
进一步的,所述渗透压调节剂为氯化钠、氯化钾中的一种或两种,所述缓冲盐为硼酸-硼砂、磷酸氢二钠和磷酸二氢钠、柠檬酸-柠檬酸钠,所述pH调节剂为无机酸或无机碱。渗透压调节剂、缓冲盐和pH调节剂起到稳定pH值和渗透压的作用。通过这些成分用量的控制,保证本发明抑菌滴眼凝胶的渗透压为260-340mOsm/L,pH为5.5-7.5。优选的,本发明抑菌滴眼凝胶的渗透压为280-310mOsm/L。
进一步的,水为溶剂,其用量补足余量,使各成分含量满足要求。
在本发明某一具体实施方式中,提供了一种抑菌滴眼凝胶的具体配方,如下:小分子量透明质酸锌0.5-3wt%、麦角硫因0.5-2wt%、依克多因0.5-2wt%、羟苯乙酯钠0.005~0.01wt%、渗透压调节剂0.6-0.9wt%、缓冲盐0.3-1wt%,水余量。
本发明还提供了上述抑菌滴眼凝胶的制备方法,包括以下步骤:
(1)将除小分子量透明质酸锌外的其他成分混合均匀,得到pH和渗透压符合要求的混合液;
(2)在搅拌下将小分子量透明质酸锌加入上述混合液中,搅拌至充分溶解,得到抑菌滴眼凝胶。
进一步的,步骤(2)中,在40-50℃下加入小分子量透明质酸锌,并搅拌至充分溶解。
本发明提供了一种使低浓度、小分子量透明质酸锌形成凝胶的方法,将小分子量透明质酸锌、麦角硫因和依克多因复配,可以使低浓度小分子量透明质酸锌形成凝胶,克服了现有眼部凝胶产品的不足。与现有技术相比,本发明具有如下有益效果:
(1)采用透明质酸锌、麦角硫因和依克多因共同作用,能够使低浓度、低分子量的透明质酸锌形成凝胶剂型。该凝胶跟高浓度大分子量的透明质酸锌凝胶相比有更好的延展性和透明性,粘度更低,提高了患者的舒适度,使用依从性好;此外,低粘度的凝胶还提高了药物成分在角膜上的渗透性,提高了药物的吸收和利用率。
(2)透明质酸锌、麦角硫因和依克多因形成的凝胶能够迅速的在眼表形成膜,持续的为患处提供治疗作用,延长了在眼部的滞留时间。
(3)本发明抑菌滴眼凝胶对金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌和白色念珠菌具有很好的抗菌作用。低分子量透明质酸锌与高分子量透明质酸锌相比抑菌作用更强,麦角硫因和依克多因的加入更增强了其抑菌、杀菌的作用,并且还能够清除自由基,稳定泪膜,减少泪液的蒸发,预防和治疗轻度白内障。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施方式,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施方式仅用以解释本发明,并不用于限定本发明。
下述实施例中,所用各原料均为市售产品,其中透明质酸锌、麦角硫因、依克多因均来自华熙生物科技股份有限公司。
实施例1-13及对比例1-5
1、按照表1中的配方表,称取各原料。
表1各实施例以及对比例的配方表(wt%)
2、将麦角硫因、依克多因加入注射用水中,搅拌至充分溶解;
3、将透明质酸锌边搅拌边缓慢加至上述溶液中,升温至45℃,搅拌至充分溶解,最后分别用0.45μm、0.22μm滤膜过滤除菌,得产品。
在实验过程中观察各实施例和对比例产品的外观情况,其中,各实施例和对比例的产品外观均无色透明,而且实施例1-8、10-13和对比例5的产品均形成了不同程度的粘性胶体,即凝胶。而对比例2-4由于没有麦角硫因和依克多因的协同作用,不能形成凝胶,对比例1由于透明质酸锌含量过低,即使有麦角硫因和依克多因的协同作用,也不能形成凝胶。
采用运动粘度计测试各产品的粘度,结果如下表2所示:
表2
从上述结果可以看出,所有实施例的产品的粘度在56mm2/s以下,均低于对比例5的产品粘度,这说明本发明实施例的产品有更好的延展性和透明性,提高了患者的舒适度,使用依从性好。
低粘度的凝胶可以提高药物成分在角膜上的渗透性和储留,使药物的吸收和利用率提高。从实施例1-5、对比例2-4可以看出,单独的低分子量、低含量的透明质酸锌很难形成凝胶,通过一定比例的麦角硫因和依克多因的协同复配,可以使低分子量、低含量的透明质酸锌形成低粘度的凝胶,提高药物成分在角膜上的渗透性和储留,使药物的吸收和利用率提高。
凝胶的粘度和透明质酸锌的分子量有较大关系,从实施例5-9、对比例5可以看出,随着透明质酸锌分子量增加,产品的粘度也逐渐增加,当透明质酸锌分子量较低时,形成的凝胶的粘度较低,但是当透明质酸锌分子量过低时,即使与麦角硫因和依克多因复配也不能形成凝胶。
样品1-13及对比样品1-5
1、配制抑菌滴眼样品,其各原料配方如下表3所示:
表3各样品的配方表(wt%)
2、称取配方量的各原料,将麦角硫因、依克多因、羟苯乙酯钠、氯化钠和硼酸、硼砂加入到90%的注射用水中,然后补足余量注射用水,搅拌至充分溶解;
3、将透明质酸锌边搅拌边缓慢加至上述溶液中,升温至45℃,搅拌至充分溶解,最后分别用0.45μm、0.22μm滤膜过滤除菌,得抑菌滴眼样品。所得样品pH值在5.5-7.5之间,渗透压在260-340mOsm/kg之间。
上述样品1-13和对比样品1-5的各产品外观均无色透明,而且样品1-8、10-13和对比样品5的产品均形成了不同程度的粘性胶体,即凝胶,而对比样品1-4的产品未形成凝胶。
试验例
1、刺激性试验
以新西兰家兔为实验对象,随机分为18组,每组6只,每组兔子的年龄、体重无明显差异。每组分别用样品1-13和对比样品1-5制备的抑菌滴眼产品进行试验,组里每只兔子的左眼滴入抑菌滴眼产品,右眼为空白对照,滴入等量的注射用水。
各组兔子每日滴加一次受试物,连续观察30天,并记录给药1小时后和给药前眼部的反应和状态。
眼部刺激反应评分标准和眼刺激评价标准如表4和表5所示:
表4:眼部刺激反应评分标准
表5:眼刺激评价标准
刺激程度 | 积分 |
无刺激性 | 0-3 |
轻度刺激性 | 4-8 |
中度刺激性 | 9-12 |
强度刺激性 | 13-16 |
实验结果:
将各组兔子的实验结果取平均值,作为该组的实验结果。第1天、第7天、第15天、第30天滴眼后各处理组的刺激性考察结果如表6所示,最终每组分数四舍五入取整数计数。
表6眼刺激性实验结果
结果表明:低粘度凝胶与高粘度凝胶相比,对眼部具有较低的刺激性;同时,依克多因和麦角硫因具有去刺激的作用,添加依克多因或麦角硫因后能有效的减轻眼用凝胶对眼部的刺激作用,减少因使用滴眼凝胶产生的不适感。
2、抑菌效力实验
以大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌、白色念珠菌为试验菌株,采用抑菌率来验证产品的抑菌效果。
配制实验用菌悬液,铜绿假单胞菌、金黄色葡萄球菌、大肠埃希菌、白色念珠菌用琼脂培养基培养。加入适量的0.9%无菌氯化钠溶液将琼脂表面的培养物洗脱,并将菌悬液移至无菌试管内,用0.9%无菌氯化钠溶液稀释并制成每1ml含菌数约为108cfu的菌悬液。取0.5ml试验用菌悬液于试管中,再加入0.5ml有机干扰物质(3%牛血清蛋白溶液),混匀,置20℃±1℃水浴中5min后,用无菌吸管分别吸取上述样品1-13和对比样品1-5的产品各4.0ml注入其中,迅速混匀并立即记时。
待试验菌与各实施例及对比例的样品相互作用至各预定时间后,分别吸取0.5ml试验菌与样品混合液加于4.5ml经灭菌的中和剂中,混匀。各管试验菌与样品混合液经加中和剂作用10min后,分别吸取1.0ml样液,按活菌培养计数方法测定存活菌数,每管样液接种2个平皿即可。如平板上生长的菌落数较多时,可进行系列10倍稀释后,再进行活菌培养计数。同时用稀释液代替样品,进行平行试验,作为对照。
所有试验样本均在37℃温箱中培养,对细菌繁殖体培养48h观察最终结果;对细菌芽孢需培养72h观察最终结果。试验重复3次,计算各组的活菌数,然后按下式计算抑菌率:
抑菌率=(对照组活菌数-试验组活菌数)/对照组活菌数×100%。
表7抑菌效果实验结果
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抑菌效力实验结果表明:添加透明质酸锌的各实施例产品有很好的抗微生物的作用,一方面体现在透明质酸锌对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌、白色念珠菌的生长繁殖有一定的抑制作用,另一方面,加入依克多因、麦角硫因后能够增强透明质酸锌的抑菌效果。
3、滞留时间实验
向样品5和对比样品1-4的抑菌滴眼产品中加入2%的荧光素钠,充分混匀。取5组新西兰兔,每组5只,每组兔子分别使用样品5和对比样品1-4的抑菌滴眼产品。拉开兔眼的一侧眼皮,向兔眼中分别滴加不同的抑菌滴眼产品30μL,将兔眼手动闭合10s。之后每2min用紫外灯照射眼部,观察眼角膜表面连续荧光层的强弱,连续荧光层消失的时间计为眼部滞留时间。连续测定3次,取平均值为眼部滞留时间。
表8抑菌滴眼产品在兔眼滞留时间
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从上述结果可以看出,本发明抑菌滴眼产品在兔眼的滞留时间明显延长,低分子量的透明质酸锌加入麦角硫因和依克多因后可形成缓释性更好的凝胶,增加在眼部的作用时间,提高眼用凝胶的生物利用率。
Claims (11)
1.一种使低浓度、小分子量透明质酸锌形成凝胶的方法,其特征是:在低浓度小分子量透明质酸锌溶液中加入麦角硫因和依克多因,促进透明质酸锌形成凝胶;小分子量透明质酸锌的含量为0.5-3wt%,小分子量透明质酸锌的分子量为10kDa-80kDa,麦角硫因的含量为0.5-2wt%,依克多因的含量为0.5-2wt%。
2.根据权利要求1所述的方法,其特征是:小分子量透明质酸锌的含量为0.5-1.5wt%;麦角硫因的含量为0.6-1wt%;依克多因的含量为1-1.5wt%。
3.根据权利要求1所述的方法,其特征是:所述小分子量透明质酸锌的分子量为10kDa-60kDa。
4.一种抑菌滴眼凝胶,其特征是:包括小分子量透明质酸锌、麦角硫因和依克多因;其中,小分子量透明质酸锌的含量为0.5-3wt%,麦角硫因的含量为0.5-2wt%,依克多因的含量为0.5-2wt%,所述小分子量透明质酸锌的分子量为10kDa-80kDa。
5.根据权利要求4所述的抑菌滴眼凝胶,其特征是:小分子量透明质酸锌的含量为0.5-1.5wt%。
6.根据权利要求4或5所述的抑菌滴眼凝胶,其特征是:所述小分子量透明质酸锌的分子量为10-60kDa。
7.根据权利要求4或5所述的抑菌滴眼凝胶,其特征是:麦角硫因的含量为0.6-1wt%;依克多因的含量为1-1.5wt%。
8.根据权利要求4所述的抑菌滴眼凝胶,其特征是:还包括防腐剂、渗透压调节剂、缓冲盐、pH调节剂和水中的一种或多种。
9.根据权利要求8所述的抑菌滴眼凝胶,其特征是:所述防腐剂为羟苯乙酯钠,含量为0.005-0.01wt%;所述渗透压调节剂为氯化钠、氯化钾中的一种或两种,含量保证抑菌滴眼凝胶的渗透压为260-340mOsm/L;所述缓冲盐为硼酸盐缓冲液、磷酸磷酸盐缓冲液或柠檬酸盐缓冲液,含量为0.3-1%;所述pH调节剂为无机酸或无机碱,保证抑菌滴眼凝胶的pH为5.5-7.5。
10.一种权利要求4-9中任一项所述的抑菌滴眼凝胶的制备方法,其特征是包括以下步骤:
(1)将除小分子量透明质酸锌外的其他成分混合均匀,得到pH和渗透压符合要求的混合液;
(2)在搅拌下将小分子量透明质酸锌加入上述混合液中,搅拌至充分溶解,得到抑菌滴眼凝胶。
11.根据权利要求10所述的制备方法,其特征是:在40-50℃下加入小分子量透明质酸锌,并搅拌至充分溶解。
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---|
透明质酸钠对眼用温度敏感原位凝胶体外释放和粘附力的影响;鞠凤阁;朱照静;马俐丽;;中国新药杂志;20090715(第13期);全文 * |
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