Faculty of Pharmacy, Kindai University.
Chem Pharm Bull (Tokyo). 2020;68(11):1069-1073. doi: 10.1248/cpb.c20-00540.
Ophthalmic preservatives are indispensable in eye drop formulations, but may be toxic to corneal structures. Corneal damage necessitates the discontinuation of treatment with ophthalmic solutions. Therefore, the development of a new and safe preservative system without corneal toxicity is needed. The present study investigated the effects of mannitol on the antimicrobial activities and corneal toxicities of various preservatives using Escherichia coli and a human corneal epithelial cell line (HCE-T cells). The following preservatives were examined: boric acid (BA), benzalkonium chloride (BAC), methyl parahydroxybenzoate (MP), propyl parahydroxybenzoate (PP), sodium chlorite (SC), and zinc chloride (ZC). The antimicrobial activities and HCE-T-cell toxicities of 50 µg/mL BA, MP, PP, SC, and ZC were reduced by a co-treatment with mannitol (0-300 µg/mL). The suppressed antimicrobial activities of BA, MP, PP, and SC by the co-treatment with mannitol were restored by the application of a mannitol content higher than 500 µg/mL. In contrast to these 5 preservatives, the addition of mannitol did not affect the antimicrobial activity of BAC and attenuated its HCE-T cell toxicity. Therefore, the balance between the contents of mannitol and preservatives is important in co-treatments. The present results will serve as a guide for the future development of eye drop formulations without corneal toxicity.
眼用防腐剂在滴眼剂制剂中不可或缺，但可能对角膜结构有毒性。角膜损伤需要停止使用眼用溶液进行治疗。因此，需要开发一种新的、安全的、无角膜毒性的防腐剂系统。本研究使用大肠杆菌和人角膜上皮细胞系（HCE-T 细胞）研究了甘露醇对各种防腐剂的抗菌活性和角膜毒性的影响。检查了以下防腐剂：硼酸（BA）、苯扎氯铵（BAC）、对羟基苯甲酸甲酯（MP）、对羟基苯甲酸丙酯（PP）、亚氯酸钠（SC）和氯化锌（ZC）。50μg/mL BA、MP、PP、SC 和 ZC 的抗菌活性和 HCE-T 细胞毒性在与甘露醇（0-300μg/mL）共同处理时降低。甘露醇含量高于 500μg/mL 时，BA、MP、PP 和 SC 的抗菌活性被甘露醇共同处理抑制的情况得到恢复。与这 5 种防腐剂不同，甘露醇的添加并不影响 BAC 的抗菌活性，反而减轻了其对 HCE-T 细胞的毒性。因此，甘露醇和防腐剂含量之间的平衡在共同处理中很重要。本研究结果将为未来开发无角膜毒性的滴眼剂制剂提供指导。
