Kikuchi Takayuki, Suzuki Masahiko, Kusai Akira, Iseki Ken, Sasaki Hitoshi
Pharmaceutical Development Laboratories, Sankyo Co., Ltd. 1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan.
Int J Pharm. 2005 Feb 16;290(1-2):83-9. doi: 10.1016/j.ijpharm.2004.11.019. Epub 2005 Jan 13.
In order to investigate the effects of EDTA and boric acid (EDTA/boric acid) on the corneal penetration of CS-088, an ophthalmic agent, the apparent permeability coefficient of CS-088 in the presence of EDTA/boric acid across the isolated corneal membranes of rabbits was measured using an in vitro penetration chamber system. FITC-dextran (M.W. 4400) and an electrical method based on membrane resistance were used to provide a quantitative assessment of the enhancing effect of EDTA/boric acid. The corneal penetration of CS-088 was significantly enhanced in the presence of EDTA/boric acid by approximately 1.6-fold. The permeability-enhancing effect of EDTA/boric acid was apparently synergistic and concentration-dependent on both EDTA and boric acid. The penetration of FITC-dextran, a paracellular marker, and electrical resistance of corneal membranes were not affected in the presence of EDTA/boric acid. Furthermore, no enhancing effect of EDTA/boric acid was observed in de-epithelialized corneas, although de-epithelialized corneas exhibited a markedly higher permeability of CS-088 that was 24-fold greater than that for intact corneas. In conclusion, EDTA/boric acid synergistically enhances the transcellular permeability of CS-088 in the outer layer but not in the inner layers of the corneal membrane.
为了研究乙二胺四乙酸（EDTA）和硼酸（EDTA/硼酸）对眼科制剂CS-088角膜渗透的影响，使用体外渗透室系统测量了在EDTA/硼酸存在下CS-088在兔离体角膜膜上的表观渗透系数。使用异硫氰酸荧光素标记的葡聚糖（分子量4400）和基于膜电阻的电学方法对EDTA/硼酸的增强作用进行定量评估。在EDTA/硼酸存在下，CS-088的角膜渗透显著增强，约为1.6倍。EDTA/硼酸的渗透增强作用明显具有协同性，且依赖于EDTA和硼酸的浓度。在EDTA/硼酸存在下，细胞旁标记物异硫氰酸荧光素标记葡聚糖的渗透以及角膜膜电阻均未受到影响。此外，在去上皮的角膜中未观察到EDTA/硼酸的增强作用，尽管去上皮的角膜显示出CS-088的通透性显著更高，比完整角膜高24倍。总之，EDTA/硼酸协同增强CS-088在角膜膜外层而非内层的跨细胞通透性。
