Nagai Noriaki, Yoshioka Chiaki, Mano Yu, Tnabe Wataru, Ito Yoshimasa, Okamoto Norio, Shimomura Yoshikazu
Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
Exp Eye Res. 2015 Mar;132:115-23. doi: 10.1016/j.exer.2015.01.022. Epub 2015 Jan 26.
The goal in the search for successful therapies for glaucoma is the reduction of intraocular pressure (IOP), and the search for effective eye drops that reduce IOP is a high priority. We previously reported the potential of a 2-hydroxypropyl-β-cyclodextrin (HPβCD) solution containing 0.5% DSF (DSF solution) to provide effective anti-glaucoma treatment in eye drop form. In this study, we designed new ophthalmic formulations containing 0.5% DSF nanoparticles prepared by a bead mill method (DSFnano dispersion; particle size 183 ± 92 nm, mean ± S.D.), and compared the IOP-reducing effects of a DSFnano dispersion with those of a DSF solution. The high stability of the DSFnano dispersion was observed until 7 days after preparation, and the DSFnano dispersion showed high antimicrobial activity against Escherichia coli (ATCC 8739). In transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while no DSF was detected. The DDC penetration level (area under the curve, AUC) and corneal residence time (mean residence time, MRT) of the DSFnano dispersion were approximately 1.45- and 1.44-fold higher than those of the DSF, respectively. Moreover, the IOP-reducing effects of the DSFnano dispersion were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, DSFnano dispersion are tolerated better by a corneal epithelial cell than DSF solution and commercially available timolol maleate eye drops. It is possible that dispersions containing DSF nanoparticles will provide new possibilities for the effective treatment of glaucoma, and that an ocular drug delivery system using drug nanoparticles may expand their usage as therapy in the ophthalmologic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma drugs.
寻找成功的青光眼治疗方法的目标是降低眼压（IOP），因此寻找能降低眼压的有效眼药水是当务之急。我们之前报道了含0.5%二硫代琥珀酸（DSF）的2-羟丙基-β-环糊精（HPβCD）溶液（DSF溶液）有制成眼药水提供有效抗青光眼治疗的潜力。在本研究中，我们设计了含通过珠磨机法制备的0.5% DSF纳米颗粒的新型眼科制剂（DSF纳米分散液；粒径183±92nm，平均值±标准差），并比较了DSF纳米分散液与DSF溶液降低眼压的效果。观察到DSF纳米分散液在制备后7天内具有高稳定性，并且DSF纳米分散液对大肠杆菌（ATCC 8739）显示出高抗菌活性。在使用兔角膜的经角膜渗透实验中，房水中仅检测到二乙基二硫代氨基甲酸盐（DDC），而未检测到DSF。DSF纳米分散液的DDC渗透水平（曲线下面积，AUC）和角膜滞留时间（平均滞留时间，MRT）分别比DSF的高约1.45倍和1.44倍。此外，在兔中，DSF纳米分散液降低眼压的效果明显大于DSF溶液（将兔置于暗室5小时可提高眼压）。另外，角膜上皮细胞对DSF纳米分散液的耐受性比DSF溶液和市售马来酸噻吗洛尔眼药水更好。含DSF纳米颗粒的分散液有可能为青光眼的有效治疗提供新的可能性，并且使用药物纳米颗粒的眼部给药系统可能会扩大其在眼科领域作为治疗方法的应用。这些发现提供了重要信息，可用于设计旨在开发抗青光眼药物的进一步研究。
