Ahn Jun-Hyun, Kim Hyun-Do, Abuzar Sharif-Md, Lee Ji-Yeon, Jin Su-Eon, Kim Eung Kweon, Hwang Sung-Joo
College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea; Yonsei Institute of Pharmaceutical Sciences, Incheon, 21983, Republic of Korea.
Corneal Dystrophy Research Institute, Department of Ophthalmology, The Institute of Vision Research, Severance Biomedical Research Institute, College of Medicine, Yonsei University, Seoul, 03722, Republic of Korea.
Int J Pharm. 2017 Aug 30;529(1-2):608-616. doi: 10.1016/j.ijpharm.2017.07.016. Epub 2017 Jul 8.
Melatonin (MT), an effective antioxidant, has therapeutic implications for granular corneal dystrophy type 2 (GCD2) treatment. Eye drop formulations containing cyclodextrins (CDs) were studied with the objective of improving MT solubility, stability, and ocular absorption, while decreasing eye irritation. MT complexes with αCD, βCD, γCD, and 2-hydroxypropyl-βCD (HPβCD) were characterized by phase solubility studies, which demonstrated Higuchi's A-type phase solubility profiles. The MT/HPβCD complex showed the highest MT solubility (2.75mg/mL). Ocular irritation experiments showed HPβCD inclusion alleviated irritation of the eye. After administration of MT formulations to rabbit corneas, each harvested cornea was separated into corneal epithelium, stroma, and endothelium. MT concentrations in the corneal epithelium, stroma, and endothelium for the F1-treated group were 55.5±9.24, 26.7±2.66, and 21.1±1.77μM while those for the F2-treated group were 127.2±21.01, 43.7±16.93, and 51.0±13.91μM, respectively. Stability studies for 60days showed no significant change in pH, osmolarity, and MT content. In conclusion, MT/HPβCD formulations can lower irritation, enhance MT stability, and improve therapeutic efficacy.
褪黑素（MT）是一种有效的抗氧化剂，对2型颗粒状角膜营养不良（GCD2）的治疗具有潜在的治疗意义。为了提高MT的溶解度、稳定性和眼部吸收，同时减少眼部刺激，对含有环糊精（CDs）的滴眼液制剂进行了研究。通过相溶解度研究对MT与αCD、βCD、γCD和2-羟丙基-βCD（HPβCD）形成的复合物进行了表征，结果显示为Higuchi A型相溶解度曲线。MT/HPβCD复合物表现出最高的MT溶解度（2.75mg/mL）。眼部刺激实验表明，HPβCD包合物减轻了眼部刺激。将MT制剂滴入兔角膜后，将每个采集的角膜分离为角膜上皮、基质和内皮。F1处理组角膜上皮、基质和内皮中的MT浓度分别为55.5±9.24、26.7±2.66和21.1±1.77μM，而F2处理组分别为127.2±21.01、43.7±16.93和51.0±13.91μM。60天的稳定性研究表明，pH值、渗透压和MT含量没有显著变化。总之，MT/HPβCD制剂可以降低刺激性，增强MT稳定性，并提高治疗效果。
