Controlled release drug delivery systems of eye drops are a promising ophthalmic therapy with advantages of good patient compliance and low irritation. However, the lack of a suitable drug carrier for ophthalmic use limits the development of the aforementioned system. Herein, the crosslinked cyclodextrin organic framework (COF) with a cubic porous structure and a uniform particle size was synthesized and applied to solidify vitamin A palmitate (VAP) by using the solvent-free method. The VAP@COF suspension eye drops were formulated by screening co-solvents, suspending agents, and stabilizing agents to achieve a homogeneous state and improve stability. According to the in vitro release study, the VAP@COF suspension exhibited a controlled release of VAP within 12 h. Both the ex vivo corneal contact angle and in vivo fluorescence tracking indicated that the VAP@COF suspension prolonged the VAP residence time on the ocular surface. This suspension accelerated the recovery of the dry eye disease (DED) model in New Zealand rabbits. Furthermore, the suspension was non-cytotoxic to human corneal epithelial cells and non-irritation to rabbit eyes. In summary, the particulate COF is an eye-acceptable novel carrier that sustains release and prolongs the VAP residence time on the ocular surface for DED treatment.
Though ionic liquids (ILs) as novel enhancers had garnered wide attention, detailed studies elucidating molecular design of drug-ILs were missing and mechanisms of their formation and skin permeation were still lacking. Herein, we systematically investigated effects of counterions structures on formation and skin permeation of drug-ILs. Firstly, effects of counterions on formation of drug-ILs were dependent on polarizability, molecular weight (M.W.) and polar surface area of counterions. It was caused by strong charge assisted hydrogen bond and van der Waals interactions revealed through FT-IR, X-ray photoelectron spectroscopy and molecular docking, which undermined ionic interactions and reduced total interaction strength, thereby produced lower lattice energy. Then, skin permeability of drug-ILs had a good parabola relationship with M.W., polarizability and log P of counterions. The underlying mechanism was the increased drug miscibility with stratum corneum, which caused conformational disorder and phase transition of lipid bilayers characterized by ATR-FTIR, DSC and confocal laser scanning microscopy. Finally, the drug-ILs proved to be non-irritating using in vivo skin erythema analysis. In conclusion, the quantitative structure-activity relationship models based on counterions structure to predict formation and skin permeation of drug-ILs were developed, which provided basic theory for design of drug-ILs with high permeation-enhancing efficiency.
危险品化学品经营许可证（带存储）