LAUSR

ABSTRACT To facilitate the hydrophobic drugs modeled by coumarin‐6 (Cou‐6) acrossing the cornea to the anterior chamber of the rabbit eye, chitosan (CS) derivatives including chitosan‐N‐acetyl‐l‐cysteine (CS‐NAC), chitosan oligosaccharides (COS) and carboxymethyl chitosan (CMCS) modified nanostructured lipid carriers (NLCs) were designed and characterized. We found that, with similar size distribution and positive charges, different CS derivatives based on NLCs led to distinctive delivery performance. In vivo precorneal retention study on rabbits revealed that these CS derivatives coating exhibited a stronger resistant effect than Cou‐6 eye drops and Cou‐6‐NLC (P < 0.05), moreover, the AUC(0−∞), Cmax and MRT(0−∞) of them followed the sequence of CMCS‐Cou‐6‐NLC < COS‐Cou‐6‐NLC < CS‐NAC‐Cou‐6‐NLC. Confocal laser fluorescence microscopy (CLSM) for in vitro corneal penetration study showed that COS‐, and CS‐NAC‐coated NLCs penetrated through the whole corneal epithelium barrier (about 40 &mgr;m), while CMCS failed to significantly enhance the intraocular drug penetration as expected, displayed a negligible fluorescence at 30 &mgr;m deep. In addition, penetration through the intact cornea was achieved and the penetration levels through the ocular tissues were increased thoroughly for the COS and CS‐NAC coating ones compared with CMCS‐NLC (P < 0.05), and successfully reduced the conjunctival‐to‐corneal permeability ratio (ratio(C‐S/C)) thus resulted in a higher bioavailability, which was confirmed by ex vivo fluorescence imaging on ocular tissues. In summary, CS‐NAC‐NLC and COS‐NLC are promising ocular drug delivery systems to achieve prolonged precorneal retention, higher corneal permeability and enhanced ocular bioavailability. And comparatively speaking, CS‐NAC‐NLC possesses the highest potential for ocular drug delivery.