Formulation of in-situ ophthalmic microemulsion gel loaded with tacrolimus / 中国药学杂志

ABSTRACT

OBJECTIVE: To develop the formulation of in-situ ophthalmic microemulsion gel loaded with tacrolimus and evaluate its quality and safety. METHODS: The formulation to make tacrolimus microemulsion into thermosensitive in-situ ophthalmic gel was optimized by orthogonal experiment design using poloxamer 407(F127)and poloxamer 188(F68)as the thermosensitive gel matrix and the gelatinization temperature(Tg) of in-situ gel before and after diluting in simulated tear fluid as compounding effect indicator. The appearance, particle size, gelation temperature, morphological characteristics, rheological properties and dissolution behavior of the optimal in situ microemulsion gel were determined. Simultaneously, the residence time of tacrolimus microemulsion and its in-situ gel were examined using tacrolimus suspension eye drops as control. Irritation of these ophthalmic preparations after single and multiple dose administrations were evaluated against normal saline as control by intra-individual self-control method with Draize test criteria. RESULTS: The gel matrix of the optimal in-situ microemulsion gel containing 1 mg•mL-1 tacrolimus was composed of 140 mg•mL-1 F127 and 20 mg•mL-1 F68. The oval-shaped emulsion droplets homogenously dispersed in the in-situ emulsion gel with average particle size of 18.70 nm. Its gelation temperatures inside and outside eyes were 27.1 and 33.9 ℃, respectively. In vitro dissolution and release tests showed that its releasing characteristics followed zero-order kinetics. The average residence time of tacrolimus in-situ microemulsion gel in rabbit eyes was 22.67 min,significantly longer than those of the suspension and microemulsion of tacrolimus. No irritation was observed for tacrolimus suspension drops, microemulsion and its in-situ gel. CONCLUSION: It would be feasible to prepare tacrolimus temperature-sensitive in-situ gel from microemulsion with a simple preparation process. The gel was of controllable quality, good stability,good temperature sensitivity,and good spreadability, with low eye irritation. Compared with suspension eye drops, in-situ microemulsion gel can be expected to be a superior ophthalmic drug delivery system for hydrophobic drugs due to its steady and sustained release characteristics.