The purpose of the present study was to optimize the formulations of the thermoresponsive ophthalmic in situ gels of a poorly water-soluble drug fluconazole (FLU) and evaluate the in vitro and in vivo properties of the formulations. The thermoresponsive ophthalmic FLU in situ gels were prepared by mixing FLU, Poloxamer407, Tween80, benzalkonium chloride and carbopol934 in borate buffer solution. The in vivo eye irritation tests and ophthalmic absorption were carried out in rabbits. The formulation compositions influenced the physicochemical properties of FLU in situ gels. The amount of poloxamer407 in the formulation was the main factor that affected the sol-gel transition temperature of the products. Tween80 not only improved the solubility of the FLU but also affected the products' sol-gel transition temperature. In this study, sol-gel transition temperature was not affected by carbopol934. However, carbopol934 affected pH value, transparency and gelling capacity of the products. The product of the optimized formulation was a pseudoplastic fluid and its sol-gel transition temperature was 30.6 ± 1.2 °C. The autoclaving test showed that the sol-gel transition temperature, the flow ability and the flow behavior of the test samples did not change obviously after autoclaving sterilization at 121 °C and 15 psi for 20 min, thus the autoclaving was an acceptable sterilization method for this preparation. The thermoresponsive ophthalmic FLU in situ gels' in vivo ophthalmic absorption was superior to the conventional FLU eye drop. In conclusion, the thermoresponsive ophthalmic FLU in situ gel is a better alternative than the FLU eye drop.

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The enyne substrate (I) undergoes an unprecedented transformation into product (III) in which a nitroarene reduction step initiates an endocyclic Nicholas reaction followed by an intramolecular Pauson—Khand cyclization.