Corneal endothelial changes with azone, a penetration enhancer

Azone has been used to enhance percutaneous absorption. Its ability to improve penetration makes it an attractive candidate for incorporation into ophthalmic formulations to increase therapeutic action of a drug or achieve an equivalent effect with a lower concentration of the active ingredients. Ophthalmic vehicles containing 0, 1, or 2% Azone were studied to determine their ocular irritation potential in the rabbit. The vehicle ingredients were poloxamer 188, hydroxy-ethylcellulose, benzalkonium chloride and phosphate buffer. Rabbits received 30mcl topically of each of the test products three times daily for 29 days. Clinical and histopathological evidence of ocular toxicity occurred in eyes treated with the vehicle containing 1 or 2% Azone, but not in the vehicle without Azone. Clinical signs of ocular irritation were transient and included redness of conjunctivae and iris, discharge and corneal edema. Scanning electron microscopy and semi-thin sections revealed corneal changes characterized by ballooning and vacuolation of endothelial cells resulting in distortion of the typical polygonal appearance. These results indicate that instillation of ophthalmic vehicles containing 1 or 2% Azone damages corneal endothelial cells of the rabbit. It is not clear, however, if this irritation is due to the direct action of Azone on the endothelium or the enhanced penetration of potential irritants in the formulation such as benzalkonium chloride.