EX-VIVO PERMEATION STUDY OF INDOMETHACIN FROM A SUBMICRON EMULSION THROUGH ALBINO RABBIT CORNEA

Indomethacin was incorporated in an original emulsion formulation stab ilized by a combination of phospholipids and an amphoteric surfactant, lauroamphodiacetate. The solubility of indomethacin in the various em ulsion phases was pH-dependent. The pH of the emulsion was adjusted to 3.8 in order to promote localization of the drug in the oil phase and prevent drug ionization. Ionization would increase drug aqueous solub ility and result in indomethacin precipitation. Optimal manufacturing conditions were identified yielding an emulsion with a mean droplet si ze of 110 +/- 20 nm and a zeta potential value of -50 mV. The emulsion was found to be chemically and physically stable for more than 5 mont hs at 4 degrees C. The results of the ocular tolerance study in rabbit eye indicated that hourly administration of the emulsion vehicle was well tolerated without any toxic or inflammatory response to the ocula r surface during the 5 days of the study. Scanning electron microscopy revealed a normal corneal surface resembling that of the animals trea ted with physiological saline. The penetration rate of indomethacin th rough excised rabbit eye cornea from the emulsion and from a marketed product (Indocollyre(R)) were determined and compared using a novel mo unted corneal diffusion assembly. It was shown that the apparent corne al permeability coefficient of indomethacin incorporated in the emulsi on was 3.8 times greater than that of indomethacin in the marketed aqu eous solution. The increase in corneal drug permeation could be attrib uted to various causes that are discussed in the manuscript.