Akiharu Isowaki

Ocular distribution of difluprednate ophthalmic emulsion 0.05% in rabbits.

PURPOSE To evaluate ocular distribution and excretion of tritium-labeled difluprednate ((3)H-DFBA) ophthalmic emulsion 0.05% after a single or repeated instillation to pigmented rabbit eyes. METHODS (3)H-DFBA ophthalmic emulsion 0.05% was instilled in the right eyes of pigmented rabbits, in either a single or repeated quater in die (QID) for 3 days or 7 days) dose of 25  μg/50  μL. The radioactivity in right and left ocular tissues, urine, blood, plasma, and feces were measured with a liquid scintillation counter. Additionally, the distribution of radioactivity around ocular tissues was investigated with autoradiography. RESULTS After a single instillation, the highest maximum radioactive concentrations were found in the cornea (2,081  ng eq./g), followed by the iris/ciliary body (926  ng eq./g), conjunctiva (330  ng eq./g), anterior retina/choroid (273  ng eq./g), sclera (222  ng eq./g), and aqueous humor (144  ng eq./mL) of treated eyes. The maximum radioactivity concentration of the posterior retina/choroid was 59  ng eq./g, and difluprednate delivered as a topical ophthalmic emulsion reached the back of the eye. However, radioactivity in untreated eyes was very low. Total radioactivity excreted in urine and feces 168  h after a single instillation was 99.5% of the total dose. Radioactivity concentration levels measured 24  h after 28 instillations were no more than twice those measured 24  h after 12 instillations. Radioactive concentrations in ocular and periocular tissues were highest at 0.5 or 1  h after a single instillation, and were mostly eliminated from these tissues by the end of the study. Radioactivity was barely detectable in the blood, with very little accumulation even after multiple doses. CONCLUSIONS After instillation of (3)H-DFBA ophthalmic emulsion 0.05% in rabbit eyes, radioactivity was distributed at the anterior segment and cleared rapidly. Some radioactivity was detected in the posterior retina/choroid, suggesting that difluprednate and its metabolites reach these tissues. These results suggest that difluprednate delivered as a topical ophthalmic emulsion reached the anterior and posterior segments of the eye quickly and may be a potential treatment for ocular inflammation in these areas.

Corneal Critical Barrier against the Penetration of Dexamethasone and Lomefloxacin Hydrochloride: Evaluation by the Activation Energy for Drug Partition and Diffusion in Cornea

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approch to investigate the mechanism of drug permeability.