CYCLOSPORINE IN COLLAGEN PARTICLES - CORNEAL PENETRATION AND SUPPRESSION OF ALLOGRAFT-REJECTION

The purpose of this study was to determine the pharmacokinetics of cyc losporine in the cornea and aqueous humor following topical applicatio n in collagen particles and to determine the capacity of cyclosporine in collagen particles to suppress corneal allograft rejection. Cyclosp orine was prepared for topical application in three vehicles: collagen particles suspended in methylcellulose, collagen shields, and corn oi l. Rabbit eyes were treated with a single application of one formulati on. Corneas, aqueous humor samples, and blood samples were collected a t 2, 4, 8, 12, and 24 hours. Peak concentrations of drug were reached between 2 and 4 hours in the cornea and between 4 and 8 hours in the a queous humor. No drug was found in the blood. Collagen particles and s hields produced significantly higher concentrations of cyclosporine in the aqueous humor and cornea, compared with corn oil drops, at virtua lly all time points. In the second part of the study, rabbits with vas cularized corneas underwent corneal transplantation and were treated w ith one of the formulations beginning either at the time of transplant ation (prophylactically) or at the first sign of an allograft immune r eaction (delayed treatment). Cyclosporine delivered in collagen partic les was effective in preventing primary corneal allograft rejection in nearly all of the grafts (96%) treated prophylactically, and in 67% o f the grafts treated when signs of the first stage (grade 1) of immune graft reaction were observed. Grafts treated with cyclosporine in col lagen shields showed similar survival rates (87% and 64%, respectively ), whereas only 40% of the grafts treated prophylactically and only on e (18%) receiving delayed treatment with the corn oil preparation surv ived. These results demonstrate the efficacy of collagen particles for delivery of hydrophobic drugs to the ocular surface and the potential for preventing corneal graft rejection with topically applied cyclosp orine in a collagen-particle vehicle.