Pharmacokinetic simulation reveals in vivo deviations from in vitro release of timolol from polymer matrices

Abstract

In some glaucoma patients timolol eye drops may cause severe cardiovascular and respiratory side-effects due to systemic absorption. Administration of timolol in controlled release devices reduces the harmful systemic absorption of the drug, however, as in the case of many drug delivery systems, the in vivo release rate relative to the in vitro rate is not known. In the present investigation, the concentrations of timolol in lacrimal fluid and plasma after administration into rabbit eyes in different matrices of monoisopropyi ester of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) was analysed using STELLA® simulation software. In the model, in vitro release rates of timolol were used as input values and preocular and systemic kinetic parameters from literature were included. The simulation model calculated predicted drug concentration profiles in tear fluid and plasma. The simulations showed that drug release in vivo in tear fluid was decreased compared to the in vitro experiments in the case of the unbuffered and phosphate buffered matrices. Differences in the conjunctival permeability of timolol after administration of various matrix types were revealed by the simulations where measured concentrations in tear fluid were used as input values. The phosphate buffered matrix showed similar tear fluid — plasma transfer of timolol in simulations and experimentally. Sodium acetate buffer in the matrix reduced the permeability of timolol in the conjunctival epithelium, thus decreasing the systemic absorption of the drug. In the case of the unbuffered matrix, probably a decrease in the pH of tear fluid close to the matrix may reduce the transport of timolol through the conjunctiva. STELLA® simulations proved useful in the in vitro — in vivo comparisons of ophthalmic timolol.